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Mohammadhosseini, M, Venditti, A, Sarker, SD, Nahar, L and Akbarzadeh, A
The genus Ferula: ethnobotany, phytochemistry and bioactivities - a review
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Mohammadhosseini, M, Venditti, A, Sarker, SD, Nahar, L and Akbarzadeh, A
(2018) The genus Ferula: ethnobotany, phytochemistry and bioactivities - a
review. Industrial Crops and Products, 129. pp. 350-394. ISSN 0926-6690
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1
The genus Ferula: ethnobotany, phytochemistry and
2
bioactivities - a review
3
4
Majid Mohammadhosseini1*, Alessandro Venditti2, Satyajit D.
5
Sarker3, Lutfun Nahar3, and Abolfazl Akbarzadeh4
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7
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1
Department of Chemistry, Shahrood Branch, Islamic Azad University,
Shahrood, Iran
Dipartimento di Chimica, Università di Roma “La Sapienza”, Piazzale Aldo
Moro 5, 00185 Rome, Italy
2
3
12
Medicinal Chemistry and Natural Products Research Group, School of
Pharmacy and Biomolecular Sciences, Liverpool John Moores University,
Byrom Street, Liverpool L3 3AF, United Kingdom
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4
10
11
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Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz,
Iran
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*Corresponding author at: Department of Chemistry, Shahrood Branch, Islamic
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Azad University, Shahrood, Iran. Tel: +98-023-32394530; Fax: +98-023-
18
32394537
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E-mail addresses:
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majidmohammadhosseini@yahoo.com; majidmohammadhosseini@gmail.com;
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m_mhosseini@iau-shahrood.ac.ir (M. Mohammadhosseini)
1
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The genus Ferula: ethnobotany, phytochemistry and bioactivities - a review
23
24
25
Table of Contents
Abstract ................................................................................................................................................... 3
26
1. Introduction ......................................................................................................................................... 3
27
2. Research methodology ........................................................................................................................ 5
28
3. Ethnobotany and traditional usage of the Ferula species ................................................................... 6
29
4. Chemical profiles of the essential oils, extracts, resins and volatiles ……………………………...11
30
5. Phytochemistry of the Ferula species (2000 to March 2018) ........................................................... 15
31
5.1. Coumarin derivatives ................................................................................................................. 16
32
5.1.1. Hemiterpene coumarins .......................................................................................................... 16
33
5.1.2. Monoterpene coumarins.......................................................................................................... 16
34
5.1.3. Sesquiterpene coumarins ........................................................................................................ 17
35
5.1.4. Coumarinyl esters ................................................................................................................... 19
36
5.1.4.1. Dihydrofuranocoumarinyl esters.......................................................................................... 20
37
5.2. Prenylated benzoic acid derivatives ........................................................................................... 20
38
5.3. Sesquiterpene chromones........................................................................................................... 20
39
5.4. Sesquiterpenes............................................................................................................................ 21
40
5.5. Sulfur containing metabolites .................................................................................................... 24
41
5.6. Miscellaneous ............................................................................................................................ 25
42
7. The bioactivities of diverse characterized compounds from the genus Ferula................................. 28
43
7.1. Anti-HIV activity ....................................................................................................................... 29
44
7.2. Inhibitory activity on cytokine production................................................................................. 29
45
7.3. Inhibitory activity on NO production......................................................................................... 30
46
7.4. The inhibitory on Epstein-Barr virus early antigen (EBV-EA) activation................................. 30
47
7.5. Inhibitory against Plasmodium falciparum ................................................................................ 31
48
7.6. Antineuroinflammatory potential in LPS-activated BV-2 microglial cells ............................... 31
49
7.7. Cytotoxicity................................................................................................................................ 31
50
7.8. Antibacterial and antimicrobial activity ..................................................................................... 34
51
7.9. Anti-inflammatory activity ........................................................................................................ 36
52
7.10. Inhibitory behavior of transcription-activating factors for iNOS mRNA ................................ 36
53
7.11. Antiprolifertive/anticancer activity .......................................................................................... 37
54
7.12. Antioxidant activity ................................................................................................................. 40
55
7.13. The antileishmanial activity ..................................................................................................... 40
56
7.14. The ferulosis............................................................................................................................. 41
57
8. Propagation of Ferula species........................................................................................................... 44
2
58
9. Conclusion and future perspectives .................................................................................................. 47
59
Acknowledgments................................................................................................................................. 49
60
References ............................................................................................................................................. 51
61
62
Abstract
63
This study aims to provide a comprehensive overview of the medicinal, folkloric and
64
traditional culinary uses of Ferula species, related products and extracts in different countries
65
together with the description of recently isolated new components and the related
66
bioactivities. The phytochemical composition of the essential oils (EOs), oleo-gum-resin
67
(OGR) and the non-volatile fractions obtained from several endemic and indigenous Ferula
68
species is also reported. A special emphasis is placed on their unusual components, i.e.
69
sulfur-containing volatiles from the EOs and the new phytochemicals with mixed biogenetic
70
origins. More than 180 chemical constituents (excluding common essential oils components),
71
including sulfur-containing metabolites, terpenoids, coumarins, sesquiterpene coumarins,
72
etc., as both aglycones and glycosides, are reported, along with their occurrence and
73
biological activities when available. A large number of new secondary metabolites, belonging
74
to different classes of natural products possessing interesting biological activities, from the
75
antiproliferative to the anti-inflammatory to the neuroprotective ones, among the others, have
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been recently found in the Ferula genus. Several of these phytochemicals are exclusive to
77
this genus; therefore may be considered chemotaxonomic markers. All these aspects are
78
extensively discussed in this review.
79
Keywords: Ferula spp.; Apiaceae; Ethnomedicine; Secondary metabolites; Traditional uses;
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Essential oil; Non-volatile components
81
1. Introduction
3
82
The genus Ferula, the third largest genus of the Apiaceae (alt. Umbelliferae) family, is
83
composed of ca. 180 species (Yaqoob and Nawchoo, 2016), 15 of which are endemic to Iran
84
(Mozaffarian, 1996), nine species to Turkey, seven to China (Yaqoob and Nawchoo, 2016)
85
and one species to Italy (Conti et al, 2005), and the rest are indigenous entities of several
86
other countries.
87
The majority of the Ferula plants have a pungent odor and can be used for different purposes.
88
The endemic and indigenous species of the Ferula in the flora of some countries, of which
89
the data are available, are listed in Table 1.
90
In the literature, numerous reports have described various biological and medicinal activities
91
for different essential oils (EOs) and extracts of the Ferula plants. These include anticancer
92
(Paydar et al., 2013; Perveen et al., 2017; Upadhyay et al., 2017), anthelmintic (Kakar et al.,
93
2013; Upadhyay et al., 2017), anti-epileptic (Sayyah et al., 2001; Kiasalari et al., 2013),
94
aphicidal (Stepanycheva et al., 2012), antioxidant (Kavoosi et al., 2013; Paydar et al., 2013;
95
Amiri, 2014; Znati et al., 2014; Lahazi et al., 2015; Moosavi et al., 2015; Yusufoglu et al.,
96
2015c; Zhang et al., 2015; Nguir et al., 2016), antimicrobial (Yang et al., 2007; Kavoosi et
97
al., 2013; Liu et al., 2013; Paydar et al., 2013; Bashir et al., 2014b; Pavlovic et al., 2015),
98
antihypertensive (Ghanbari et al., 2012), antifungal (Rani et al., 2009; Al-Ja'Fari et al., 2013;
99
Bashir et al., 2014b; Upadhyay et al., 2017), antidepressant (Mohammadhosseini, 2016),
100
phytotoxic (Bashir et al., 2014b), (Kavoosi et al., 2013; Paydar et al., 2013; Pavlovic et al.,
101
2015), antiproliferative (Poli et al., 2005; Moradzadeh et al., 2017), acetylcholinesterase
102
inhibitory (Adhami et al., 2014) and muscarinic receptors inhibitory (Khazdair et al., 2015),
103
antiprotozoal activity (El Deeb et al., 2012; Bafghi et al., 2014; Barati et al., 2014),
104
antihemolytic (Nabavi et al., 2011), antimycobacterial (Mossa et al., 2004; Fallah et al.,
105
2015), anti-ulcer (Alqasoumi et al., 2011), antitumor (Zhang et al., 2015; Bagheri et al.,
106
2017), anticoagulant (Lamnaouer, 1999; Fraigui et al., 2002), antifertility (Keshri et al.,
4
107
1999), antispasmodic (Fatehi et al., 2004; Upadhyay et al., 2017), anticonvulsant (Sayyah and
108
Mandgary, 2003; Bagheri et al., 2014b), relaxant (Sadraei et al., 2001), antinociceptive
109
(Mandegary et al., 2004; Bagheri et al., 2014a), hypnotic (Abbasnia and Aeinfar, 2016),
110
hypotensive (Upadhyay et al., 2017), muscle relaxant (Upadhyay et al., 2017), memory
111
enhancing (Upadhyay et al., 2017), enhancing digestive enzyme (Upadhyay et al., 2017),
112
antiviral (Lee et al., 2009; Ghannadi et al., 2014; Upadhyay et al., 2017), anxiolytics
113
(Upadhyay et al., 2017), antihyperlipidemic (Yusufoglu et al., 2015a; Yusufoglu et al.,
114
2015b), antigenotoxic (Hu et al., 2009; Abbasnia and Aeinfar, 2016), anti-inflammatory
115
(Mandegary et al., 2004; Paydar et al., 2013; Bagheri et al., 2015; Moosavi et al., 2015),
116
cytotoxic (Elouzi et al., 2008; Valiahdi et al., 2013; Gudarzi et al., 2015; Mohd Shafri et al.,
117
2015; Hosseini et al., 2017), antihyperglycemic (Yusufoglu et al., 2015a; Yusufoglu et al.,
118
2015b; Yusufoglu et al., 2015c), acaricidal (Fatemikia et al., 2017), antidiabetic (Yarizade et
119
al., 2017), hepatoprotective (Upadhyay et al., 2017) and antibiotic modulation (Paydar et al.,
120
2013) activities.
121
In this review paper, we aim to cover the ethnobotany, phytochemistry and pharmacological
122
activities along with chemical composition of the essential oils (EOs), volatiles, oleo-gum-
123
resins (OGRs) and extracts of different species of the genus Ferula described in recent
124
decades.
125
2. Research methodology
126
To prepare a comprehensive phytochemical and ethnobotanical review on the plants of the
127
genus Ferula, the corresponding data were integrated in this report. To organize this review
128
paper, ISI-WOS, PubMed, Scopus (date of access: 18 September 2017 and revisited on 10
129
March 2018) and Google scholar databases, papers published in recent decades by publishers
130
such as Elsevier, Springer, Taylor and Francis and John Wiley, and English and non-English
5
131
reference books dealing with useful properties of the Ferula plants have been systematically
132
reviewed.
133
3. Ethnobotany and traditional usage of the Ferula species
134
Medicinal plants have been of prime importance in the folkloric traditional medicine systems
135
for centuries (Mohammadhosseini, 2017). The remedial properties of these plants are
136
remarkable (Mohammadhosseini et al., 2017a; Mohammadhosseini et al., 2017b). Due to the
137
unpleasant side effects and ineffectivness of many conventional drugs, the search for new
138
drugs from natural origin has gained momentum in recent years.
139
In this regard, different species of the genus Ferula have always been in the focus,
140
specifically in the Middle East and Asian countries including Iran, Pakistan, Iraq, India and
141
others. According to the flora of Iran, different Ferula species are widespread in eastern and
142
central parts of the country. Most Ferula species have a bitter taste and pungent odor. The
143
genus Ferula has a Latin root meaning “vehicle” or “carrier”. In Persian, “asa” means resin.
144
It is also noteworthy that the word “foetida” originates from the Latin word “foetidus”
145
meaning “smell” accounting for its pungent sulfur-based odor. In the folk medicine of Iran,
146
China, Germany, Italy, France and India, Asafoetida is often called "Anghouzeh", "A Wei",
147
"Teufellsdreck or Stinkasant", "Assafoetida", and "ase-fetide", respectively (Iranshahy and
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Iranshahi, 2011). An oleo-gum-resin (OGR), as a milky and bitter substance, is exudated
149
from the stem of some Ferula plants, e.g. F. assa-foetida and F. gummosa Boiss. and
150
coagulates when exposed to the air.
151
The gum of the most important species of the genus Ferula, namely F. assa-foetida L. has
152
many therapeutic properties. Significant amounts of this gum are annually exported from Iran
153
and Afghanistan to the East Asian countries like China and Japan, via Mongolia, as well as to
154
European and North American countries. Many people believe that the sticky gum from F.
6
155
assa-foetida L. is a strong carminative agent that can remove the stomach worms. In children,
156
it is used as an antiparasite remedy. It has been reported that the roots of two species of
157
Ferula, namely F. assa-foetida L. (Fig. 1) and F. gummosa Boiss., are rich sources of
158
valuable natural compounds (Mozaffarian, 2012). The general properties of F. assa-foetida L.
159
in traditional medicine are reported to have potent antiseptic, antimucous, anti-epilepsy
160
(specifically in the children), anticonvulsant, antitetanus and aphrodisiac (see Table 2)
161
activities, and to be of value in the regulation of the menstruation, and as an antidote for
162
insect and animal bites (Mohammadhosseini, 2016). In the latter case, certain amount of the
163
gum is dissolved in olive oil and subsequently placed on the site of the bite. This can lower
164
the pain and considerably improve inflamed and infected wounds. The suspension of F. assa-
165
foetida L. can be used to repel wild animals.
166
The gum or decoctions of F. assa-foetida L. has been used to treat certain wounds,
167
hemorrhoids and rheumatism, and as a useful remedy to refine the liver blood in trade
168
markets. In addition, its pickling serves as an effective agent to remove some parasites from
169
the human body and it appears to have strong antiviral activity against influenza.
170
In some ancient civilizations, a necklace of F. assa-foetida L. was placed around the neck of
171
patients suffering from severe cold or hay fever. In traditional Persian medicine, people
172
believed that F. assa-foetida L. was effective in the treatment of a broad range of diseases
173
and disorders, and for this reason it was called “food of God”. Interestingly, among the
174
different stories about F. assa-foetida L., it was suggested that the name originates from the
175
idea of God’s semen fertilizing the earth.
176
This valuable species is widely used as an additive in foodstuffs. Some nomads of central
177
Iran still use fried F. assa-foetida L. along with some condiments as a carminative food. The
178
rural people and nomads of Semnan province (Abbas Abad Village, Shahrood, Iran) use the
179
dried aerial parts of F. assa-foetida L. in the preparation of their delicious local food,
7
180
“Loghri”, which also contains barley, Nagorno Qrvt (Qareh Qurut), tomato or tomato
181
paste, beans and other vegetables (Fig. 2).
182
There are myths of a spiritual nature that F. assa-foetida L. can strengthen the human body,
183
and repulse negative energy, evils and demons (Mahendra and Bisht, 2012).
184
Apart from some biological and medicinal properties, the spice prepared from F. assa-foetida
185
L. is regarded as an effective remedy for Angina pectoris (Srinivasan, 2005).
186
In Afghan folk medicine, the dried gum of F. assa-foetida is immersed in hot water and the
187
extract is used as an herbal drug to treat ulcers, whooping cough and hysteria (Mahran et al.,
188
1973).
189
In Morocco, F. assa-foetida L. is reputed to be a magical anti-epileptic drug, and another
190
endemic species of Ferula (F. communis L.) has been regarded as an antispasmodic agent
191
with some degree of toxicity (Bellakhdar et al., 1991).
192
In Nepal, the resins of F. assa-foetida L. are extracted with water and the extract is used
193
orally as an anthelmintic agent (Bhattarai, 1992). In desert localities of Saudi Arabia, the
194
inhabitants utilize the gum of F. assa-foetida L. for treating asthma, bronchitis and cough
195
(Seabrook, 1927).
196
In Brazil, the hot water extract from the dried leaves and stems of F. assa-foetida L. are used
197
orally to treat erectile dysfunction, and as an aphrodisiac (Elisabetsky et al., 1992).
198
Moreover, the crushed powder obtained from an OGR of F. assa-foetida L. has been used as
199
a condiment in India for many years (Seetharam and Pasricha, 1987).
200
In USA, resin extracts of F. assa-foetida L. taken orally have been used as an antispasmodic,
201
expectorant, aphrodisiac and a stimulant for the human nervous system (Lilly, 1898). In
202
addition, the black American people reportedly use the gum of F. assa-foetida L. for many
203
purposes, e.g. cancer, menstruatal problems, asthma, convulsion, laryngitis, corns of the feet,
204
hand and foot callous and madness. In America, F. assa-foetida L. is prescribed as an
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205
effective diuretic, stimulant and sedative phytoremedy. In addition to diverse medicinal uses,
206
different organs of F. assa-foetida L., either in fresh or dried form are used for cooking, as
207
even small parts of this plant can give a pungent smell to foodstuffs. It has also found many
208
applications as a condiment and flavoring agent in chocolates, seasoning and soft drinks. Due
209
to emmenagogue properties of F. assa-foetida L., it is not recommended in the breast-feeding
210
period and its overuse may cause abortion. Antipain, antitumor, digestive, lactating,
211
fungicide, mutagenic, uterus tonic are among the other properties attributed to this plant. It
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also prevents platelet adhesion of the blood and lowers the fever and blood pressure. To treat
213
pneumonia, bronchitis, cough and cold, F. assa-foetida L. is often considered among the
214
frequently options in the folk medicine of many Asian countries. It is reported to cure
215
rheumatism, gout, hysteria, and sciatica.
216
The stem of F. gummosa Boiss. has numerous elliptical ducts dispersed in the phloem tissues.
217
In the vegetative stage of this plant, the OGR in these ducts is exuded manually or naturally
218
(Mortazaienezhad and Sadeghian, 2006). In fact, the gum of F. gummosa Boiss. is reported to
219
have numerous medicinal properties. When it is mixed with honey, it is said to aid removal of
220
large kidney and bladder stones. The diluted gum of this plant is used by the local midwifes
221
to expel the dead fetus.
222
In Iranian folk medicine, it is said that if the gum of F. gummosa Boiss. is dissolved in water
223
and drunk for three sequential days, it can treat hemorrhoids. Moreover, when this gum is
224
dissolved in nettle decoction and mixed with olive oil and put on painful places as a poultice,
225
it can decrease the severe pains of waist. In different European countries, the gum, called
226
galbanum, exuded from F. gummosa Boiss. has also been used to treat epilepsy, stomachache
227
and as an effective wound healing agent (Miyazawa et al., 2009). This material has also been
228
used as an anthelmintic agent and to treat diarrhea, constipation, and abdominal pains. In
229
Iranian folk medicine, the OGR (galbanum) from F. gummosa Boiss. has been widely
9
230
prescribed as an antispasmodic and stimulant to treat digestive disorders such as colic and
231
flatulence. It is also reported as a uterine tonic and to have expectorant properties in the
232
treatment of chronic bronchitis.
233
Another species of this genus, F. narthex Boiss, is found widespread in Pakistan, especially
234
in Gilgit and Chitral. The Pakistani people highly use this herbal plant or its gum resin to treat
235
hysteria, gastric malfunctions, cough, fever, the sting of scorpions, constipation and habitual
236
abortion as well as a strong sedative agent in painful toothaches (Bashir et al., 2013).
237
F. communis L., having two subspecies, namely F. communis subsp. communis and F.
238
communis subsp. glauca (Pesmen, 1972) has been used in Sardinian folk medicine on
239
account of reported antiseptic features of decoctions of its roots (Sanna et al., 2006; Maggi et
240
al., 2016; Rahali et al., 2016). It has been reported that in the ancient Rome, assa-foetida was
241
stored in jars with pine nuts which were used to give pleasant and specific flavors and odors
242
to certain foods, including vegetables, barbecued meats, meatballs, pickles and other cooked
243
dishes (Mahendra and Bisht, 2012; Mohammadhosseini, 2016).
244
During investigation of the chemistry and biology of the Umbelliferae plants (now Apiaceae),
245
French (1971) pointed out the reported antihysteric properties of F. communis L. and its
246
potential to treat dysentery. In fact, this species is a source of several medicinal and
247
pharmaceutical substances. According to the Greek mythology, F. communis L. (Narthex)
248
was employed by Prometheus, of Greek legend, to set fire to the earth where this species
249
grew (Gennadios, 1914). Despite the high toxicity of some chemotypes of this plant to
250
humans and animals (Marchi et al., 2003), it has been used to treat skin infections, dysentery
251
and fever (Al-Yahya et al., 1998). In a study of the hormonal impact of Ferula plants, F.
252
hermonis Boiss. has been introduced as containing a phytoestrogen having a high affinity
253
toward estrogen receptors and capable of having a positive impact on certain disorders (Ikeda
254
et al., 2002).
10
255
In Tunisian folk medicine, F. communis L., has been reported to treat foot cracks, joint pains,
256
parasitic worms, rheumatism, dysentery, hysteria and skin diseases (Nguir et al., 2016).
257
However, domestic animals fed with F. communis L. can develop haemorragic and ferulotic
258
diseases (Lamnaouer et al., 1991; Lamnaouer et al., 1994; Tanji and Nassif, 1995).
259
In the traditional medicine of Syria and Lebanon, F. hermonis Boiss. is called “Shirsh-el-
260
Zallouh,” which means “having a hairy root” on account of its general morphology. This
261
plant has been long used as an aphrodisiac agent (Table 2) in the treatment of impotence and
262
frigidity (Auzi et al., 2008; Al-Ja'Fari et al., 2011).
263
264
4. Chemical profiles of the essential oils, extracts, resins and volatiles from
different Ferula species
265
Essential oil (EOs) are mixtures of natural compounds released from the secretory glands of a
266
wide array of plants. EOs are often used in a variety of the industrial disciplines. In addition,
267
EOs have a great impact on perfumery and fragrance enterprises.
268
Classical hydrodistillation (HD) and steam distillation (SD) have been used to extract EOs
269
since antiquity. However, within the last decades of the 20th century, microwave methods
270
have resulted in faster and more efficient separations of EOs. Accordingly, microwave-
271
assisted hydrodistillation (MAHD) (Mohammadhosseini et al., 2013; Hashemi-Moghaddam
272
et al., 2014; Hashemi-Moghaddam et al., 2015) along with solvent-free microwave extraction
273
(SFME) (Mohammadhosseini, 2015a; Nekoei and Mohammadhosseini, 2017), are now
274
considered to be effective and advanced approaches for the isolation of volatile EOs.
275
On the other hand, volatiles produced by different organs of plant materials can be released
276
thermally and can be directed onto the surface of diverse organic fibers (Mohammadhosseini,
277
2015b; Mohammadhosseini et al., 2016). The volatile parts can also be introduced directly
278
into the injection port of gas chromatographic-based devices (Mohammadhosseini et al.,
279
2017a).
11
280
The main components in the chemical profiles of a vast number of EOs, extracts and volatiles
281
of the Ferula plants from 1989 to March 2018 are listed in Table 3. A careful perusal of
282
Table 3 reveals that the most abundant non-terpenoid hydrocarbons found in the reported
283
chemical profiles were sulfur-containing compounds involving (E)-1-propenyl-sec-butyl
284
disulfide, dimethyl-trisulphide, sec-butyl-(Z)-propenyl-disulphide, sec-butyl-(E)-propenyl-
285
disulphide, di-sec-butyl-disulphide, phenol 2-methyl-5-(1-methylethyl), trimethylthiophene,
286
2,5-diethylthiophene, 1-methylpropyl-(1E)-prop-1-en-1-yl-disulfide, 1-methylpropyl-(1Z)-
287
prop-1-en-1-yl-disulfide and bis-[(1-methylthio)propyl]-disulfide (Khajeh et al., 2005;
288
Iranshahi et al., 2006; Iranshahi et al., 2008; Dehpour et al., 2009; Sahebkar et al., 2010;
289
Kanani et al., 2011; Li et al., 2011; Kavoosi et al., 2012; Mirzaei and Hasanloo, 2012;
290
Kavoosi and Purfard, 2013; Kavoosi and Rowshan, 2013; Özek et al., 2017), along with 2-
291
methyl octane (Kanani et al., 2011), nonane (Baser et al., 2000; Kanani et al., 2011) and
292
aromatic derivatives (benzene-1-3-dimethyl etc.) (Sadraei et al., 2001; Chibani et al., 2012).
293
Furthermore, the most frequently occurring monoterpene hydrocarbons in the characterized
294
profiles were found to be α-pinene, β-pinene, limonene, p-cymene, γ-terpinene, δ-3-carene
295
and myrcene (Garg et al., 1989; Rustaiyan et al., 2001a; Sadraei et al., 2001; Sayyah and
296
Mandgary, 2003; Akhgar et al., 2005; Ferrari et al., 2005; Kose et al., 2010; Al-Ja'Fari et al.,
297
2011; Kanani et al., 2011; Amiri, 2014; Bouratoua et al., 2014; Alipour et al., 2015; Ben
298
Salem et al., 2016; Schepetkin et al., 2016; Najafabadi et al., 2017; Znati et al., 2017). On the
299
other hand, oxygenated sesquiterpenes like carvacrol, neryl acetate, verbenone, thymol, cis-
300
chrysanthenol and camphor had the highest frequencies in the reported profiles (Ghannadi et
301
al., 2002; Chibani et al., 2012; Alipour et al., 2015). Moreover, germacrene D,
302
bicyclogermacrene, (E)-caryophyllene, α-gurjunene, δ-cadinene, γ-cadinene and γ-elemene
303
(Habibi et al., 2006a; Maggi et al., 2009a; Maggi et al., 2009b; Kanani et al., 2011; Bahramia
304
et al., 2013; Mohammadhosseini et al., 2015) were instead the dominant sesquiterpene
12
305
hydrocarbons. The major oxygenated sesquiterpenes contributing to the aforementioned
306
chemical profiles in Table 3 were α-cadinol, guaiol, (E)-nerolidol, α-eudesmol, (Z)-
307
ocimenone, (E)-ocimenone, viridiflorol, epi-α-muurolol, carotol, valerianol and hinesol
308
(Rustaiyan et al., 2001b; Shatar, 2005; Habibi et al., 2006b; Benchabane et al., 2012; Ozkan
309
et al., 2014; Labed-Zouad et al., 2015; Kasaian et al., 2016; Nguir et al., 2016).
310
In the search for compounds of chemotaxonomic relevance from species in the genus Ferula,
311
EOs of 23 populations relating to 18 species were screened (Kanani et al., 2011). Fig. 3,
312
shows the molecular structures of the most prevalent compounds recognized in that study.
313
The sulfur-containing compounds have the highest frequency and are responsible for the
314
specific odors of different Ferula species. Furthermore, a cluster analysis (Ward dendrogram)
315
of the most abundant components in the characterized profiles of the EOs of the Ferula
316
species revealed the presence of four groups, namely i) monoterpene hydrocarbons (first
317
cluster) consisting of α-pinene (52%-69%) as well as α-pinene (16-37%) and β-pinene (36-
318
66%) for the first and second subgroups, respectively;
319
ii) oxygenated monoterpenes (second cluster) involving α-terpinyl acetate (73%) and
320
sabinene (20%), verbenone (69%) and ar-curcumene (6%);
321
iii) organosulfur compounds (third cluster) including 2,3,4-trimethylthiophene (2) (49%), and
322
2,5-diethylthiophene (6) (28%);
323
iv) monoterpene + sesquiterpene + aliphatic hydrocarbons (fourth cluster) containing (Z)-β-
324
ocimene (42%), myrcene (35%), sabinene (75%) and (E)-caryophyllene (16%).
325
Maggi and collaborators (2009b) reported chemical profiles of the EOs from different parts,
326
e.g. flowers, fruits, roots and leaves of F. glauca L. growing wild in Marche (Central Italy).
327
In their study, EOs were obtained using classical hydrodistillation and were sequentially
328
analyzed using GC-FID and GC-MS techniques. A total of 74 constituents were
329
characterized, representing 87-95% of the total leaves oil. The predominant constituents were
13
330
sesquiterpene hydrocarbons that included (E)-caryophyllene, α-humulene and germacrene D,
331
respectively involving 16-25%, 10-18%, 7-9%, and 5-10% of the total chemical profile.
332
Furthermore, 95 compounds, accounting for 90-97% of the flower oils were identified. Once
333
again, sesquiterpene hydrocarbons dominated over the other groups, with (E)-caryophyllene
334
and germacrene D accounting, respectively, for 6-14% and 14-21% of the oil composition.
335
On the other hand, the analysis of the oil from the fruits of F. glauca L. revealed the presence
336
of a total of 55 components (69-90%). In contrast to the oils from the leaves and flowers of F.
337
glauca L., monoterpene hydrocarbons contributed to the profiles as the major fractions with
338
pinene derivatives (α: 24-45%; β: 15-20%) being the most abundant. Finally, in the essential
339
oil separated from the roots of F. glauca L., 54 compounds were identified altogether
340
accounting for 69-80% of the oil. Similar to the oil profile from the leaves and flowers of F.
341
glauca L., the root oil was rich in sesquiterpene hydrocarbons with (E)-β-farnesene and α-
342
zingiberene each accounting for 5-10% of the compounds.
343
Recently, Moghaddam and Farhadi (2015), have studied chemical compositions of nine
344
populations of F. assa-foetida L. growing wild in different localities of Kerman province,
345
Iran. As shown in Table 3, a total of 30 constituents, accounting for 96-99% of the oil, were
346
identified in the EOs of F. assa-foetida L. This study revealed the presence of some non-
347
terpene sulfur-containing hydrocarbons, namely (E)-propenyl,sec-butyl disulfide (37-54%),
348
(Z)-propenyl,sec-butyl disulfide (12-23%) and n-propyl,sec-butyl disulfide (0-5%) along with
349
lower quantities of some monoterpene hydrocarbons such as α-pinene (4-7%), β-pinene (8-
350
15%) and (E)-β-ocimene (3-6%). This study showed a great variation in the mean yields of
351
the resins from F. assa-foetida L. Moreover, a statistical analysis displayed a positive
352
correlation between the precipitation rates in the sampling area and the yield of the obtained
353
resins. In addition, a remarkable increase in the yield of the obtained resins was noted when
14
354
the temperature increased. Accordingly, the highest contents of EOs were found in localities
355
having the highest precipitation rates and altitude.
356
5. Phytochemistry of the Ferula species (2000 to March 2018)
357
In the literature, some reports occasionally discuss phytochemistry in addition to the
358
biological and medicinal properties of some species of the genus Ferula (Iranshahy and
359
Iranshahi, 2011; Sahebkar and Iranshahi, 2011; Zare et al., 2011; Kareparamban et al., 2012;
360
Akaberi et al., 2015; Amalraj and Gopi, 2017; Sattar and Iranshahi, 2017a, b; Upadhyay et
361
al., 2017; Zhou et al., 2017). However, the current review paper aims to give a deeper insight
362
into the major ethnopharmaceutical properties, along with chemical compositions of the
363
essential oils, organic extracts and volatiles from the different Ferula species growing wild
364
worldwide. In addition, the phytochemistry of the different species of this genus is discussed
365
over the period of 2000-to the present time (March 2018). It is also noteworthy that before
366
the year 2000, many reports were published relating to natural bioactive sulfur compounds
367
(Al-Said et al., 1996), triterpenes (Diaz et al., 1984; Díaz et al., 1984), sesquiterpene esters
368
(Miski et al., 1983; Miski et al., 1984; Razdan et al., 1989; Appendino et al., 1990; González
369
et al., 1993; Khalilova and Saidkhodzhaev, 1998a), sesquiterpene derivatives of the farnesyl-
370
benzofuranone type (Kojima et al., 1999), esters (Saidkhodzhaev et al., 1985a;
371
Saidkhodzhaev et al., 1985b; Golovina et al., 1987; Kerimov et al., 1987; Saidkhodzhaev et
372
al., 1993b; Saidkhodzhaev et al., 1993d; Kobilov et al., 1995b, a; Nazhimutdinova et al.,
373
1995), isocarotane esters (Garg et al., 1998), daucane esters (Miski and Mabry, 1985; Miski
374
and Jakupovic, 1990; Appendino et al., 1997), sesquiterpene coumarins (Buddrus et al., 1985;
375
Nassar et al., 1995; Ahmed, 1999), sesquiterpene lactones (Kir'yalov and Serkerov, 1966;
376
Bagirov et al., 1979a, b; Bagirov et al., 1984; Sagitdinova et al., 1991; Serkerov et al., 1992;
377
Kabilov et al., 1994), terpenoids (Nazhimitdinova and Saidkhodzhaev, 1993; Saidkhodzhaev
15
378
et al., 1993a; Saidkhodzhaev and Mamatkhanov, 1995; Khalilova and Saidkhodzhaev,
379
1998b), and terpene coumarins (Vandyshev et al., 1974; Savina et al., 1978; Sokolova et al.,
380
1978; Veselovskaya et al., 1979; Kir'yanova et al., 1980; Kuliev et al., 1980; Veselovskaya et
381
al., 1980; Sklyar et al., 1982; Veselovskaya et al., 1982; Nabiev and Malikov, 1983; Al-
382
Hazimi, 1986; Serkerov and Mir-Babaev, 1987; Saidkhodzhaev et al., 1991; Saidkhozhaev et
383
al., 1991; Saidkhodzhaev et al., 1993c).
384
In the recent decades, several natural products from different organs of a wide variety of the
385
Ferula plants have been reported. The sulfur-containing compounds in these plants are often
386
responsible for the pungent odors of the corresponding products. Furthermore, a large number
387
of phytochemical reports have revealed the presence of novel natural compounds in the
388
diverse species of the genus Ferula. In the following sub-sections, new identified metabolites
389
are reviewed and subdivided in classes of natural compounds.
390
391
5.1. Coumarin derivatives
392
393
5.1.1. Hemiterpene coumarins
394
A variety of coumarin derivatives were identified in the methanol extract obtained from the
395
dried roots of F. sumbul (Kauffm.) Hook.F. (Fig. 4), including two furanocoumarin esters:
396
fesumtuorin A (13) and fesumtuorin B (14); one bicoumarin, fesumtuorin C (15); five
397
spirobicoumarins, fesumtuorin D (16), fesumtuorin E (17), fesumtuorin F (18), fesumtuorin
398
G (19) and fesumtuorin H (20), in addition to nineteen known coumarins (Zhou et al., 2000).
399
400
5.1.2. Monoterpene coumarins
401
In a different work, the group by El-Razek (El-Razek et al., 2001) was able to separate two
402
monoterpene coumarins, namely ferulagol A (21) and ferulagol B (22) (Fig. 5) from a
403
dichloromethane extract of F. ferulago L.
16
404
405
5.1.3. Sesquiterpene coumarins
406
Six sesquiterpenoids, named pallidones A-F (23-28) (Fig. 6), together with two known
407
sesquiterpenes (feselol and conferol) already found in several Ferula species, were isolated
408
from the ethyl acetate extract of the roots of F. pallida Korovin (Su et al., 2000). The possible
409
biogenetic pathway of the sesquiterpene coumarins, pallidones A (23) and B (24) was also
410
discussed: A common biosynthetic precursor for pallidones A-F and other sesquiterpene-
411
coumarins was hypothesized in 2-hydroxy-4-methoxycinnamic acid. This might be involved
412
in two different pathways: one proceed through cyclization to form the coumarin skeleton,
413
the other implies the addition of water to the double bond and the subsequent oxidation of
414
hydroxyl function to constitute the appropriate intermediate, then both pathways imply the
415
reaction of condensation with the appropriate sesquiterpene derivative.
416
Assafoetidnol A (29) and assafoetidnol B (30) (Fig. 7) were reported by Abd El-Razek et al.
417
(2001) in the organic extracts prepared of the roots of F. assa-foetida L. in addition to six
418
other compounds, gummosin, polyanthin, badrakemin, neveskone, samarcandin and galbanic
419
acid.
420
Motai et al (2004) purified six sesquiterpene coumarin derivatives, 2,3-dihydro-7-hydroxy-
421
2R*,3R*-dimethyl-2-[4,8-dimethyl-3(E),7-nonadien-6-onyl]furo[3,2-c]coumarin
422
fukanefuromarin A (32), fukanefuromarin B (33), fukanefuromarin C (34), fukanefuromarin
423
D (35), and fukanemarin A (36) (Fig. 8), from the water-methanol extract of the roots of F.
424
fukanensis K.M.Shen.
425
Motai and Kitanaka (2004) identified four sesquiterpene coumarin derivatives from an 80%
426
aqueous methanol extract of the roots of F. fukanensis K.M.Shen: fukanemarin B (37),
427
fukanefuromarin E (38), fukanefuromarin F (39) and fukanefuromarin G (40) (Fig. 9).
17
(31),
428
Saradaferin
([decahydro-(3-α-hydroxy-4,4,10-trimethyl-8-methylene-9-naphthenyl)-α-
429
hydroxymethyl] ether of umbelliferone), a sesquiterpene coumarin, (41) (Fig. 10) was
430
separated from an OGR of F. assa-foetida L. (Bandyopadhyay et al., 2006).
431
Isofeterin (42), lehmannolol (43) and shinkianone (44) (Fig. 11) were identified from the
432
95% ethanol extract of the roots of F. teterrima Kar. & Kir. and F. sinkiangensis K. M. Shen
433
(Yang et al., 2006).
434
Three sesquiterpene derivatives, together with ten other compounds, were isolated from the
435
methanol extract from the roots of F. gummosa Boiss. Among those three compounds,
436
gumosin (45) is a coumarin derivative, and gumosides A and B (46 and 47, Fig. 12) are
437
coumarin glycosides (Iranshahi et al., 2010a).
438
The phytochemical characterization of the aqueous-ethanol (5:95, v/v) extract of the roots of
439
F. ferulaeoides (Steud.) Korov led to the separation of three sesquiterpenoid coumarins,
440
ferulin A-C (48-50) (Fig. 13) along with seven known sesquiterpenoid derivatives (Meng et
441
al., 2013a).
442
Recently, Bashir and colleagues (2014a) have identified two sesquiterpene coumarins,
443
fnarthexone (51) and fnarthexol (52) (Fig. 14), as well as three known coumarin derivatives
444
(umbelliferone, conferone and conferol) from the methanol extract of F. narthex Boiss.
445
obtained by using a maceration method. It is interesting to note that from the stereochemical
446
point of view, fnartexol (52) is the epimer at C-5′ of conferol, a natural compound also
447
identified in F. nartex Boiss. during the reported study.
448
Liu and collaborators (2015) separated 28 sesquiterpenoids from the ethanol extract of the
449
roots of F. ferulioides (Steud.) Korovin. Seven of these terpenoids were described for the first
450
time from the genus Ferula. Of these, three compounds (53-55) resulted to be sesquiterpene
451
coumarins (Fig. 15).
18
452
Dastan and co-workers (2012) separated two disesquiterpene coumarins from the n-hexane
453
extract of F. pseudalliacea Rech.f. roots (56-57) (Fig. 16), in addition to four known
454
sesquiterpene coumarins.
455
Li and colleagues (2015a) reported a sesquiterpene coumarin, namely sinkiangenorin D (58)
456
(Fig. 17), along with ten known sesquiterpene coumarins from the seeds of F. sinkiangensis
457
KM Shen. It is interesting to note that (58) is a sesquiterpenoid with a rare cycloheptene unit
458
in its structure. This structural feature might be subsequent to several rearrangements since
459
the common head-tail connenction between the isoprene units is no longer observable in its
460
structure.
461
In a similar study, sinkiangenorin F (59) and 8-O-acetyl sinkiangenorin F (60) (Fig. 18) were
462
characterized as the sesquiterpene coumarins in the ethanol extract of F. sinkiangensis KM
463
Shen (Li et al., 2015b).
464
Among the sixteen identified compounds in the chloroform extract of F. sinkiangensis K. M.
465
Shen, two compounds, (3′S, 8′R, 9′S, 10′R)-sinkianol A (61) and (3′R, 5′R, 10′R)-sinkianol B
466
(62) (Fig. 19) were identified for the first time (Xing et al., 2017). In addition, eleven known
467
compounds,
468
deacetylkellerin, farnesiferol A, farnesiferone A, gummosin, polyanthinin, (3'R,5'R,10'R)-
469
sinkianol B, galbanic acid, methyl galbanate and karatavicinol were reported for the first time
470
for this species.
471
472
5.1.4. Coumarinyl esters
473
In a related study, coumarin esters, 7-O-(4,8,12,16-tetrahydroxy-4,8,12,16-tetramethyl-
474
heptadecanoyl)-coumarin, ferulone A (63), and 7-O-(4-hydroxy-4,8,12-trimethyl-trideca-
475
7,11-dienoyl)-coumarin, ferulone B (64), (Fig. 20) were isolated from the non-polar (n-
476
hexane) fraction of extracts from the roots of F. orientalis L. (Razavi et al., 2016). These two
477
coumarin esters were isolated by a combination of vacuum liquid chromatography (VLC) and
including
ferukrin,
(3'S,5'S,8'R,9'S,10'R)-kellerin,
19
(3'S,5'S,8'R,9'S,10'R)-
478
preparative thin-layer chromatographic (PTLC) and were characterized by means of
479
spectroscopic methods.
480
Razavi and Janani (2015) isolated a coumarinyl ester, ferulone C [7-O-(4,8,12-trihydroxy-
481
4,8,12-trimethyl-tridecanoyl)-chromen-2-one] (65) (Fig. 21) , from an n-hexane extract of the
482
roots of F. persica Wild.
483
484
5.1.4.1. Dihydrofuranocoumarinyl esters
485
Analysis of the dichloromethane soluble fraction of a methanolic extract from the roots of F.
486
lutea (Poir.) Maire afforded an inseparable mixture of two isomeric dihydrofuranocoumarin
487
esters with senecioic and angelic acids, respectively, (−)-5-hydroxyprantschimgin (66) and
488
(−)-5-hydroxydeltoin (67) (Fig. 22) (Ben Salem et al., 2013), together with eight other
489
compounds, (−)-prantschimgin, (−)-deltoin, psoralen, xanthotoxin, umbelliferone, caffeic
490
acid, β-sitosterol and stigmasterol.
491
492
5.2. Prenylated benzoic acid derivatives
493
Chen et al. (2000a) characterized the prenylated benzoic acid derivatives, kuhistanol A (68),
494
kuhistanol B (69), kuhistanol C (70), and kuhistanol D (71) (Fig. 23), in F. kuhistanica
495
Korovin, one of the most important medicinal plants of Uzbekistan.
496
Finally, this group introduced four further derivatives of farnesyl hydroxybenzoic acid,
497
kuhistanol E (72), kuhistanol F (73), kuhistanol G (74) and kuhistanol H (75) (Fig. 24) from
498
F. kuhistanica Korovin a medicinal plant growing wild in the Uzbekistan region (Chen et al.,
499
2001).
500
501
5.3. Sesquiterpene chromones
502
In a complimentary work by Motai and Kitanaka (2005a), five sesquiterpene chromone
503
derivatives, fukanefurochromones (A-E) (76-80) (Fig. 25) from a water-methanol (20:80,
504
v/v) extract of F. fukanensis K.M.Shen roots were isolated.
20
505
Phytochemical analysis of the aqueous-ethanol (5:95, v/v) extract of the roots of F.
506
ferulaeoides (Steud.) Korov led to the separation of two sesquiterpene chromone derivatives,
507
ferulin D,E (81-82) (Fig. 26), along with seven known sesquiterpenoid derivatives (Meng et
508
al., 2013a).
509
510
5.4. Sesquiterpenes
511
Chen and colleagues (2000b) isolated five daucane-type sesquiterpenes, kuhistanicaol A (83),
512
kuhistanicaol B (84), kuhistanicaol C (85), kuhistanicaol D (86) and kuhistanicaol G (87)
513
(Fig. 27) from the methanol extract of the air-dried of stems and roots of F. kuhistanica
514
Korovin.
515
An eudesmanolide (88) and a carotene derivative (89) (Fig. 28) were isolated from a
516
methanol-methylene chloride (1:1) extract from the leaves of F. sinaica Boiss. (Ahmed et al.,
517
2001).
518
An oxygenated sesquiterpenoid, (1S,4S,5R,6S,7S,10S)-5,10,11-cadinanetriol (90) (Fig. 29),
519
from a distinct Sardinian chemotype of F. communis L. was isolated from the acetone extract
520
(Appendino et al., 2001).
521
Diab and co-workers (2001) isolated 2,3-α-epoxyjaeschkeanadiol 5-benzoate (91) (Fig. 30)
522
from the methylene chloride extract of F. hermonis Boiss roots.
523
Two daucane esters, 14-(4'-hydroxybenzoyloxy)dauc-4,8-diene (92,) (Fig. 31) and 14-(4'-
524
hydroxy-3'-methoxybenzoyloxy)dauc-4,8-diene (93) (Fig. 31), were obtained from the n-
525
hexane fraction of F. hermonis Boiss (roots) (Galal et al., 2001) together with four other
526
diterpenes.
527
Found in the ethyl acetate extracts of the dried fruits of F. kuhistanica Korovin., were three
528
derivatives of daucane esters, namely kuhistanicaol H (94), kuhistanicaol I (95) and
529
kuhistanicaol J (96) (Fig. 32) (Tamemoto et al., 2001), along with nine other compounds.
21
530
Shikishima and collaborators (2002) characterized 17 sesquiterpenes in the ethyl acetate
531
extract from the dry roots of F. penninervis Regel and Schmalh. Fifteen of these were the
532
guaiane type (ferupennins A-O: 97-111) (Fig. 33), while the remaining two were of the
533
eudesmane type (112-113) (Fig. 33): 1α-hydroxy-2-oxo-5α,7β-11βH-eudesm-3-en-6α,12-
534
olide (112), and penninervin (113), respectively. Nine additional sesquiterpenes, already
535
known, were also identified.
536
Three daucane sesquiterpenes [(1R,4R)-4-hydroxydauca-7-ene-6-one (114), (1R,4R)-4-
537
hydroxydauca-7-ene-6,9-dione (115) and (1R,3S,8S)-3-ethoxy-8-angeloyloxydauca-4-en-9-
538
one (116), (Fig. 34) were characterized from the hexane extract prepared from the air dried
539
roots of F. hermonis Boiss (Lhuillier et al., 2005).
540
Sesquiterpene lactones 117-122 (Fig. 35) were isolated from the ethyl acetate-soluble fraction
541
obtained from the MeOH extract of F. varia (Schrenk) Trautv. roots (Suzuki et al., 2007)
542
together with five other sesquiterpenes, dehydrooopodin, oopodin, spathulenol, ferupennin L
543
and 8α-angeloyloxy-10β-hydroxyslov-3-en-6,12-olide.
544
The sesquiterpene derivatives (Fig. 36), 10-hydroxylancerodiol-6-anisate (123), 2,10-
545
diacetyl-8-hydroxyferutriol-6-anisate (124), 10-hydroxylancerodiol-6-benzoate (125), epoxy-
546
vesceritenol (126) and vesceritenone (127), along with six other compounds, were reported
547
among the components of the methylene chloride extract obtained from the aerial parts of F.
548
vesceritensis Coss. & Dur (Oughlissi-Dehak et al., 2008).
549
Alkhatib and colleagues (2008) identified two sesquiterpene esters, namely 6-
550
anthraniloyljaeschkeanadiol
551
hydroxybenzoyloxy)dauc-9-ene (elaeochytrin B) (129) (Fig. 37), from the dichlorometane
552
soluble fraction of the methanolic extract of the roots of F. elaeochytris Korovin. In the same
553
work, eight other compounds were also identified. These included 6-angeloyljaeschkeanadiol,
554
teferidin,
ferutinin,
(elaeochytrin
A)
(128)
and
4β-hydroxy-6α-(p-
6-(p-hydroxybenzoyl)epoxyjaeschkeanadiol,
22
6-(p-
555
hydroxybenzoyl)lancerotriol,
5-caffeoylquinic
556
sandrosaponin IX.
557
From the dichloromethane extract of roots of F. badrakema Koso-Pol., badrakemonin (130)
558
(Fig. 38) (Iranshahi et al., 2009), a sesquiterpene, was isolated together with six known
559
sesquiterpene coumarins: mogoltacin, feselol, badrakemin acetate, ferocaulidin, conferone
560
and conferol acetate.
561
Sesquiterpene lactones, diversolides A (131), D (132), F (133) and G (134) (Fig. 39) were
562
isolated from the roots of F. diversivittata Regel & Schmalh. by Iranshahi et al. (2010b).
563
A sesquiterpene ester, tunetanin A (135), along with a sesquiterpene coumarin,
564
tunetacoumarin A (136) (Fig. 40), were reported from the dichloromethane-soluble fraction
565
of the methanol extract of F. tunetana Pomel ex Batt. roots (Jabrane et al., 2010).
566
Dall’Acqua and colleagues (2011) isolated three daucane sesquiterpenes (137-139) (Fig. 41)
567
from the dichloromethane fraction of an ultrasound assisted methanol extract of the roots of
568
F. communis subsp. Communis. Among these, 2α-Acetoxy-6α-p-methoxybenzoyl-10α-
569
hydroxy-jaeschkeanadiol
570
jaeschkeanadiol (138) were found to be the epimers of two other daucane sesquiterpenes, 2α-
571
acetoxy-6α-p-methoxybenzoyl-10β-hydroxy-jaeschkeanadiol
572
methoxybenzoyl-10β-hydroxy-jaeschkeanadiol, respectively, which had already been
573
identified in F. communis subsp. communis. The third characterized compound (139) was the
574
8,9-dihydro-8,14-dehydro-9-hydroxyferutinin, which had been obtained previously by a
575
semisynthetic approach but had never been isolated from a natural source.
576
Three daucane esters, out of a total of seventeen, (Fig. 42), namely feruhermonins A (4β-
577
hydroxy-6α-benzoyl-dauc-7-en-9-one)
578
benzoyl-dauc-9-ene) (141) and feruhermonins C (4β,9α-dihydroxy-6α-benzoyl-dauc-7-ene)
579
(142) were reported from the n-hexane-ethyl acetate (1:1) extract of the seeds of F. hermonis
(137)
and
acid,
1,5-dicaffeoylquinic
acid
and
2α-hydroxy-6α-p-methoxybenzoyl-10β-acetoxy-
(140),
23
feruhermonins
and
B
2α-acetoxy-6α-p-
(4β,8β-dihydroxy-6α-
580
Boiss (Auzi et al., 2008). The epimer at C-8 of feruhermonins B (141), reported in Fig. 33 as
581
(141a), was isolated from the same species few years later by Ibraehim et al. (2012a).
582
From the water-soluble fraction of the methanol extract of F. varia (Schrenk) Trautv. roots, a
583
species widely used in the traditional medicine of Uzbekistan, seven other sesquiterpene
584
lactone glycosides with the eudesmane skeleton were isolated (143-149) (Fig. 43) (Kurimoto
585
et al., 2012b). To establish their absolute configurations the authors applied a modification of
586
Mosher’s method.
587
The analysis of a water extract of F. varia (Schrenk) Trautv roots resulted in the
588
characterization of eight natural compounds of which five (150-154), two (155-156) and one
589
(157) (Fig. 44) are, respectively of the eudesmane, guaiane and germacrene lactone glucoside
590
types (Kurimoto et al., 2012a).
591
Liu and collaborators (2015) separated 28 sesquiterpenoids from an ethanol extract of the
592
roots of F. ferulioides (Steud.) Korovin, of which seven were described for the first time from
593
the genus Ferula (Fig. 45). Four of these compounds (158-161) showed a structure in which a
594
resacetophenone unit is linked to a linear (158, 159) or rearranged sesquiterpene moiety to
595
form a dihydrofurane structure (160, 161).
596
597
5.5. Sulfur containing metabolites
598
From the chloroform extract of the aerial parts of F. behboudiana Rech. f. Esfand, four
599
polysulphane
600
enyl]disulphane (162), 1-sec-butyl-2-[(Z)-3-(methylthio)prop-1-enyl] disulphane (163), 1-
601
[(E)-3-(methylthio)prop-1-enyl)-2-(1-(methylthio)propyl] disulphane (164) and 1-[(Z)-3-
602
(methylthio)prop-1-enyl)-2-(1-(methylthio)propyl] disulphane (165) (Fig. 46) were reported
603
(Yousefi et al. (2010).
604
More recently, five novel sulfur-containing compounds, latisulfide A (166), latisulfide B
605
(167), latisulfide C (168), latisulfide D (169) and latisulfide E (170) (Fig. 47), have been
related
compounds,
namely
24
1-sec-butyl-2-[(E)-3-(methylthio)prop-1-
606
isolated from the dichloromethane extract of F. latisecta Rech.f. & Aellen (Soltani et al.,
607
2018).
608
Sulfur-containing heterocylcic compounds, foetithiophene C (171), foetithiophene D (172),
609
foetithiophene E (173) and foetithiophene F (174) (Fig. 48), were also obtained from the
610
roots of F. foetida Regel (petroleum ether extract) (Chitsazian-Yazdi et al., 2015).
611
612
5.6. Miscellaneous
613
Abd El-Razek (2007) isolated a caffeic acid cinnamyl ester, (2E)-3,4-dimethoxycinnamyl-3-
614
(3,4-diacetoxyphenyl) acrylate (175), from the n-hexane soluble fraction obtained from
615
methanol extract of the OGR of F. assa-foetida L. (Fig. 49).
616
Meng and collaborators (2013b) isolated eight sesquiterpenoids, ferulaeone A-H (176-183)
617
(Fig. 50) from F. ferulaeoides (Steud.) Korov. The proposed structures assignment were
618
based not only on experimental spectroscopic data, but also on biosynthetic pathway, which
619
might imply the condensation between the appropriate Coenzyme-A activated C6–C3
620
derivative and farnesyl pyrophosphate.
621
Ibraheim and colleagues (2012b), isolated a saponin (sandrosaponin XI) (184) (Fig. 51) from
622
the n-butanol extract of the root of F. hermonis Boiss. Sandrosaponin XI has an oleanane
623
pentacyclic triterpene skeleton. The complete structure of the saponin (184) was shown to be
624
the methyl ester of 3β-O-β-D-glucopyranosyl-(1→2)-β-D-galactopyranosyl-(1→2)-β-D-
625
glucuronopyranosyl-oleanolic acid-28-O-β-D-glucopyranoside.
626
The steroidal esters, sinkiangenorin A (185) and sinkiangenorin B (186) and the organic acid
627
glycoside sinkiangenorin C (187) (Fig. 52) were isolated from the ethanol extract from the
628
seeds of F. sinkiangensis KM by Shen Li and co-workers (2014). Four known lignin-related
629
compounds were also identified during the same study.
630
Screening of a methanol-water (7:3) extract of the flowers of F. lutea (Poir.) Maire yielded
631
ferunide, (E)-5-ethylidenefuran-2(5H)-one-5-O-β-D-glucopyranoside (188), in addition to 425
632
hydroxy-3-methylbut-2-enoic acid (189) (Fig. 53) (Znati et al., 2014). This extract also
633
contained nine known compounds, which could be partitioned between ethyl acetate and n-
634
butanol. Of these, six compounds, 5-O-caffeoylquinic acid, methyl caffeate, methyl 3,5-O-
635
dicaffeoylquinate,
636
rhamnopyranosyl(1→6)-β-D-glucopyranoside, narcissin, and (_)-marmesin, even if quite
637
common plant metabolites, were identified for the first time in the Ferula genus.
638
The phytochemical patterns recognized in Ferula species are varied. These include different
639
classes of natural products, i.e. coumarins, sesquiterpenes, phenylpropanoids, saponins,
640
chromones, sulfur-containing compounds and steroids. Among these phytoconstituents, the
641
coumarins, and in particular the furanocoumarins (linear and/or angular), very often esterified
642
with short chain organic acids such as acetic, angelic and/or senecioic acids, are characteristic
643
constituents of several species of the Apiaceae family, for instance, Coristospermum
644
cuneifolium (Guss.) Bertol. (Venditti et al., 2016), Ligusticum pyrenaicum W.D.J.Koch
645
(Bohlmann and Grenz, 1969), Ferulopsis hystrix (Bunge ex Ledeb.) M. Pimen. (Shulˈts et al.,
646
2012) and Ferulago angulata (Schltdl.) Boiss (Razavi et al., 2015), among the others. In this
647
context, the peculiar spirobicoumarins are noteworthy to the best of our knowledge, since
648
they have been recognized so far only in the Apiaceae family, i.e. in Pleurospermum
649
rivulorum (Diels) M. Hiroe (Taniguchi et al., 1998). The sesquiterpenoids are also considered
650
as chemotaxonomic markers in the Apiaceae, and the genus Ferula showed a widespread
651
presence of compounds of several families of sesquiterpene lactones, including derivatives
652
containing the cadinane, daucane, guaiane, eudesmane and carotane backbones. All these
653
compounds are useful taxonomic markers within the genus, but they also provide evidence of
654
the systematic proximity among various genera in the Apiaceae family itself. The main
655
metabolic feature, which may be observed by considering the wide list of compounds and
656
chemical structures reported in this review, is the presence of a huge number of metabolites
3,5-O-dicaffeoylquinic
26
acid,
isorhamnetin-3-O-α-L-
657
of mixed biosynthetic origin, such as hemi- mono- and sesquiterpene coumarins,
658
sesquiterpene chromones, sesquiterpene polyketides, furochromones and prenylated benzoic
659
acid derivatives. Concerning the sesquiterpene coumarins and the sesquiterpene chromones,
660
the species of the Ferula genus resulted to be very efficient producer of these rare
661
phytoconstituents. The occurrence of these secondary metabolites seems to be restricted to a
662
few species within the Apiaceae, the Asteraceae and the Rutaceae families (Gliszczyńska and
663
Brodelius, 2012). Last but not the least, the sulfur-containing secondary metabolites, present
664
as different derivatives such as thiophenes, disulfanes and trisulfanes, found in both the
665
volatile fraction and organic solvents extracts, are an additional distinctive chemical trait of
666
the Ferula species which confer the characteristic smell to several species of the genus.
667
The presence of a wide variety of secondary metabolites of mixed biogenetic origin (i.e.
668
hemiterpene-coumarins (Fig. 4), monoterpene-coumarins (Fig. 5), sesquiterpene-coumarins
669
(Figs. 6-19), sesquiterpene polyketides (Fig. 45) and sesquiterpene-chromones (Figs. 25-26)
670
have a relevance also from the medicinal chemistry standpoint. In fact, in recent years, the
671
approach consisting in the fusion (by the use of a suitable linking group or exploiting directly
672
the functionalizations already present on the structures to be connected) of two biologically
673
active structural moieties has been largely explored for different purposes. For instance, with
674
the scope of specific organ/tissue delivery or to enhance a specific bioactivity taking
675
advantage from the synergistic properties of molecules with different structures or with
676
different cellular targets which are involved in the development of a specific pathology.
677
Currently, it is unknown why most of the species belonging to this genus showed this
678
metabolic behavior. There could be many valid hypotheses, even different one from the other.
679
One might be, obviously, the fusion of two molecules with different biological activity in one
680
derivative so to have a compound effective toward different biological targets. Another might
681
have its rationale in the physiological field i.e. the fusion of two molecules in one will reduce
27
682
the osmotic pressure by reducing the number of particles present in the cellular environment.
683
In any case, it remains an argument that deserves further investigation with dedicated studies.
684
However, it is a case that clearly represents how much Nature has already used some of the
685
chemical-pharmaceutical approaches that we believe to be innovative and, therefore,
686
emphasizes the importance of phytochemical studies that contribute to revealing chemical
687
aspects and physiological/ecological functions of secondary (specialized) metabolites and can
688
offer interesting approaches for use in medicinal and pharmaceutical chemistry.
689
To date, there are only a limited number of Ferula species already subjected to the systematic
690
phytochemical analysis. Therefore, it is obvious that in the future, several other new
691
compounds might be recognized as phytoconstituents of the Ferula genus and new biological
692
activities may be explored. This is particularly probable for the endemic entities since it has
693
been largely confirmed that the endemism is a condition which may promote the metabolic
694
diversity (Bianco et al., 2016) in respect to species with a more wide area of distribution.
695
Considering the chemical structures of the majority of the Ferula secondary metabolites and
696
the proposed biogenesis (Su et al., 2000; Meng et al., 2013b), it is evident that the biogenetic
697
pathways involving terpenoids and phenylpropanoids are particularly active. These are also
698
interacting among them to synthesize compounds with mixed biogenetic origin, thus it is
699
most probable that new metabolites possibly isolated in future studies might exhibit these
700
structural features.
701
702
7. The bioactivities of diverse characterized compounds from the genus
Ferula
703
There have been numerous papers dealing with the biological and medicinal properties of
704
some species of the genus Ferula. These important characteristics are discussed in the
705
following subsections.
28
706
707
7.1. Anti-HIV activity
708
Some of the known compounds isolated form Ferula spp., namely oxypeucedanin hydrate,
709
heraclenol, oxypeucedanin, heraclenin, pranferol, pabulenol, osthol and xanthotoxin, were
710
tested for their anti-HIV activity by Zhou and collaborators (2000). These compounds
711
resulted effective with IC50 ranging from 11.7 to > 100 μg/mL and EC50 ranging from < 0.10
712
to 33.3 μg/mL, in comparison to AZT as positive control (IC50 and EC50, 500 and 0.032
713
μg/mL, respectively). Several of these components, namely heraclenol, oxypeucedanin,
714
heraclenin and osthol, showed a Therapeutic Index (TI) > 5, thus denoting significant
715
activity. Interestingly, pabulenol showed a TI > 1000. Therapeutic indices > 1000 are
716
characteristic values of most of the drugs currently used in therapy. Based on this data,
717
pabulenol could be an excellent drug candidate having a little intrinsic toxicity.
718
Unfortunately, in this case, it is not possible to estimate the real quantity of these constituents
719
in the plant materials since in the experimental section are reported unlikely quantities of
720
plant material (500 g) compared to the volume of extraction solvent (50 l x 3) and the amount
721
of isolated components, some of which in gram scale. Therefore, the extracted plant material
722
was likely much greater than the reported value.
723
724
7.2. Inhibitory activity on cytokine production
725
Chen et al. (2000a) evaluated the inhibitory activity on cytokine production LPS-activated
726
human peripheral mononuclear cells. In this study, kuhistanol D (71) showed significant
727
immunosuppressive activity by inhibiting the production (%) of several cytokines at
728
concentrations of 3 μg/mL (IL-4; 70%, IL-2: 77%, IFN-γ: 62%), although the other
729
compounds showed no significant inhibitory effects even at higher concentration (10 μg/mL).
730
This result may suggest that the presence of the bicyclic chromane moiety in compound (71)
731
is necessary to exert the immunosuppressive activity. A quantity of 113.5 mg of (71) was
29
732
obtained from 2.25 Kg of plant materials, thus accounting for the 0.005% w/w and so
733
resulting to be a minor component.
734
735
7.3. Inhibitory activity on NO production
736
The inhibitory activity on NO production of (76-79) was tested in a murine macrophage-like
737
cell system induced by LPS/INF-γ (Motai and Kitanaka, 2005a). In this study, compound
738
(80) was not isolated in a sufficient amount (1.5 mg) to be further tested. However,
739
compounds (76-79) were effective in inhibiting NO production with IC50 values of 9.8 μg/mL
740
(25 μM), 8.9 μg/mL (23 μM), 12 μg/mL (29 μM) and 9.5 μg/mL (24 μM), respectively, and
741
showed no cytotoxicity at the tested concentrations. Among these sesquiterpene chromones,
742
(79) showed a dose dependent inhibition of iNOS mRNA expression. Furthermore, the
743
compound (79) showed a moderate inhibitory activity in LPS-induced NO production in a
744
murine macrophage-like cells system (RAW264.7) with an IC50 value of 55 μM (Abd El-
745
Razek, 2007). From 5.9 Kg of raw plant materials were recovered 23.8 mg of (76), 5.5 mg of
746
(77), 19.6 mg of (78) and 7.9 mg of (79), accounting for 0.0004, 0.00009, 0.00033 and
747
0.00013 % (w/w), respectively, resulting so minor components.
748
749
7.4. The inhibitory on Epstein-Barr virus early antigen (EBV-EA) activation
750
The inhibitory potentialities on Epstein-Barr virus early antigen (EBV-EA) activation
751
induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) were tested in vivo in a mouse
752
model (Iranshahi et al., 2010b). All the new sesquiterpene lactones (45-47) resulted to be
753
active (IC50 ranging from 8.7 and 10.7 nM) with inhibitor percentages comprised between
754
92.5 ± 0.6 and 89.2 ± 0.9 when applied at a concentration of 32 nM and between 63.6 ± 1.3
755
and 68.3 ± 1.6 when applied ad 16 nM, in respect to the positive control experiments. The
756
compounds (45-47) accounted for the 0.0128, 0.051 and 0.042 % (w/w) in respect to the
757
extracted plant materials, resulting therefore minor components.
30
758
759
7.5. Inhibitory against Plasmodium falciparum
760
It has been reported that sanandajin (56) and kamolonol acetate (57) showed moderate
761
activity against Plasmodium falciparum strain K1, with IC50 values of 2.6 and 16 μM,
762
respectively (Dastan et al., 2012). Compounds (56) and (57) are present in a percentage of
763
0.00134 and 0.00336 % (w/w), respectively, in the raw plant materials.
764
765
7.6. Antineuroinflammatory potential in LPS-activated BV-2 microglial cells
766
Xing and colleagues (2017), tested the isolated compound (61), together with several known
767
metabolites, for the antineuroinflammatory potential in LPS-activated BV-2 microglial cells.
768
Compound (61) showed a moderate inhibition of NO production (IC50 > 50 µ M), whereas the
769
most effective, and also the major constituent, resulted to be the known (3′S,5′S,8′R,9′S,10′R)-
770
kellerin, which significantly inhibited the mRNA expression of several inflammatory factors
771
(TNF-α, IL-6, IL-1β, COX-2) at concentration between 1 and 10 µM. Conversely, the other
772
new sesquiterpene coumarin (62) was not subjected to the bioactivity test, even if isolated in
773
sufficient amount (42.1 mg). The compounds (61), (62) and the known (3′S,5′S,8′R,9′S,10′R)-
774
kellerin accounted for the 0.0036, 0.0087 and 1.5 % (w/w), respectively, of the whole
775
composition of the analyzed gum resin. Considering the relative abundance of
776
(3′S,5′S,8′R,9′S,10′R)-kellerin and its pronounced activity at µmolar concentrations it is quite
777
probable that the biological activity observable in the crude gum resin might be attributable to
778
this single compound. In addition, due to the quite high amount of (3′S,5′S,8′R,9′S,10′R)-
779
kellerin in the raw materials also the extractive approach to obtain the pure compound is
780
applicable.
781
782
7.7. Cytotoxicity
783
The sesquiterpene lactones (117-122) from the ethyl acetate-soluble fraction obtained from a
784
MeOH extract of F. varia (Schrenk) Trautv. roots, along with some known sesquiterpenes
31
785
(dehydrooopodin, oopodin, spathulenol, ferupennin L and 8α-angeloyloxy-10β-hydroxyslov-
786
3-en-6,12-olide), were tested for their cytotoxicity against multidrug-resistant cancer cells,
787
KB-C2 (colchicine-resistant KB) and K562/Adr (doxorubicin-resistant K562) (Suzuki et al.,
788
2007). This study revealed a significant selective cytotoxicity for the compound (120) (IC50
789
value of 15.7 µg/mL) against KB-C2. Differently, compounds (117), (119) and (121) showed
790
enhanced cytotoxicity (IC50 values ranging from 25.4 to 67.8 µg/mL) in the presence of non-
791
toxic concentrations of colchicine (2.5 µM) against the same cell line showing so an
792
interesting synergistic activity which may suggest a possible use in combined therapy.
793
Unfortunately, these new compounds accounted for very low percentages of plant material
794
composition, 0.00014, 0.00078, 0.00078, 0.0018, 0.00028 and 0.00064% (w/w), respectively
795
for (117-122). Therefore, estractive procedure could be not adequate to obtain sufficient
796
amount of these compounds, instead a synthetic approach might be most useful and it could
797
likely be an interesting further challenge for synthetic chemistry.
798
In a different study, the new compounds (135) a sesquiterpene ester and (136), a
799
sesquiterpene coumarins, were tested for their cytotoxicity towards two human colon cancer
800
cell lines, HT-29 and HCT-116, but were found to be not effective (Jabrane et al., 2010)
801
against these cancer cell lines, showing IC50 > 100 μΜ. Conversely, the known coladin,
802
coladonin and 13-hydroxyfeselol, also isolated in the same study and tested toward the same
803
cell lines, showed weak activity with IC50 value of 3.7 ± 1.5, 15.1 ± 1.5, 34.1 ± 2.3 μΜ,
804
respectively, against HTC-116 and 5.4 ± 1.2, 13.3 ± 2.3, 35.4 ± 4.0 μΜ, respectively, against
805
HT-29 cell line. Paclitaxel was used as positive control. The most active compounds, coladin
806
and coladonin, are sesquiterpene coumarins with a structure related to those of (136). The
807
main structural difference of the active compounds is the presence of a double bond between
808
C-8 and C-12, while in (136) C-8 is a quaternary carbon functionalized with a methyl and
809
hydroxyl group in geminal configuration, and this may suggest that the unsaturation in this
32
810
position may enhance the cytotoxic activity. A second structural feature which, on the
811
contrary, exert a lowering of the effectiveness is the presence of the ester function. In fact,
812
coladonin, the less active, has an acetyloxy function in C-3 instead of the alcoholic function
813
present in coladin at the same position. Moreover, the position and the nature of the acidic
814
moiety of the ester functionalization might have a role in lowering the effectiveness of the
815
sesquiterpene coumarins as observed in the derivative (136), bringing an angeloyloxy
816
function in C-13, which showed no efficacy. The new compound (135) accounted for
817
0.00055% and compound (136) for 0.00066% (w/w) of raw plant materials, thus representing
818
minor components. On the contrary the more active components, coladin and coladonin,
819
accounted for 0.0741 and 0.0222% (w/w), respectively, of the whole raw materials
820
composition. Considering the amount of coladin in the plant materials and its low value of
821
IC50 this could be one of the few compounds of which the extraction from the natural source
822
for medicinal purposes might be justifiable also from the economical standpoint.
823
In a similar study by Meng and colleagues (2013a), ferulins B and C (49 and 50), showed a
824
moderate level of cytotoxicity against HepG2 (IC50 = 89 ± 2 and 76 ± 2 μΜ, respectively),
825
and C6 (IC50 = 21 ± 1 and 36 ± 1 μΜ, respectively) cancer cell lines but resulted inactive
826
against the MCF-7 cell line. Also in this case, these two compounds (49 and 50) resulted to
827
be minor components of the raw plant materials, accounting for the 0.001055 and 0.000702%
828
(w/w), respectively.
829
Similar results were obtained also for the new sesquiterpenoids ferulaeone F-H (181, 182 and
830
183) which exhibited a moderate cytotoxicity against HepG2 (IC50 of 86, 87 and 82 μΜ,
831
respectively), MCF-7 (IC50 of 87, 92 and 82 μΜ, respectively), and C6 (IC50 of 65, 59 and 66
832
μΜ, respectively) cancer cell lines (Meng et al., 2013b). Among these terpenoids, the
833
compound (181) resulted to have the higher percentage in the composition of raw materials
834
with the 0.0244 % (while the other accounted for 0.001 and 0.0007% (w/w)). It should be
33
835
also underlined that the relative high value of IC50 recorded in the bioactivity test does not
836
allow classifying it as a compound with sufficiently high activity, so its possible practical use
837
is very unlikely.
838
In a different work, both of the newly characterized compounds, a glucosidic furanone
839
derivative (187) and the γ-hydroxy-senecioic acid (188) showed no cytotoxicity toward the
840
tested cell lines involving human colon carcinoma, HCT-116, human ovary carcinoma,
841
IGROV-1 and human ovary adenocarcinoma, OVCAR-3, in MTT assays (Znati et al., 2014).
842
Finally, latisulfides A-E (166-170) were tested for their in vitro cytotoxic activity against
843
human cancer cell lines including HeLa, HCT116, A2780 and A549 (Soltani et al., 2018). In
844
this relation, the majority of the characterized compounds showed IC50 values > 100 μM and
845
only latisulfide C (168) exerted a moderate cytotoxicity with IC50 values of 49, 65 and 87 μM
846
against HeLa, HCT116 and A2780 cell lines, respectively, but resulted less effective toward
847
A549 cell line. The compound (168) accounted for the 0.0012% of raw materials
848
composition. Also in this case the the relative high value of IC50 and the relative low
849
abundance in the plant materials, suggest a poor practical applicability of this compound.
850
851
7.8. Antibacterial and antimicrobial activity
852
Galal and collaborators (2001) demonstrated that 14-(4'-hydroxybenzoyloxy)dauc-4,8-diene
853
(92), isolated along with jaeschkeanadiol p-hydroxybenzoate, exhibited antibacterial activity
854
toward Staphylococcus aureus (SA) with IC50 values of 1.5 and 3.5 μg/mL, respectively, and
855
methicillin-resistant S. aureus (MRSA) having IC50 values of 2.0 and 4.0 μg/mL,
856
respectively. Tetracycline was used as positive control. The daucane derivative (92)
857
accounted for 0.025% (w/w) of plant materials, while no data about the relative abundance of
858
jaeschkeanadiol p-hydroxybenzoate have been reported in the original article. The easy
859
isolation procedure of (92) from the plant materials plays in favor to the possibility of
34
860
obtaining this compound in pure form and the low values of IC50 against MRSA and SA
861
make it a possible candidate as an antibacterial drug.
862
Actually, jaeschkeanadiol p-hydroxybenzoate, together with other known compounds,
863
namely jaeschkeanadiol vanillate, kuhistanol D and kuhistanol A, were screened for the
864
antimicrobical activity also in a different study by Tamemoto et al. (2001). In particular,
865
these compounds were tested against eight Gram-positive and Gram-negative bacterial
866
species, including methicillin-sensitive and methicillin-resistant S. aureus (MSSA, MRSA).
867
The two jaeschkeanadiol derivatives, exhibited significant activity (MIC comprised between
868
8 and 31 μg/mL) against the Gram-positive S. aureus (MSSA, MRSA), S. epidermidis, E.
869
faecalis, and B. subtilis with efficacies comparable to those of the standard antibiotics,
870
ampicillin (MIC 0.125-2 μg/mL) and chloramphenicol (MIC 2-16 μg/mL). Unfortunately,
871
these compounds were isolated in the order of 2.3 and 2.5 mg, respectively, for
872
jaeschkeanadiol p-hydroxybenzoate and jaeschkeanadiol vanillate, from 600 g of plant
873
materials, thus resulting minor components.
874
The antibacterial activities of the isolated compounds (53-55 and 158-161) were assayed
875
against a panel of bacteria including multidrug-resistant (MDR) and methicillin-resistant
876
Staphylococcus aureus (MRSA), and mostly exhibited weak activities (Liu et al., 2015). The
877
best result obtained in this study was observed for the new compound (158) (yield 0.015%
878
(w/w)) against the multidrug-resistant S. aureus (strain SA-1199B) with a MIC value of 16
879
mg/L, (37 mM) resulting more effective in respect to the antibiotic norfloxacin 32 mg/L, (100
880
mM) used as positive control.
881
Foetithiophene F (174) (yield 0.006% w/w) showed a low antifungal activity against Candida
882
albicans with an MIC value of 200 µg/mL, and its highest antimicrobial activity was
883
observed against the Gram-positive bacteria B. cereus with a MIC value of 50 µg/mL
884
(Chitsazian-Yazdi et al., 2015). The other foetithiophenes C-E (171-173) were either inactive
35
885
or showed higher MIC values, i.e., ranging from 100 to 400 µg/mL. Even if these compounds
886
showed a certain activity it was not so striking that it could justify a possible use.
887
888
7.9. Anti-inflammatory activity
889
The anti-inflammatory activity of sesquiterpene coumarins (31-36) was evaluated (Motai et
890
al., 2004). Almost all of them inhibited the inducible NO-synthase expression more
891
efficiently than quercetin as a positive control (only compound 31 resulted to be less active)
892
in both lipopolysaccharide (LPS) and recombinant mouse interferon-γ-induced inflammation
893
in a murine macrophage-like cell line (RAW 264.7). The recorded IC50 comprised between
894
8.9 and 19.5 μM suggests a great potential as an anti-inflammatory agents. The structural
895
features necessary to exert the observed activity were reconducted to the presence of the
896
following functionalization: α,β-unsaturated ketones; position and configuration of the double
897
bond in the sesquiterpene unit (Z configuration enhances the inhibitory activity).
898
Furthermore, these compounds showed no cytotoxicity in MTT assay. Unfortunately, they
899
accounted for a very little quantity of the raw plant materials (5.9 kg) being isolated in
900
amounts from 4.7 to 40 mg.
901
Other active anti-inflammatory constituents of the Ferula spp. was the newly characterized
902
glucosidic furanone derivative (188) which showed only a moderate inhibitory activity (17 ±
903
1% at 80 µmol/L) but exerted toward a different enzymatic target, the 5-lipoxygenase an
904
enzyme involved in the eicosanoids metabolism catalizing the production of other
905
inflammatory mediators than prostaglandins, such as leukotrienes and lipoxins (Znati et al.,
906
2014). In addition, in this case (188) accounted for a very little percentage of raw plant
907
materials (0.00034% w/w) thus resulting a minor components not easily useful as active
908
compound.
909
910
7.10. Inhibitory behavior of transcription-activating factors for iNOS mRNA
36
911
It has been shown that the four new sesquiterpene coumarins (37-40) inhibited the
912
transcription-activating factors for iNOS mRNA in a dose-dependent manner with IC50 values
913
of 30 ± 2 µM; IC50 = 29 ± 1 µM; IC50 = 31 ± 1 µM; IC50 = 27 ± 2 µM, respectively (Motai
914
and Kitanaka, 2004). The cytotoxic potential of these compounds, tested by the MTT assay,
915
was not significant (3-100 mM), as well. Unfortunately, they were obtained in mg amount
916
(ranging from 13.7 to 23.0) from 5.9 kg of plant materials, thus resulting to be minor
917
components.
918
919
7.11. Antiprolifertive/anticancer activity
920
The antiprolifertive activity of the compounds (114-116) in the estrogen-dependent MCF-7
921
cells was evaluated with contrasting results: Compound (114) and (116) exhibited
922
proliferative activity, whereas (115) showed an antiproliferative action (Lhuillier et al.,
923
2005). Genistein and β-estradiol were used as positive controls. Also in this case the isolated
924
amounts (10.6, 7.5 and 5.6 mg) indicate that these are minor components in plant materials
925
(5.4 kg).
926
On the other hand, Alkhatib et al. (2008) screened the antiproliferative activities of the
927
isolated compounds elaeochytrins A and B (128 and 129, respectively) on K562R human
928
chronic myeloid leukaemia (imatinib-resistant) and DA1-3b/M2BCR-ABL mouse leukemia
929
(dasatinib-resistant) cell lines. According to the findings of this is study, of the two new
930
compounds elaeochytrin A (128) was the more active compound on both cell lines (IC50
931
values 12 and 8 μM, respectively). It was also active against non-resistant human
932
promyelocytic leukemia cells (HL60), having an IC50 value of 13 μM. However, the toxicity
933
toward normal peripheral blood mononuclear cells was not observed at concentrations up to
934
100 μM, while elaeochytrin B (129) showed a low activity (IC50 = 65.0 μM) against DA1-
935
3b/M2BCR-ABL and resulted inactive toward K562R. Compound (128) accounted for 0.28%
37
936
w/w on raw materials and therefore resulted to be contained in a sufficient amoun in the plant
937
materials to justify a practical use i.e. for extractive purposes of the active compound.
938
In addition, Iranshahi et al. (2010a), determined the antiproliferative activity of the isolates
939
against a small panel of cancer cell lines [M14 (human melanoma), MCF-7 (breast
940
carcinoma), T98G (glioblastoma), A549 (lung carcinoma), Saos-2 (osteosarcoma), FRO
941
(thyroid carcinoma), and U937 (leukemic monocyte lymphoma)] using the MTT assay.
942
However, only the already known feselol was found to be active against one cell line (U937),
943
with an IC50 value of 8 μM. Unfortunately, the newly characterized compounds (45-47) were
944
found to be inactive.
945
The antiproliferative activity of the isolated compounds (137-139) was tested against several
946
human tumor cell lines. The new compounds showed varying activities: 2α-acetoxy-6α-p-
947
methoxybenzoyl-10α-hydroxy-jaeschkeanadiol (137) showed very little activity toward
948
A549, HeLa and K562, with IC50 values > 100, 52 ± 2 and 70 ± 6 μM, respectively.
949
However, this compound was more active against HL-60, Jurkat, RS 4;11 and SEM having
950
IC50 values 15 ± 5, 9 ± 4, 27 ± 4 and 27 ± 2 μM, respectively. Furthermore, 2α-hydroxy-6α-p-
951
methoxybenzoyl-10β-acetoxy-jaeschkeanadiol (138) showed promising activity against HL-
952
60 and Jurkat (IC50 values of 24 ± 4 and 34 ± 6 μM, respectively) while for the other cell
953
lines only moderate to little activity was observed with IC50 values ranging from 70 - >100
954
μM. Finally, 8,9-dihydro-8,14-dehydro-9-hydroxyferutinin (139) displayed the best
955
cytotoxicity only against RS 4;11 and SEM cell lines, specifically with IC50 values of 29 ± 4
956
and 35 ± 2 μM, respectively, and exhibited low or moderate activity against the other tested
957
cell lines, with IC50 values ranging from 43 - >100 μM (Dall’Acqua et al, 2011). These active
958
compounds (137-139) resulted present in the analyzed raw plant materials (450 g) with the
959
following amounts, respectively: 21.4, 8.2 and 13.2 mg.
38
960
An inseparable mixture of dihydrofuranocoumarin isomers (66, 67) exerted antiproliferative
961
activity against HT-29 and HCT 116 cell lines, with IC50 values of 0.290.05 and 1.6 ± 0.6
962
μM, respectively (Ben Salem et al., 2013). Unfortunately, in this report no indication about
963
the isolated quantities were provided, therefore it is not possible to estimate their abundance
964
in the plant materials and the potentiality for an effective practical application.
965
Li and colleagues (2014), tested the isolated compounds for their potential antiproliferative
966
activity. Sinkiangenorin C (187) was found to be cytotoxic against the AGS human cancer
967
cell line, with an IC50 value of 37 μM, while sinkiangenorins A and B resulted inactive
968
against all the tested cell lines. Compound (187) was obtained in 9 mg yield from 4.2 kg of
969
plant materials. Therefore, considering that it is a minor component and showed not
970
extremely high bioactivity, its practical use is quite impossible.
971
In a related study, the two new compounds (59, 60) were tested for their antiproliferative
972
activities against K562, HeLa, and AGS human cancer cell lines. Compound (59) showed a
973
moderate cytotoxic activity against the AGS cell line, with an IC50 value of 27 ± 1 μM, while
974
(60) was less effective (IC50 = 63 ± 3 μM), in comparison with the standard drug taxol (IC50 =
975
3.5 ± 0.04 μM) (Li et al., 2015b). Conversely, cell lines K562 and HeLa did not show any
976
appreciable sensitivity towards these compounds (59, 60). Furtermore, in this case these
977
compounds resulted to be only minor components being isolated in 16.0 and 9.0 mg,
978
respectively, from 4.2 kg of raw plant materials.
979
Lastly, the cytotoxic tests of the characterized sulfur containing foetithiophenes C-F (171-
980
173) implied that none of the identified compounds showed cytotoxicity (IC50 > 100 μM)
981
against MCF-7 and K562 cell lines (Chitsazian-Yazdi et al., 2015).
982
Accordingly to the data reported by Li and collaborators (2015a), the compound
983
sinkiangenorin D (58) showed promising anticancer activity in AGS with an IC50 value of 20
984
± 1 μM, while resulted moderately active against HeLa and K562 human cancer cell lines,
39
985
with IC50values of 81 ± 1 and 105 ± 1 μM, respectively. A quantity of 13.0 mg of (58) was
986
obtained from 4.2 kg of plant materials together with ten known metabolites, also present in
987
mg scale.
988
989
7.12. Antioxidant activity
990
The antioxidant potential of a mixture of identified compounds (66, 67) was assessed by
991
some standard assays including DPPH·, ABTS·+, singlet oxygen (1O2) and hydrogen peroxide
992
(H2O2), which resulted in IC50 values of 19, 13, 7.6, and 4.8 μM, respectively (Ben Salem et
993
al., 2013). They showed to be less active in respect to BHT, used as positive control, in both
994
DPPH· and ABTS·+ tests (IC50 = 9.02 ± 0.49 μg/mL and 6.85 ± 0.11 μg/mL, respectively).
995
Conversely, they showed an effectiveness comparable to BHT (IC50 = 7.26 ± 0.13 μg/mL)
996
against singlet oxygen and resulted more active than the positive control (IC50 = 6.38 ± 0.04
997
μg/mL) in hydrogen peroxide assay. The ability to act as antioxidant compounds was
998
attributed to the presence of the OH phenolic function in C-5 of both compounds.
999
Unfortunately, in this report no indication about the isolated quantities were provided,
1000
therefore it is not possible to estimate their abundance in the plant materials and the
1001
potentiality for an effective application.
1002
The new compounds (63 and 64), ferulone A and B, respectively, were tested for their
1003
antioxidant potential in DPPH· assay but showed only a low level of free-radical-scavenging
1004
activity with values of 0.25 and 0.56 mg/mL, respectively, in comparison to that observed for
1005
the positive control (quercetin, 0.004 mg/mL) (Razavi et al., 2016). Their amounts accounted
1006
for 0.0081 and 0.0089% w/w of plant materials.
1007
1008
7.13. The antileishmanial activity
1009
The antileishmanial activities of extract, fractions and pure compounds involving fnarthexone
1010
(51) and fnarthexol (52) together with three known natural compounds, namely
40
1011
umbelliferone, conferone and conferol have been tested (Bashir et al., 2014a). As shown in
1012
this work, the new compounds (51 and 52) showed only moderate activity with IC50 values of
1013
43.77 ± 0.56 and 46.81 ± 0.81 μg/mL, respectively. The most potent antileishmanial activity
1014
observed in this study was attributed to conferol with an IC50 value of 11.51 ± 0.09 μg/mL. It
1015
is interesting to note the different bioactivity level recorded for the two epimers fnartexol (52)
1016
and conferol, because the only structural difference between these two compounds stands in
1017
the opposite configuration at C-5′. This may obviously suggest an important influence of the
1018
stereochemistry at this site (this imply a different configuration of the fused rings in the cis-
1019
form) for what concerns the enhancing of the antileishmanial activity of sesquiterpene
1020
coumarins and could be an useful structural feature in projecting new synthetic active
1021
derivatives. The new fnarthexone (51) and the known fnarthexol (52) were isolated in the
1022
order of mg (18.0 and 24.0, respectively) from 8 kg of plant materials, thus providing a very
1023
low yield. On the contrary, conferol was isolated in huge amount (800 mg) accounting for
1024
0.01 % w/w.
1025
1026
7.14. The ferulosis
1027
In the context of bioactivities ascribed to Ferula spp., it is worth mentioning the case of
1028
“ferulosis”, a lethal haemorragic syndrome affecting sheeps, cattle, horses and goats (and
1029
even humans) (Carta, 1951a) caused by consumption of giant fennel (F. communis L.) (Carta,
1030
1951b; Carta and Delitala, 1951; Carta, 1955). This obviously leads to suffering of the
1031
affected animals that in many cases come to death, together with a negative impact on
1032
economy relying on animal resources. Several cases of ferulosis are reported in Sardinia
1033
(Appendino, 1997). The connection between the toxic symptoms and the consumption of
1034
giant fennel was demonstrated by the Sardinian veterinary Altara (Altara, 1925), who
1035
postulated the existence of two different chemotypes of giant fennel to explain the contrasting
1036
evidences of toxicity. The existence of two different chemotypes, undistinguishable by
41
1037
morphology, has been unambiguously confirmed by several phytochemical studies (Valle et
1038
al., 1986; Appendino et al., 1988a; Appendino et al., 1988b). Furthermore, several analytical
1039
approaches have been conducted to discriminate the two chemotypes on the basis of the
1040
presence (or absence) of specific chemical markers (Sacchetti et al., 2003; Rubiolo et al.,
1041
2006; Alzweiri et al., 2015). Plants of the toxic chemotype showed the presence of prenylated
1042
4-hydroxy-coumarins with haemorragic properties such as ferulenol, 15-hydroxy-ferulenol,
1043
ferprenin. Conversely, these coumarins were not detected from the non-poisonous
1044
chemotype, which instead contained daucane sesquiterpenoids, some of which endowed with
1045
estrogenic properties, i.e. ferutinin (Valle et al., 1986; Appendino et al., 1988a; Appendino et
1046
al., 1988b; Appendino et al., 2001). It is interesting to note that within the toxic chemotype,
1047
highly poisonous plants were also recognized, which contain the polyacetylene falcarindiol
1048
endowed with pronounced antiplatelet activity (Appendino et al., 1993) besides the
1049
prenylated coumarins. In these higly poisonous plants, the contemporaneous presence of both
1050
polyacetylene and prenylated coumarins is most likely responsible of a synergistic toxicity.
1051
Fortunately, the toxic components have been identified and several analytical methods
1052
developed to discriminate between the two chemotypes. This is one clear case which
1053
demonstrates the importance of phytochemical analysis in both natural product studies and
1054
bioactivity and the primary role they have in the analysis of plant raw materials employed in
1055
botanicals, food supplements and phytotherapy (Toniolo et al., 2014).
1056
As just reported, a wide number of the newly described metabolites from Ferula spp. have
1057
been tested for their biological activities. Besides the quite common antioxidant
1058
characteristics, some of these compounds have showed a wide range of activities such as
1059
antimicrobial, antiviral (HIV), antibacterial (against multidrug-resistant and methicillin-
1060
resistant S. aureus) and antiprotozoal (against Leishmania and Plasmodium), thus offering
1061
new potentially useful compounds for the therapeutic treatment of various diseases. This is of
42
1062
potential importance considering that traditional antibiotics are losing their efficacy due to the
1063
emergence of new resistant disease-causing strains. On the other hand, new active molecules
1064
are becoming available for the treatment of diseases that have not been yet considered as
1065
drugs of choice. Furthermore, there are many drugs with reduced therapeutic indices and
1066
therefore high intrinsic toxicity.
1067
The antiprolifertive potential against several human cancer cell lines and the
1068
immunosuppresive activity, exerted by inhibition of the production of several cytokines, have
1069
been observed for several unusual metabolites from Ferula. In addition, there is the
1070
remarkable anti-inflammatory activity displayed by inhibition of both inflammation
1071
mediators and the mRNA expression of inflammatory factors such as iNOS, TNF-α, IL-6, IL-
1072
1β and COX-2. In this context, it is worth mentioning the antineuroinflammatory potential
1073
observed in microglial LPS-activated cells, since inflammatory and oxidative processes are
1074
considered as important factors in the etiopathogenesis of neurodegenerative diseases such as
1075
Alzheimer and Parkinson diseases and Multiple Sclerosis. Previous studies suggested that the
1076
ability to quench the induction of microglial activation might have interesting applications in
1077
several neurodegenerative and neuroinflammatory pathologies (Salemme et al., 2016) since it
1078
is known that microglia-dependent inflammation is strictly associated with the onset of
1079
neurodegenerative
1080
neuroinflammation. Therefore, the Ferula metabolites, which act as inhibitors of microglial
1081
activation, possess interesting potentialities also as possible neuroprotective agents.
1082
It should be also underlined that the majority of these compounds, in particular the newly
1083
described ones, are contained in their natural sources in very little amounts. Therefore, a
1084
possible estractive procedure to obtain them as pure compounds could be quite expensive
1085
considering the low yields that would be obtained. It is obviously not possible to exclude a
1086
priori that in the original works of their first description no exhaustive extraction has been
diseases,
characterized
43
by
increased
oxidative
stress
and
1087
obtained and that further studies in this sense can improve the yields. Anyway, in many cases,
1088
the extraction of the pure compounds seems to be the only possibility to use them because,
1089
given their small presence in the plant material, it is unlikely that they can give a biological
1090
effect when using the plant materials or the crude extract since the effective doses would not
1091
be achieved (Gertsch, 2009). This is an even more probable eventuality for those compounds
1092
which showed high values of IC50 i.e. ≥ 25 μM (Cos et al., 2006). A second limiting
1093
condition is that the majority of the described compounds have been tested only in in vitro
1094
assays. Nothing is known about their fate when administered to a living organism. The
1095
pharmacokinetic profile is an important factor to establish if a compound will be absorbed in
1096
sufficient amount to reach the effective dose and target tissues/organs, if it is metabolized and
1097
inactivated as well as if the eventual metabolites are still active or not. This in our opinion
1098
could be the future development regarding the bioactivity potential of the numerous
1099
metabolites isolated from Ferula species: the study of their pharmacokinetics and in vivo tests
1100
in order to obtain a complete picture of their real therapeutic and toxicological aspects.
1101
8. Propagation of Ferula species
1102
In recent years, the possibility to reproduce plants of Ferula spp. has also been studied by
1103
means of biothechnologic methods. To the date, there are only a few papers dealing with
1104
these aspects. Anyway, we are of the advice that in the future this area of research will be
1105
developed due to the high interest in the active secondary metabolites and the wide uses of
1106
Ferula spp. in the traditional medicine of several countries worldwide together with the
1107
increased interest in the protection of endangered species. Single node explants from F.
1108
orientalis L. were studied by Tuncer (2017) and shoots induction was obtained by culturing
1109
in Murashige/Skoog (MS) medium with the addition of 2,4-dichlorophenoxyacetic acid (2,4-
1110
D) and 6-benzylaminopurine (BAP) (0.5 and 2.0 mg/L, respectively) as plant growth
44
1111
regulators. With this method, the production of three shoots was obtained for each explants,
1112
thus resulting to be a useful in vitro regeneration method. Explants of root, hypocotyl and
1113
cotyledon (embryonal leaves) of F. assa-foetida L. were studied to evaluate the effects of
1114
different variables such as explants type, medium and plant growth regulators (Roozbeh et
1115
al., 2012). The results obtained in this study showed that the best somatic embryogenesis or
1116
the highest percent of induction was obtained from explants of leaves treated with 2,4-D (0.2
1117
mg/L) and KT (kinetin) (0.2 mg/L) in MS medium, while no significant effect was observed
1118
for both explants from cotyledon and hypocotyls. The best indirect somatic embryogenesis
1119
was instead obtained from roots explants treated with 2,4-D (0.5 mg/L) and KT (0.2 mg/L) in
1120
B5 medium. The maximum percentage of seedling development from embryos was found
1121
with simultaneous use of 2,4-D (0.5 mg/L) and KT (0.2 mg/L) as plant growth regulators in
1122
B5 medium, while the highest callogenesis induction was observed in B5 medium added with
1123
naphthaleneacetic acid (NAA) (1 mg/L) and KT (1 mg/L). A similar study was conducted by
1124
Zhu and colleagues (2009) in F. sinkiangensis K. M. Shen to explore the effect of different
1125
culture conditions and hormone combinations on callus induction. In addition, in this study
1126
different explants types were employed involving young cotyledon, hypocotyl and radicles. It
1127
resulted that the optimum medium for hypocotyl induction was MS added with 2,4-D (1.0
1128
mg/L) and KT (1.5 mg/L), while for radicle induction was MS added of NAA (0.5 mg/L) and
1129
BAP (0.5 mg/L) as plant growth regulators. The best subculture medium was MS added with
1130
NAA (1.5 mg/L) and BAP (2.5 mg/L), as well. The results were similar to those reported in
1131
the previous study with F. assa-foetida L. explants. It was observed that NAA, 2,4-D and
1132
BAP resulted to exert the inductive effect, while BAP showed better results than the KT in
1133
the proliferation step, and the GA3 (giberellin A3) had a coinductive role in the process of
1134
subculture embryogenic callus production. Somatic embryos production was also studied in
1135
F. gummosa Boiss. (Bernard et al., 2007) by induction of callus in zygotic embryonic axes in
45
1136
MS medium. The differentiation of tissues was obtained under induction with NAA and after
1137
the exposure to thermo-phototperiod of 16 h of light at 19 °C and 8 h in the dark at 7 °C. The
1138
maturation of embryos and development of plantlets were obtained in MS induction medium
1139
added with NAA or 2,4-D as plant growth regulators. However, better results were obtained
1140
after transfer in hormone free medium, even if a high percentage of abnormal embryos was
1141
recorded. A second study on F. gummosa Boiss. callus and organogenesis induction was
1142
conducted by Sarabadani et al. (2008). Moreover, various organs including roots, cotyledons,
1143
main leaf, hypocotyle, embryo and cutting embryo were used in the induction phase
1144
promoted by various combinations of plant growth regulators. In this relation, cutting
1145
embryos and roots were detected as best explants for callus induction with 1.2 mg/L-1 BAP
1146
and 10 mg/L-1 NAA as plant growth promoter, while shoot organogenesis was observed only
1147
under treatment with 1.5 mg/L-1 BAP and 0.5 mg/L-1 ADS (adenine sulfate) conditions.
1148
A new cryopreservation technique, based on vitrification of internal solutes, has been
1149
developed with the scope of conservation of seeds and embryonic axes obtained from F.
1150
gummosa Boiss. (Rajaee et al., 2012). The plant seeds were cultured to obtain the embryonic
1151
axes which were pre-treated in sucrose cultures prior to cryotreatment with liquid nitrogen by
1152
applying two different encapsulation-dehydration and vitrification methods. The major
1153
survival percentage of cryopreserved materials was obtained when the technique was applied
1154
on embryos. During this study, a higher percentage of germination was also recorded for
1155
embryonic axes in comparison with Ferula seeds subjected to natural germination.
1156
Dormancy break and germination induction were already studied earlier by Nadjafi and
1157
coworkers (2006) on the seeds of the same plant species (F. gummosa Boiss.) which were
1158
subjected to different treatments such as exposure to GA3, acid scarification with H2SO4 or
1159
HNO3, chilling and soaking in water at different temperatures. Accordingly, germination
46
1160
grade was noted after treatment with GA3 and dormancy breaking was efficiently obtained
1161
by chilling at 5 °C for two weeks.
1162
Other two studies which could give interesting information for what concerns the cultivation
1163
and conservation procedures were more recently conducted on F. jaeschkeana Vatke, a
1164
severely threatened medicinal plant native of the Himalayan region by Yaqoob and Nawchoo
1165
(2017b, a). Seed dormancy was interrupted after contemporaneous treatment with kinetin and
1166
dry stratification for 60 days and the higher percentage of germination was obtained after 24
1167
h of treatment with kinetin in sand:soil media (2:1). Differently, higher sprouting and rooting
1168
response in roots cuttings were observed after treatment with GA3 (500 ppm). Furthermore,
1169
the habitat variability impact on the reproductive success was studied. Several morphologic
1170
parameters (such as number of shoots per plant, root tuber dimensions, plant height, basal
1171
leaf length, pinnae number, pinnae length, pinnule length, number of flowering stems per
1172
plant, flowering stem length, sheath number per plant, sheath length, number of umbels,
1173
umbel diameter, umbels per flowering stem, umbellule’s per umbel, number of flowers, fruit
1174
morphology and fruit number) were considered to evaluate the reproductive success of this
1175
plant species. The best environmental conditions were also determined for a possible
1176
cultivation of this species as well as to develop effective strategies in the conservation of the
1177
wild populations and possibly for their sustainable use. In this study, it was concluded that
1178
the better conditions of growth of this species are those of altitudes comprised between 1500
1179
and 2000 m a.s.l..
1180
9. Conclusion and future perspectives
1181
The increasing trend of industrialization and emergence of unknown and persistent diseases
1182
are among the greatest challenges to scientists in near future. Plant derivatives have exhibited
1183
novel therapeutic characteristics as a result of a large number of scientific investigations over
47
1184
the past few decades. Therefore, replacing chemical and synthesized drugs with natural-based
1185
plant products seems highly rational. The genus Ferula is the third largest genus of the
1186
Apiaceae family and comprises about 180 species mainly distributed in Asia, India and
1187
Mediterranean basin. Many of these species are endemic or indigenous entities with a
1188
consolidated use in the traditional medicines of the countries of origin. To date, a large
1189
number of bioactive compounds possessing interesting biological and medicinal activities
1190
have been separated from a wide array of Ferula plants. The present overview describes the
1191
large number of new compounds, which have been identified as components of Ferula
1192
species in recent decades, and makes note of the main ethnobotanical aspects of these species
1193
together with the pharmacological potentialities. The huge number of structures reported,
1194
belonging to different classes of natural products, highlighted the great variability in
1195
secondary metabolites in Ferula spp.. Several of them are metabolites restricted to this genus
1196
and, as such, are useful makers in the chemotaxonomy field. A great number of these new
1197
compounds resulted to be active as antibiotics against drug-resistant bacterial strains offering
1198
so new possible therapeutic approaches and new chemical structures, in comparison with
1199
those of traditional drugs, to develop new semisynthetic derivatives. Several Ferula
1200
metabolites resulted active against different tumor cell lines and, in the majority of the cases,
1201
showing little or no toxicity toward somatic cells. Both these two therapeutic areas, the
1202
microorganisms infections treatment and the chemotherapy of cancer, need new active
1203
molecules since the effectiveness of traditional drugs is decreasing due to the establishment
1204
of resistance and Ferula metabolites have demonstered to posses the potentiality to be
1205
effective drug candidates and to be useful starting materials to develop new semisynthetic
1206
derivatives. The inhibitory action in microglia-mediated neuroinflammation showed by some
1207
of the Ferula components is also worth of mention since this pathologic mechanism is widely
1208
considered responsible of the development of several neurodegenerative diseases. In this
48
1209
specific pharmaceutical field, only a little number of compounds resulted effective and the
1210
search of new active molecules is still in the limelight. Finally yet importantly, is noteworthy
1211
the antiprotozoal activity exerted by some metabolites against Leishmania and Plasmodium.
1212
There are currently very few drugs available for antiprotozoal therapy and the majority have a
1213
reduced therapeutic index due to their intrinsic toxicity. Differently from bacteria the
1214
protozoa offer limited and non-selective molecular targets, and this is one of the reasons why
1215
only a few compounds are currently available as antiprotozoal drugs. Therefore, the
1216
potentialities of Ferula metabolites represent a resource to be exploited in projecting new
1217
antiprotozoal molecules. Moreover, since only a limited number of species have been
1218
analyzed until now, we are of the opinion that several new components, also endowed with
1219
currently unexplored bioactivities, might be discovered in other so far unanalyzed species of
1220
the genus. We are also of the advice that the high pharmaceutical potential of Ferula
1221
metabolites will not go unnoticed by the scientific community and that in the future different
1222
studies will bring new developments, especially in the practical application of the various
1223
biological activities found so far. In conclusion, the presence in Ferula species of unusual
1224
bioactive phytochemicals demonstrates that this genus is a precious source of active natural
1225
products and has great potential in the pharmaceutical and medicinal fields. What is lacking
1226
in the current state of the art, for what concerns the bioactivity tests, is an approach that
1227
effectively assesses the therapeutic potential of these secondary metabolites through studies
1228
conducted in in vivo systems, and above all, investigating the pharmacokinetic aspects of
1229
compounds already resulted active in in vitro experiments. We hope these studies will be a
1230
prevalent aspect of future research.
1231
Acknowledgments
49
1232
Financial support from the Office for Research Affairs of the Islamic Azad University,
1233
Shahrood Branch is gratefully acknowledged.
1234
50
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2119
Table 1
Some endemic and indigenous species of the genus Ferula growing wild in different parts of
the world.
Country
flora
Italy
Number
3
Iran
15
Turkey
9
Tunisia
4
Algeria
2
Pakistan
15
Saudi
Arabia
4
India
3
Endemic/indigenous species
Name
Ferula arrigonii Bocchieri, F. communis L. and F. glauca L.
F. pseudalliacea Rech.f., F. gabrielii Rech.f., F. kashanica Rech.f.,
F. persica Wild., F. macrocolea (Boiss.) Boiss., F. microcolea
(Boiss.) Boiss., F. stenocarpa Boiss. & Hausskn, F. tabasensis
Rech.f., F. behboudiana Rech. f. & Esfand, F. lutensis Rech.f., F.
assa-foetida L., F. sharifii Rech.f., F. serpentinica Rech.f., F.
flabelliloba Rech. f. & Aell. and F. xylorhachis Rech.f.
F. amanicola Hub.-Mor. Et Pesmen, F. anatolica (Boiss.) Boiss., F.
drudeana Korovin, F. halophila Pesmen, F. huber-morathii Pesmen,
F. longipedunculata Pesmen, F. lycia Boiss., F. parva Freyn et
Bornm. and F. tenuissima Hub.-Mor. et Pesmen
F. communis L., F. tingitana L., F. tunetana Pomel ex
Batt. and F. lutea (Poir.) Maire
F. logipes Coss. ex Bonnier and Maury (also named F. cossoniana
Batt.) and F. vesceritensis coss. et Dur.
F. assa-foetida L., F. baluchistanica, F. communis L.,
F. costata, F. hindukushensis, F. jaeschkeanaVatke,
F. kokanica Rgl. et Schmalh., F. lehmannii Boiss.,
F. microloba Boiss., F. narthex (Falc.) Drude,
F.oopoda (Boiss. Et Buhse) Boiss., F. ovina Boiss., F. reppiae,
F. rubicaulis, and F. stewartiana
F. communis var. communis L./var. glauca (L.) Rouy and Camus,
F. ovina (Boiss.) Boiss., F. rutbaensis C.C. Townsend. and
F. sinaica Boiss.
F. narthex (Falc.) Drude, F. thomsoni and F. jaeschkeana Vatke
2120
2121
2122
88
Ref.
(Conti et al., 2005;
Maggi
et
al.,
2009b)
(Mozaffarian,
1996)
(Pesmen,
1972;
Saǧiroǧlu
and
Duman, 2010)
(Jabrane et al.,
2010; Znati et al.,
2012)
(Labed-Zouad et
al., 2015)
(Anonymous;
Yaqoob
and
Nawchoo, 2016)
(Anonymous;
Yaqoob
and
Nawchoo, 2016)
(Hooker, 1897)
Table 2
Remedial traditional, pharmaceutical and medicinal properties of the different species from the genus Ferula growing wild in different parts of the world.
Ferula species
Organ/part
Properties
Different parts
Tonic, spice and as a strong antioxidant, antibacterial, antifungal, anticoagulant, antimicrobial, anti-ulcer, anticonvulsant, antispasmodic, antiinflammatory, antihelmintic, antidiabetic, aphrodisiac, alterative,
hypotensive, sedative, laxative, stimulant, diuretic, neuroprotective and
carminative remedy; widely administered to address asthma, impotence,
bronchitis, flatulence, infection, stomachache, hysteresis; as a flavoring
agent to table sauces and for seasoning the food products, to lower blood
pressure, acting as a vermifuge when its decoction is taken orally
Promising neuroprotective impact against the cultured neurons, a proper
remedy for intestinal parasites, whooping cough, emmenagogue,
influenza, gasterointestinal problems, insects and snake bites, respiratory
malfunctions, an antifertility, antihepatotoxic, antihyperglycemic and
antiviral drug, an acaricide, anticholesterol and anticarcinogenic plant
F. assa-foetida L.
OGR 1
Aerial parts,
flowers, leaves,
seeds, stems and
roots
F. gummosa Boiss.
2
Used as/for;
prescription
mode
Decoction,
extract, row,
air dried, and
fried
Country/continent
Ref.
Iran, Asia
(Mahran et al., 1973; Zargari,
1990; Rafiq Siddiqui et al.,
1995; Sefidkon et al., 1998;
Dehpour et al., 2009; Iranshahy
and Iranshahi, 2011; Mahendra
and Bisht, 2012; Amiri, 2014)
Raw
Iran, Asia
As a flavoring agent and condiment in the vegetarian diet of the Indian
people and in Indian pickles
Effective against amenorrhea when is being chewed
Effective in the treatment of stomach problems, flatulence, chronic,
antibacterial, bronchitis, colic, chorea as well as some neurological
disorders, tonic, as an anti-hysteric, antihemolytic, anti-diarrhea, antiparasitic, antinociceptive, antioxidant, emmenagogue, antispasmodic,
anti-inflammatory, anti-convulsant, decongestant, analgesic, digestive,
expectorant, uterine tonic drug, stimulant, epilepsy, and as an effective
wound healing remedy, to withdraw morphine
Raw
India, Asia
(Heravi, 1967; Mahran et al.,
1973; Samsam Shariat and
Moattar, 1990; SamsamShariat, 1992; Keshri et al.,
1999; Mallikarjuna et al., 2003;
Iranshahy and Iranshahi, 2011;
Kanani et al., 2011; Moghadam
et al., 2013; Ghannadi et al.,
2014; Hadavand Mirzaei and
Hasanloo, 2014; Homayouni
Moghadam et al., 2014;
Fatemikia et al., 2017)
(Guenther, 1952)
Raw
Air dried, raw,
poultice, and
extract
Malaysia, Asia
Iran, Asia
Used as a carminative and softening agent, a proper remedy against
seizure, earache, asthma, headache, chorea, epilepsy and stomachache,
inflammation, in wound healing, and to address liver disorders and
inability; industrial uses: to prepare varnishes and paints of high
Raw
Japan, Iran, Asia
89
(Buddrus et al., 1985)
(Zargari, 1990; Fazly-Bazzaz et
al., 1997; Ramezani et al.,
2001; Eftekhar et al., 2004;
Mandegary et al., 2004;
Iranshahi et al., 2010a; Nabavi
et al., 2010; Kanani et al., 2011;
Mozaffarian, 2012; Amiri,
2014; Mahboubi, 2016)
(Howlett, 1980; Panda, 2003;
Javidnia et al., 2005;
Mortazaienezhad and
Sadeghian, 2006;
OGR
Aerial parts
Roots
F. communis L. 3
Rhizomes
Roasted flower
Fresh kernel
F. foetida Regel
F.
microcolea
(Boiss.) Boiss.
Aerial parts
Roots
Aerial parts,
flowers, leaves,
and stems
Different parts
qualities, as a flavoring agent or emulsifier to food products and
beverages and additive to some detergents and soaps
To address some disorders and diseases like rheumatism, bronchitis,
acne, poor circulation, muscle, aches, stretch marks and to improve
scars, wounds, sores and cuts; serving as a proper aphrodisiac,
antihysteric, anti-diabetic, anti-nociceptive, antiseptic, anti-catarrh, and
as an analgesic drug
Raw, extract
Iran, Asia
Mohammadzadeh Milani et al.,
2007; Miyazawa et al., 2009;
Mahboubi, 2016)
(Sayyah et al., 2001;
Mandegary et al., 2004;
Kouyakhi et al., 2008; Fallah et
al., 2015)
As a medicinal plant from antiquity for the treatment of dysentery, an
antihysteric agent
Acting as a strong female sterilizing agent, an analgesic, anti-helmintic,
and diuretic remedy as well as in the treatment of rheumatism, joins
pains and in hair care
To treat skin disorders
Effective against dysentery and hay fever
Treating of snakebite, hysteria, convulsion, diarrhea, diabetes, dizziness
and stomachache, to improve muscle cramps, to stop bleeding
Edible with high diuretic, antispasmodic and anthelminthic potentials
Effective to cure of backache and rheumatism
As a spice, food additive and flavoring agent and acting as an
antioxidant agent
Raw and dried
Different parts of
the world
Morocco, Africa
(Heywood, 1971;
Mohammadhosseini, 2016)
(Nguir et al., 2016)
Saudi Arabia,
Asia
Some African
countries
Iran, Asia
(Collenette, 1985)
Iran, Asia
(Zargari, 1990; Amiri, 2014)
Lebanon and
Syria, Asia
United States of
America
India, Asia
(Lev and Amar, 2002; Hadidi et
al., 2003)
(Hadidi et al., 2003)
(Sadraei et al., 2001; Radulović
et al., 2013)
(Sadraei et al., 2001; Radulović
et al., 2013)
(Afifi and Abu-Irmaileh, 2000;
Amiri, 2014)
(Zhang and Hu, 1987; Yang et
al., 2006; Xiaojin and Jiang Lin,
2007; Yang et al., 2007; Zhang
et al., 2015; Li et al., 2016;
Xing et al., 2017)
(Yang et al., 2006)
As a tonic aphrodisiac agent 4
Raw
Raw and dried
Dried and
crushed
Raw and dried
Raw, dried,
crushed,
extracts
Raw and dried
F. hermonis Boiss.
Aerial parts
F.
jaeschkeana
Vatke
F.
galbaniflua
Boiss. & Buhse
F.
rubricaulis
Boiss.
F. persica Wild.
Resin
F. sinkiangensis K.
M. Shen
Aerial parts
F. teterrima Kar. &
Kir.
Aerial parts
Recommended as a highly aphrodisiac in the American dietary
supplement protocols
Antiseptic agent
Raw and dried
An additive to candy and to address intestinal malfunctions
Aerial parts
and stems
Aerial parts
and stems
Raw, dried or
powder form
Raw and dried
Iran, Asia
Raw and dried
Xinjiang, China,
Asia
Galbanum
An additive to candy and to address intestinal malfunctions
Aerial parts, roots
To treat lumbago, backache, rheumatism and diabetes; as a potent
carminative, laxative, and antihysteric agent
Having immunopharmacological, anti-inflammatory, antibacterial,
antiulcerative activities as well as remedial properties against stomach
problems along with rheumatoid arthritis; an antioxidant, anti-tumor and
a deodorant agent; in the preparation of a special Chinese food; acting as
neuroinflammation inhibitors5
For the treatment of rheumatoid arthritis along with intestinal (stomach)
problems
90
Raw
Iran, Asia
Iran and Jordan,
Asia
Xinjiang, China,
Asia
(Boulos, 1983; Dioscorides,
2000)
(Zargari, 1990)
(Anonymous, 1948)
Aerial parts
An anti-cholinergic, anti-spasmodic remedy with remarkable smooth
muscle relaxant properties, as a condiment and spice
Air dried, raw,
and extract
Jordan, Asia
Aerial parts and
roots
Aerial parts
In vitro apoptosis and cytotoxic influences 6; antimicrobial impacts
Raw and dried
Iran, Asia
Lowering blood pressure and enhancing intestinal muscle contractibility
in rabbits and to cure inflammation
Kazakhstan, Asia
Aerial parts
To cure peptic disease
Juice, extracts
and essential
oils
Raw and dried
China, Asia
(Tan et al., 2017)
Different parts
Resins
To treat infant colic
An antihysteric agent; used as an effective remedy against insects,
dysentery, feminine sterility, hay fever, colon, asthma, spasm, epilepsy,
rheumatism and malaria
Raw and dried
Raw and dried
Iran, Asia
China, Asia;
African countries
Aerial parts
In the treatment of bronchitis along with rheumatoid arthritis
Raw and dried
Aerial parts
Roots
Raw and dried
Dried powder
Aerial parts
To flavor the local pickles
Ruminant feeding (sheep and cattle); promotion of the rate of animal
fertility
As a sedative drug, effective against abdominal pain and diarrhea
Central Asia (arid
lands)
Turkey, Europe
Turkey, Europe
Raw and dried
Iran, Asia
(Iranshahi et al., 2008)
(Boulos, 1983; Trease and
Evans, 1983; Martinetz and
Lohs, 1988; Habibi et al.,
2006b)
(Motai and Kitanaka, 2005b;
Xing et al., 2017)
(Kartal et al., 2007)
(Miski et al., 1983;
Klevenhusen et al., 2015)
(Lahazi et al., 2015)
Aerial parts
As a sedative drug, effective against abdominal pain and diarrhea
Raw and dried
Iran, Asia
(Lahazi et al., 2015)
Aerial parts
Raw and dried
Iran, Asia
(Saghravanian et al., 2016)
Aerial parts,
flowers and stems
To relief pain due to its impact on different receptors involving
adenosine, cannabinoid and cannabinoid
Known as a strengthening agent and also an appetite stimulator; an
antimicrobial agent
Raw and dried
Turkey, Europe
(Özek et al., 2008)
Roots
Recommended against epilepsy and spasms
Raw and dried
Iran, Asia
(Asili et al., 2009)
Aerial parts
As a strong anti-hysteric, decongestant and anticonvulsant remedy,
effective in treating some neurological disorders and a tonic herbal drug
Raw and dried
Tunisia, Africa
(Eigner and Scholz, 1990; Afifi
and Abu-Irmaileh, 2000; Znati
et al., 2017)
Different parts
Extract, raw
and dried
Extract
Iran, Asia
(Esmaeili et al., 2009)
Underground parts
Representing remarkable antiplasmodial and remedial features against
migraine as well as cough
Spasmolytic activity
Serbia, Europe
(Pavlović et al., 2014)
Aerial parts,
leaves, flowers and
For the treatment of persistent headache, throat infections and fever,
having antioxidant and antibacterial properties
Fresh and dried
Algeria, Africa
(Benchabane et al., 2012;
Labed-Zouad et al., 2015)
F. ovina (Boiss.)
Boiss.
F. iliensis Krasn.
ex Korov
F. syreitschikowii
Koso-Pol.
F. latisecta
Rech. f. & Aell
F.
fukanensis
K.M.Shen
F. orientalis L.
F.
elaeochytris
Korovin
F.
flabelliloba
Rech. F. et Aell
F.
diversivittata
Regel & Schmalh.
F. szowitsiana DC.
7
F. badrakema
Koso-Pol.
F. badrakema
Koso-Pol. and F.
gummosa Boiss.
(Mixed together)
F. oopoda (Boiss.
& Buhse) Boiss.
F. heuffelii Griseb.
ex Heuffel
F.
vesceritensis
Coss. & Dur 8
91
(Al-Khalil et al., 1990; Aqel et
al., 1992; Radulović et al.,
2013)
(Amooaghaie, 2009; Matin et
al., 2014)
(Aqel et al., 1992; Özek et al.,
2017)
F. tingitana L
F.
cupularis
(Boiss.) Spalik et
S. R. Downie
stems
Different parts
Flowers, leaves
and stems
As an abortive plant with high menstruation-inducing properties;
recommended for the treatment of indigestion, fever, pains and sore
throat
To cure ulcer and also to preserve foodstuffs (oil and meat)
Libya, Africa
(Elghwaji et al., 2017)
Dried parts
Iran, Asia
(Alipour et al., 2015)
As one of the potential sources of asafoetida representing traditional and Raw and dried
Iran, Asia
(Kasaian et al., 2016)
medical uses like F. assa-foetida L.
1 Oleo-gum-resin; 2 Known as "Barijeh" and "Ghasni" in the Iranian folk medicine; 3 Giant fennel formerly known as "Narthex" by the Romans; 4 Known as "Lebanese Viagra";5 Due to the
presence of sesquiterpene coumarins; 6 Related to ferutinin isolated from the roots of F. ovina (Boiss.) Boiss.; 7 Known as “Sivas Kasnisi” in Turkish traditional folk medicine; 8 Traditionally
known
as
"Kelkha"
F. alliacea Boiss.
Different parts
Fresh and dried
92
Table 3
Main components of essential oils, oleo-gum-resins, volatile constituents and extracts from different species of Ferula genus growing wild in
different parts of the world.
Plant name (s)
F.
L.
assa-foetida
F. elaeochytris
Korovin
F.
flabelliloba
Rech. F. et Aell
F.
stenocarpa
Boiss.
&
Hausskn
F.
gummosa
Boiss.
Major constituents (%)
Limonene (26.0%), pcymene (14.3%), α-pinene
(8.3%), and
terpinen-4-01 (5.8%)
Nonane (27.1%), α-pinene
(12.7%), and germacrene B
(10.3%)
δ-Cadinene (13.2%), αcadinol (12.0%), and
cadina-4,1(10.0)-dien-8β-ol
(10.9%), and α-pinene
(10.0%)
α-Pinene (48.8%) and βpinene (30.1%)
EO f: Limonene (14.0%), αpinene (13.0%), myrcene
(10.0%), terpinolene
(10.0%), linalool (9.0%), δ3-carene (9.0%), γterpinene (6.0%),
phellandral (5.0%),
butyl isovalerate
(3.0%), α-terpinolene
(2.5%), β-pinene (2.0%),
and hexyl isovalerate
(2.0%)
EE g: β-Pinene (62.0%), αpinene (34.0%), and δ-3carene (4.0%)
PE h: Guaiole (31.0%), βpinene (21.0%), valencene
(14.0%), α-pinene (11.0%),
YEO a
Prevailing
group
Extraction
method
(s)/Solvent
Analysis or
characterization
methods (s)
Organ(s)/Part(s)
Country
1.0
MH b
HD c
GC and GC-MS
Oleo-gum-resin
0.27
NH d
HD
GC-MS
0.87
OS e
HD
0.33
MH
HD
18
MH
HD
Identified
Ref.
Number
%
India
44
97.9
(Garg et al., 1989)
Fruits
Turkey
43
76.7
(Baser et al.,
2000)
GC and GC-MS
Aerial parts
Iran
20
80
(Rustaiyan et al.,
2001b)
GC and GC-MS
Aerial parts
Iran
26
97.8
(Rustaiyan et al.,
2001a)
>30
88
GC-FID and GCMS
Oleo-gum resin
(Sadraei et al.,
2001)
Iran
26
MH
Ether
3
100
25
MH
Petroleum
ether
6
99
93
F.
gummosa
Boiss.
F. ovina (Boiss.)
Boiss.
F.
galbaniflua
Boiss. et Buhse.
F.
microcolea
(Boiss.) Boiss.
F. hirtella Boiss.
F. communis L.
F. persica Wild.
F.
L.
assa-foetida
δ-cadinene (11.0%), and
pyrimidine (10.0%)
ME i: Benzene-1-3dimethyl (38.0%), benzene1-2-dimethyl
(16.0%), benzene ethyl
(12.0%), and benzene-1ethyl-2-methyl (4.0%)
β-Pinene (50.1%), α-pinene
(18.3%), δ-3-carene (6.7%),
α-thujene (3.3%), and
sabinene (3.1%)
Carvacrol (9.0%), α-pinene
(8.2%), geranyl isovalerate
(7.2%), and geranyl
propionate (7.0%)
β-Pinene (46.4%), cischrysanthenyl acetate
(6.1%), (E)-nerolidol
(5.2%), and α-pinene
(2.8%)
β-Pinene (58.8%), cischrysanthenyl acetate
(6.1%), and (E)-nerolidol
(5.2%)
α-Pinene (19.2%), nonane
(13.2%), and β-pinene
(13.0%)
α-Pinene (15.4%), and
thymol (14.9%)
Myrcene (53.5%), and
aristolene (8.5%)
Dill-apiole (57.3%), and
elemicine (5.6%)
(E)-1-Propenyl sec-butyl
disulfide (40.0%), and
germacrene B (7.8%)
(E)-1-Propenyl sec-butyl
disulfide (50.3-59.4%) l
15
NH
MeOH
6-7
MH
HD
GC and GC-MS
Fruits
1.0
OM j
HD
GC-MS
Aerial parts
1.2
4
70
Iran
17
94.6
(Sayyah et al.,
2001)
Iran
43
86.7
(Ghannadi et al.,
2002)
41
87.4
Stem
MH
HD
GC and GC-MS
3.0
Root
1.5
MH
HD
GC and GC-MS
(Rustaiyan and
Monfared, 2002)
Iran
Aerial parts
34
86.1
30
88.9
35
84.8
Iran
0.4
HD
GC, GC-MS and
13C-NMR
Leaves
Corsica
47
95.0
0.2
HD
GC and GC-MS
Aerial parts
Iran
61
93.7
1.13
HD
25
94
NR k
MH
NH
0.8-5.5
SFE m:
Supercritica
l fluid
extraction
GC and GC-MS
NR
Iran
16-22
94
91.899
(Akhgar et al.,
2005)
(Ferrari et al.,
2005)
(Javidnia et al.,
2005)
(Khajeh et al.,
2005)
F. macrocolea
(Boiss.) Boiss.
F.
ferulaoides
Korov.
F.
gummosa
Boiss.
F.
szowitsiana
DC. n
F. latisecta
Rech. f. & Aell
F. persica Willd.
var. persica
F.
szovitsiana
D.C.
β-Pinene (15.9%), α-pinene
(10.4%), and βcaryophyllene (8.6%)
Guaiol (58.8%), (E)nerolidol (10.2%), and αeudesmol (3.0%)
β-Pinene (43.8%), α-pinene
(27.3%), and
myrcene (3.4%)
α-Pinene (12.6%),
germacrene D (12.5%), βpinene (10.1%), epi-αcadinol (8.9%),
myrcene (7.0%),
bicyclogermacrene (5.6%),
and β-phellandrene (5.6%)
(Z)-Ocimenone (32.4%),
(E)-ocimenone (20.3%),
and cis-pinocarvone
(11.4%)
Dimethyl trisulphide
(18.2%), myristicin (8.9%),
dimethyl tetrasulphide
(7.6%), α-terpinyl npentanoate
(5.8%), lavandulyl 2-methyl
butanoate (3.7%), α-terpinyl
isovalerate (3.5%), and αbarbatene (3.1%)
Neryl acetate (33.0%), βcaryophyllene (8.9%), αpinene (8.0%), β-pinene
(6.7%), bicyclogermacrene
(4.5%), caryophyllene oxide
(4.1%), limonene (4.6%),
and α-terpineol (3.2%)
Neryl acetate (41.5%),
bicyclogermacrene (9.0%),
α-pinene (5.5%), β-pinene
(3.9%), γ-cadinene (3.5%),
and calarene (3.2%)
NR
MH
HD
GC-MS
Aerial parts
Iran
42
86.3
(Rustaiyan et al.,
2005)
2.4-3.2
OS
HD
GC-MS
Air-dried roots
Mongolia
42
95.8
(Shatar, 2005)
4.0
MH
HD
GC-MS
Air-dried fruits
Iran
73
96.9
(Ghasemi et al.,
2005)
0.3
SH o
HD
GC and GC-MS
Aerial parts
Iran
23
100
(Habibi et al.,
2006a)
0.4
OS
HD
GC and GC-MS
Aerial parts
Iran
22
87.7
(Habibi et al.,
2006b)
0.15
NH
HD
GC and GC-MS
Root
Iran
39
82.0
(Iranshahi et al.,
2006)
51
97.7
0.18
Stem/Leaves
OM
HD
GC and GC-MS
0.2
Flower/fruits
95
(Dehghan et al.,
2007)
Iran
47
95.9
F.
latisecta
Rech. F. et Aell.
sec-Butyl-(Z)-propenyl
disulphide (65.2%), secbutyl-(E)-propenyl
disulphide (6.8%), and disec-butyl disulphide (2.1%)
2.0
NH
HD
GC and GC-MS
Fruits
Iran
41
88.9
(Iranshahi et al.,
2008)
F.
gummosa
Boiss.
β-Pinene (26.8-69.2%), and
α-pinene (1.4-33.9%)
1.663.85
MH
HD
GC and GC-MS
Fruits
Iran
9-21
79.4100
(Kouyakhi et al.,
2008)
4.0
MH
HD
GC, GC-MS and
13C-NMR
Fruits
Iran
74
98.2
(Asili et al., 2009)
0.94
NH
HD
GC-MS
Aerial parts
Iran
61
98.8
(Dehpour et al.,
2009)
Leaves
60
87.3
Flowers
82
96.8
Fruits
19
68.7
SH
Roots
23
79.7
0.05
SH
Leaves
74
89.8
0.06
SH
95
92.8
0.09
MH
55
79.1
F. badrakema
Koso-Pol.
F.
L.
assa-foetida
F. glauca L. p
β-Pinene (45.8%), α-pinene
(10.9%), cisisolongifolanone (4.1%), βphellandrene (2.7%),
myrcene (2.4%), and
carvacrol methyl ether
(2.4%)
Phenol, 2-methyl-5-(1methyl ethyl) (18.2%), αbisabolol (10.4%), and
arsine triethyl (8.7%)
(E)-Caryophyllene (24.9%),
and caryophyllene oxide
(14.3%)
Germacrene D (14.2%),
myrcene (13.6%), and αpinene (11.7%)
α-Pinene (24.2%), and βpinene (14.7%)
SH
0.020.07
(E)-β-Farnesene (10.0%),
elemicin (9.0%), and
myristicin (7.4%)
F. glauca L.
(E)-Caryophyllene (20.5%),
caryophyllene oxide
(13.9%), and germacrene D
(6.8%)
Germacrene D (16.4%),
myrcene (10.1%), (E)caryophyllene (9.4%), and
α-pinene (6.8%)
α-Pinene (36.6%), β-pinene
(17.8%), and myrcene
(4.1%)
SH
HD
MH
HD
GC-FID and GCMS
GC-FID and GCMS
Italy
Flowers
Fruits
96
Italy
(Maggi et al.,
2009a)
(Maggi et al.,
2009b)
F.
L.
assa-foetida
F. lycia Boiss
F.
Rech.
Aell.
latisecta
f. and
F.
oopoda
(Boiss. & Buhse)
Boiss.
F.
badghysi
Elemicin (9.0%), (E)-βfarnesene (8.4%), αzingiberene (6.9%),
myristicin (6.0%), and βbarbatene (4.0%)
Sample 1 q: (E)-1-Propenyl
sec-butyl disulfide (30.7%),
10-epi-γ-eudesmol (12.7%),
(Z)-1-propenyl sec-butyl
disulfide (12.4%), methyl l(methylthio) propyl
disulfide (10.9%), eudesmol
(7-epi-α) (4.8%), and
agarospirol (2.8%)
Sample 2 r: (E)-1-Propenyl
sec-butyl disulfide (18.8%),
10-epi-γ-eudesmol (18.7%),
(Z)-1-propenyl sec-butyl
disulfide (9.2%), 7-epi-αeudesmol (8.2%),
agarospirol (5.1%), and
methyl l-(methylthio)
propyl disulfide (4.3%)
α-Pinene (59.9%), β-pinene
(19.0%), limonene (3.2%),
and bornyl acetate (2.1%)
sec-Butyl-(Z)-propenyl
disulfide (50.5%),
sesquicineol-2-one (7.2 %),
sec-butyl-(E)-propenyl
disulfide (6.2%), and δcadinene (2.9%)
β-Phellandrene (22.4%),
thymol-methyl ether
(15.3%), and myrcene
(8.7%)
Myrcene (36.1%), βphellandrene (28.2%), and
germacrene D (5.5%)
β-Phellandrene (21.7%),
thymol-methyl ether
0.03
SH
Roots
0.8
NH
HD
GC and GC-MS
Roots
54
76.3
26
98.5
(Mirzaei and
Hasanloo, 2009)
Iran
1.6
26
93.3
NR
MH
HD
GC-MS
Roots
Turkey
36
96.8
(Kose et al., 2010)
0.3
NH
HD
GC-MS
Roots
Iran
14
73.3
(Sahebkar et al.,
2010)
16
97.3
20
98.2
17
95.8
0.9
1.1
Leaves
MH
HD
GC and GC-MS
0.7
Seeds
Leaves
97
Iran
(Akhgar et al.,
2011)
(Korovin.)
F.
hermonis
Boiss.
F. ovina (Boiss.)
Boiss.
F.
foetida
(Bunge) Regel
F.
L.
assa-foetida
(13.8%) and myrcene
(13.5%), α-ylangene
(11.3%)
Myrcene (32.8%), βphellandrene (24.1%), and
germacrene D (6.8%)
α-Pinene (43.3%), αbisabolol (11.1%), and 3,5nonadiyne (4.4%)
Fresh: Limonene (16.9%),
α-pinene (15.2%), βmyrcene (7.7%), cis-βocimene (6.1%),
isosylvestrene (5.1%), and
β-pinene (4.4%)
Dried: α-Pinene (20.2%),
spathulenol (9.6%),
germacrene D (6.3%), βcaryophyllene (5.1%),
α-terpineol (5.0%), and
caryophyllene oxide (4.4%)
2,3,4-Trimethylthiophene
(49.0%), 2,5diethylthiophene (27.5%),
elemicine (8.1%), and αpinene (3.4%)
1-Methylpropyl (1E)-prop1-en-1-yl disulfide (32.8%),
α-pinene (11.3%), 1methylpropyl (1Z)-prop-1en-1-yl disulfide (9.1%),
and β-pinene (6.1%)
1.2
1.5
Seeds
MH
HD
GC-FID, GC-MS
and 13C-NMR
Rhizome and roots
Jordan
0.4
MH
HD
GC and GC-MS
Aerial parts
22
94.7
79
92.8
42
95.0
(Azarnivand et al.,
2011)
Iran
0.25
21
91.1
NH
14
97.3
NH
18
81.3
NR
HD
GC-FID and GCMS
Aerial parts
(Kanani et al.,
2011)
Iran
F. behboudiana
(Rech.
f.
&
Esfand.)
Chamberlain
Sabinene (75.3%), (E)caryophyllene (16.1%), and
α-pinene (2.0%)
MH
13
99.1
F.
flabelliloba
Rech. f. & Aell.
epi-α-Cadinol (17.8%),
(E)-γ-bisabolene (8.0%),
and α-pinene (5.4%)
SH
33
84.2
F. hirtella Boiss.
Germacrene B (15.5%),
SH
16
87.0
98
(Al-Ja'Fari et al.,
2011)
F.
latisecta
Rech. f. & Aell.
bicyclogermacrene (12.9%),
α-pinene (9.9%), γ-elemene
(8.5%), germacrene-D
(8.5%), β-elemene (6.3%),
β-pinene (4.6%), and
limonene (4.4%)
α-Pinene (51.6%), β-pinene
(13.7%), limonene (10.0%),
and sabinene (5.5%)
α-Pinene (33.5%),
spathulenol (8.2%),
citronellyl acetate (5.3%),
and β-elemene (5.1%)
α-Pinene (55.0%),
camphene (20.5%),
limonene (4.8%), limonene
(4.8%), and sabinene
(4.1%)
MH
23
96.9
MH
24
96.6
MH
17
98.7
1-Methylpropyl (1Z)- prop1-en-1-yl disulfide (88.1%),
and 1-methylpropyl (1E)prop-1-en-1-yl disulfide
(5.0%)
NH
8
98.8
F. diversivittata
Regel
&
Schmalh.
Verbenone (69.4%), and arcurcumene (6.2%)
OM
22
87.3
F.
galbaniflua
Boiss. & Buhse
β-Pinene (59.0%), and αpinene (36.6%)
MH
12
99.9
F.
gummosa
Boiss.
β-Pinene (66.3%), α-pinene
(20.3%), and δ-3-carene
(8.6%)
β-Pinene (40.7%), βphellandrene (22.7%), αpinene (16.2%), and δcadinene (7.2%)
α-Pinene (37.3%), and βpinene (36.2%)
MH
10
98.8
MH
16
93.2
MH
18
97.3
F. persica Willd.
var. latisecta
F. persica Willd.
var. persica
F.
szowitsiana
DC.
F.
stenocarpa
Boiss.
&
Hausskn.
F.
hezarlalehzarica
99
Y. Ajani
F. macrocolea
(Boiss.) Boiss.
F.
microcolea
(Boiss.) Boiss.
F.
orientalis
Boiss.
F. ovina (Boiss.)
Boiss.
F. ovina (Boiss.)
Boiss.
F. ovina (Boiss.)
Boiss.
F. ovina (Boiss.)
Boiss.
(Z)-β-Ocimene (41.7%),
and myrcene (35.3%)
α-Pinene (21.9%), β-pinene
(17.8%), (Z)-caryophyllene
(6.2%), caryophyllene oxide
(4.6%), (E)-caryophyllene
(4.4%), and limonene
(4.3%)
α-Pinene (41.2%), nonane
(16.0%), β-pinene (13.8%),
myrcene (4.7%), limonene
(4.4%), and sabinene
(4.3%)
Nonane (45.6%), α-pinene
(32.1%), and 2- methyl
octane (19.4%)
α-Pinene (61.0%), myrcene
(6.3%), limonene (6.3%),
and camphene (5.6%)
α-Pinene (63.8%),
camphene (6.5%), and
limonene (4.9%)
α-Pinene (68.7%), myrcene
(4.7%), camphene (4.2%),
β-pinene (4.2%), and
limonene (4.1%)
MH
11
85.3
MH
18
89.3
MH
16
99.4
NH
12
99.4
MH
16
91.5
MH
11
83.7
MH
12
90.1
F. ovina (Boiss.)
Boiss.
α-Pinene (65.4%), and βpinene (5.1%)
MH
18
92.1
F.
oopoda
(Boiss. & Buhse)
Boiss.
α-Terpinyl acetate (73.3%),
sabinene (19.7%), and αpinene (1.1%)
MH
10
99.0
F. sinkiangensis
K. M. Shen
n-Propyl sec-butyl disulfide
(55.8%)
3.8
26
99.1
F. fukangensis
K. M. Shen
n-Propyl sec-butyl disulfide
(49.8%)
1.2
21
100
NH
HD
GC-MS
100
Seeds
China
(Li et al., 2011)
F. ovina (Boiss.)
Boiss.
n-Propyl sec-butyl disulfide
(53.8%)
F. vesceritensis
coss. et Dur.
Viridiflorol (13.4%), δcadinene (10.1%), and
farnesol (8.1%)
A mixture of 1-sec-butyl-2[(E)-3-(methilthio)
prop-1-enyl] disulphane and
1-sec-butyl-2-[(Z)-3(methilthio) prop-1-enyl]
disulphane (59.4%),
glubolol (12.5%), α-pinene
(8.8%), α-bisabolol (6.1%),
and
β-pinene (3.9%)
2,3,6-Trimethyl benzene
(25.0%), cis-chrysanthenol
(20.8%), α-pinene (10.9%),
and thymol (10.2%)
(E)-1-Propenyl-sec-butyl
disulfide (62.7%), βocimene (21.7%), and βpinene (5.0%)
F. behboudiana
(Rech.
f.
&
Esfand.)
Chamberlain
F. lutea Poiret
F.
L.
F.
L.
assa-foetida
assa-foetida
Sample 1 s: (E)-1-Propenyl
sec-butyl
disulfide (25.5%), (Z)-1propenyl sec-butyl
disulfide (23.0%),
bis [(1-methylthio) propyl]
disulfide (11.0%), bulnesol
(4.3%), agaruspirol (4.0%),
germacerene B (3.2%),
hinesol (2.5%),
and guaiol acetate (2.3%)
Sample 2 t: (Z)-1-propenyl
sec-butyl disulfide (23.9
%), bis [(1methylthio) propyl]
disulfide (19.4%), (E)-1propenyl sec-butyl disulfide
1.8
0.1
OS
25
99.5
HD
GC and GC-MS
Leaves
Algeria
89
96.8
(Benchabane et
al., 2012)
Aerial parts
Iran
27
97.2
(Yousefi et al.,
2011)
0.9
NH
HD
GC, GC-MS, 1HNMR, 13C-NMR,
DEPT, H-HCOSY, C-HCOSY
and HMBC
1.0
OM
HD
GC and GC-MS
Aerial parts
Algeria
21
84.9
(Chibani et al.,
2012)
7.0
NH
HD
GC-MS
Latex
Iran
11
99.9
(Kavoosi et al.,
2012)
41
93.5
2.3
NH
HD
GC and GC-MS
2.85
Seeds
(Mirzaei and
Hasanloo, 2012)
Iran
42
101
97.3
(18.8%),
bulnesol (6.7%), and αbisabolol (3.1%)
F.
heuffelii
Griseb.
ex
Heuffel
F.
L.
assa-foetida
F.
L.
assa-foetida
F.
L.
assa-foetida
Elemicin (35.4%), and
myristicin (20.6%)
epi-α-Cadinol (23.2%),
germacrene B (11.0%), αgurjunene (6.2%), (Z)-1propenyl sec-butyl disulfide
(5.9%), 5-epi-7-epi-αeudesmol (4.9%), δcadinene (4.8%), γ-cadinene
(3.4%), and germacrene D
(3.1%)
(E)-1-Propenyl-sec-butyl
disulfide (62.7%), βocimene (21.7%), and βpinene (5.0%)
OGR v1: (E)-1-Propenyl
sec-butyl disulfide (23.9%),
10-epi-γ-eudesmol (15.1%),
(Z)-1-propenyl sec butyl
disulfide (8.0%), (Z)-βocimene (5.6%), αeudesmol (4.5%),
α-pinene (4.4%), β-pinene
(4.2%), βdihydroagarofuran (4.1%),
γ-eudesmol
(3.5%), guaiol (3.0%),
agarospiral (3.0%),
limonene (2.9%), αphellandrene (2.9%), (E)-βocimene (2.5%), 5-epi-7epi-αeudesmol (2.1%), and βeudesmol (1.1%)
OGR2: (Z)-1-Propenyl secbutyl disulfide (27.7%),
0.08
NH
0.3
SH
NR
NH
9.0
NH
6.0
GC and GC-MS
Underground parts
Serbia
67
94.4
(Pavlović et al.,
2012)
GC-MS
Fruit
Iran
54
96.9
(Bahramia et al.,
2013)
HD
GC-MS
Leaves and latex
Iran
NR
NR
(Kavoosi and
Purfard, 2013)
45
99.7
HD
GC and GC-MS
OGR
Iran
45
99.9
HD
SDSE u
NH
102
(Kavoosi and
Rowshan, 2013)
F.
L.
assa-foetida
F.
microcolea
(Boiss.) Boiss
F.
L.
assa-foetida
F. vesceritensis
Coss. & Dur
F. ovina (Boiss.)
(E)-1-propenyl sec-butyl
disulfide (20.3%), α-pinene
(10.7%), β-pinene
(10.2%), (Z)-β-ocimene
(7.8%), 10-epi-γ-eudesmol
(5.3%),
(E)-β-ocimene (2.9%), and
β-dihydroagarofuran (1.8%)
OGR3: β-Pinene (47.1%),
and α-pinene (21.3%), 1, 2dithiolane (18.6%), nitrite
propyl (3.6%), thionol
(2.6%), (Z)-β-ocimene
(2.4%), and (E)-β-ocimene
(1.4%)
β-Pinene (47.1%), α-pinene
(21.4%), and 1,2-dithiolane
(18.6%), nitrite propyl
(3.7%), thionol (2.6%), and
cis-β-ocimene (2.4%)
α-Pinene (27.3%), β-pinene
(16.4%), nonanal (8.7%), βcaryophyllene (8.5%), and
thymol (6.7%)
(E)-1-Propenyl sec butyl
disulphide (56.0%), 1-(1propenylthio) propyl methyl
disulfide (16.9%), and 1,2dithiolane (5.7%) x
(E)-1-Propenyl sec-butyl
disulfide (28.8%), (Z)-1propenyl sec-butyl disulfide
(14.4%), and 1-(1propenythio) propyl methyl
disulfide
(10.1%) y
β-Pinene (24.3%), α-pinene
(17.3%), limonene (10.0%),
β-myrcene (6.6%), and
carotol (6.1%)
α-Pinene (25.7%), myristcin
4.0
MH
NR
MH
HD
GC and GC-MS
Latex
1.1
MH
HD
GC and GC-MS
ADHP w
45
100
Iran
15
98.5
(Kavoosi et al.,
2013)
Iran
22
93.6
(Amiri, 2014)
14
NR
10.6
NH
HD
GC-MS
Resins
(Divya et al.,
2014)
India
1.9
16
NR
1.4
MH
HD
GC-FID and GCMS
Seeds
Algeria
50
96
(Bouratoua et al.,
2014)
0.28
MH
HD
GC and GC-MS
Aerial parts
Iran
14
100
(Mohammadhosse
103
Boiss.
F. orientalis L.
F.
cupularis
(Boiss.) Spalik et
S. R. Downie
(10.1%), limonene (9.6%),
camphene (9.5%), δ-3carene (9.3%), linalool
(7.4%), and citronellol
(5.6%)
Myristcin (14.7%),
limonene (12.2%),
α-pinene (9.6%), myrcene
(9.5%), endo-fenchyl
acetate (5.7%), and
camphene (4.3%)
α-Pinene (23.9%), limonene
(17.0%), myrcene (16.0%),
camphene (8.3%), myristcin
(4.9%), and bornyl acetate
(4.0%)
Myrcene (26.0%),
α-pinene (17.6%), limonene
(18.4%), camphene (4.3%),
and endo-fenchyl acetate
(3.0%)
α-Cadinol (10.4%), δcadinene (8.1%),
germacrene D-4-ol (6.8%),
epi-α-muurolol (5.9%), and
α-pinene (5.7%)
α-Cadinol (11.7%),
germacrene D-4-ol (11.9%),
δ-cadinene (9.3%), α-pinene
(7.2%), and epi-α-muurolol
(6.1%)
Limonene (25.0%), δ-2carene (15.8%),
sabinene (8.0%), βphellandrene (6.9%), αterpinolene (5.6%), δ-3carene (5.2%), p-mentha-1en-9-ol (2.8%), and γterpinene (2.2%)
β-Pinene (13.9%), βocimene (9.0%),
ini and Nekoei,
2014)
0.24
SFME z
30
95.6
0.33
MWHD aa
20
97.4
28
98.2
69
83.4
HS-SPME
-
ab
Leaves
NR
OS
HD
GC and GC-MS
Flowers
0.36
MH
Flowers
HD
0.45
GC and GC-MS
MH
68
84.3
30
98.6
36
93.7
Iran
Leaves
104
(Ozkan et al.,
2014)
Turkey
(Alipour et al.,
2015)
F. vesceritensis
Coss. & Dur.
bornyl angelate (6.6%),
allo-ocimene (6.1%),
trans-isolimonene (5.8%),
dihydro-linalool acetate
(5.0%),
β-phellandrene (4.2%), pmentha-1,5,8-triene (4.0%),
α-terpinyl isobutyrate
(3.7%), terpin-4-ol (3.4%),
cis-dihydro- α-terpinyl
acetate (3.1%), δ-2-carene
(2.9%), camphene
(2.7%), neo-allo-ocimene
(2.7%), citronellyl nbutyrate
(2.6%), decane (2.4%), and
α-phellandrene (2.4%)
α-Terpinyl isobutyrate
(8.7%), δ-3-carene (8.4%),
bornyl
angelate (7.4%), transsabinol (6.9%), sothol
(6.0%),
p-cymen-9-ol (5.5%),
terpinyl acetate (5.2%),
linalool
isobutyrate (3.4%),
camphor (3.0%), βbourbonene
(2.7%), p-menth-1-en-9-ol
acetate (2.6%), citronellyl
butyrate
(2.6%), myrcenone (2.4%),
trans-sabinyl acetate
(2.2%), and iso-verbanol
acetate (2.2%)
α-Pinene (32%), carotol
(13.9%), fenchyl acetate
(10.4%), α-phellandrene
(8.5%), and aristolene
(5.4%)
α-Phellandrene (24.3%), α-
0.39
OM
1.8
MH
1.6
MH
Stem
HD
GC-FID and GCMS
FF ac
DF ad
105
Algeria
32
91.9
42
97.9
37
88.6
(Labed-Zouad et
al., 2015)
pinene (16.1%), carotol
(10.7%), and elixene (6.3%)
Carotol (18.8%), α-pinene
(11.5%), β-pinene (8.1%),
caryophyllene oxide (7.6%),
fenchyl acetate (7.3%),
aristolene (7.2%), and
elixene (5.4%)
α-Pinene (17.4%), carotol
(10.8%), β-pinene (8.9%),
fenchyl acetate (8.8%), and
aristolene (6.8%)
S1: (E)-Propenyl sec-butyl
disulfide (40.4%), (Z)propenyl sec-butyl disulfide
(23.1%), β-pinene (9.7%),
(E)-β-ocimene (5.5%), and
α-pinene (4.7%) ag
S2: (E)-Propenyl sec-butyl
disulfide (40.3%), (Z)propenyl sec-butyl disulfide
(22.1%), β-pinene (10.7%),
α-pinene (5.0%), n-propyl
sec-butyl disulfide (4.1%),
and (E)-β-ocimene (3.2%)
1.6
OS
FS ae
48
96.4
1.4
MH
DS af
36
87.4
7.79
18
97.4
10.07
24
97.7
ah
S3: (E)-Propenyl sec-butyl
disulfide (44.4%), (Z)propenyl sec-butyl disulfide
(22.8%), β-pinene (9.6%),
(E)-β-ocimene (6.3%), and
α-pinene (4.2%) ai
S4: (E)-Propenyl sec-butyl
disulfide (50.0%), β-pinene
(14.9%), (Z)-propenyl secbutyl disulfide (13.5%), αpinene (5.1%), n-propyl
sec-butyl disulfide (3.6%),
and (E)-β-ocimene (2.6%) aj
S5: (E)-Propenyl sec-butyl
disulfide (49.1%), (Z)-
NH
HD
GC and GC-MS
Resin
(Moghaddam and
Farhadi, 2015)
Iran
8.52
16
97.2
7.39
22
98.9
8.36
19
97.3
106
propenyl sec-butyl disulfide
(12.1%), β-pinene (12.0%),
α-pinene (6.2%), n-propyl
sec-butyl disulfide (3.7%),
and (E)-β-ocimene (2.5%)
ak
S6: (E)-Propenyl sec-butyl
disulfide (37.3%), (Z)propenyl sec-butyl disulfide
(17.8%), β-pinene (11.8%),
α-pinene (6.7%), (E)-βocimene (4.0%), and npropyl sec-butyl disulfide
(2.5%) al
S7: (E)-Propenyl sec-butyl
disulfide (42.6%), (Z)propenyl sec-butyl disulfide
(17.2%), β-pinene (14.4%),
α-pinene (5.1%), n-propyl
sec-butyl disulfide (5.0%),
and (E)-β-ocimene (2.6%)
7.24
27
96.3
8.10
16
98.1
8.53
30
99.0
9.52
26
97.3
42
96.5
am
S8: (E)-Propenyl sec-butyl
disulfide (52.2%), (Z)propenyl sec-butyl disulfide
(13.2%), β-pinene (9.5%),
α-pinene (4.2%), n-propyl
sec-butyl disulfide (4.0%),
and (E)-β-ocimene (2.9%)
an
S9: (E)-Propenyl sec-butyl
disulfide (54.0%) and (Z)propenyl sec-butyl disulfide
(12.7%), β-pinene (8.0%),
α-pinene (5.6%), n-propyl
sec-butyl disulfide (4.0%),
and (E)-β-ocimene (3.0%)
ao
F.
gummosa
Boiss.
γ-Elemene (14.1%),
germacrene B (11.8%), (E)γ-bisabolene (10.7%),
viridiflorene (8.1%), and
0.32
SH
HD
GC and GC-MS
107
Aerial parts
Iran
(Mohammadhosse
ini et al., 2015)
epizonaren (6.2%)
F. lutea (Poir.)
Maire
F.
Boiss.
alliacea
F. communis L.
F. communis L.
Aromadendrene (17.6%),
germacrene B (16.2%), γelemene (6.5%), (E)-γbisabolene (6.3%), and βelemene (5.1%)
δ-3-Carene (72.6%), αpinene (5.8%), myrcene
(5.1%), and α-phellandrene
(4.0%)
10-epi-γ-Eudesmol
(22.3%), valerianol
(12.5%), hinesol (8.3%),
guaiol (7.3%), and Zpropenyl-sec-butyl
trisulphide (6.5%)
α-Pinene (10.5%),
hedycariol (8.4%), and γterpinene (7.6%)
α-Pinene (55.9%), β-pinene
(16.8%), and myrcene
(5.9%)
β-Eudesmol (12.1%), αeudesmol (12.1%), and
hedycariol (10.3%)
(E)-β-Farnesene (9.5%), βcubebene (8.2%), and (E)caryophyllene (7.2%)
Camphor (18.3%), α-pinene
(15.3%), β-eudesmol
(9.3%), caryophyllene oxide
(8.0%), and myrcene (5.0%)
β-Eudesmol (28.1%), δeudesmol (11.1%), and αeudesmol (9.6%)
Dillapiole (7.9%), guaiol
(7.3%), spathulenol (6.8%),
myristicin (6.0%), and Tcadinol (5.9%)
0.4
SH
SFME
0.09
MH
HD
GC(FID), GC-MS
and 13C-NMR
Roots
0.13
OS
HD
GC-MS
Roots
0.13
MH
0.03
MH
HD
39
98.4
Tunisia
9
95.1
(Ben Salem et al.,
2016)
Iran
76
99.5
(Kasaian et al.,
2016)
Flowers
80
95.1
Fruits
102
97.7
GC-FID and GCMS
(Maggi et al.,
2016)
Italy
0.06
OS
Leaves
73
95.5
0.02
SH
Roots
50
70.9
0.18
OS
Flowers
32
97.3
0.15
OS
39
91.3
0.024
OS
20
90.4
HD
GC and GC-MS
Stems
Roots
108
Tunisia
(Nguir et al.,
2016)
F. communis L.
F. akitschkensis
B.Fedtsch.
ex
Koso-Pol.
F. clematidifolia
Koso-Pol.
F.
gummosa
α-Eudesmol (25.2%), βeudesmol (20.7%), δeudesmol (10.1%), and
caryophyllene oxide (7.2%)
Bizerte: Chamazulene
(9.3%), α-humulene (6.4%),
α-cubebene (6.4%) and
caryophyllene
(4.0%)
Rades: α-Terpinene (7.4%)
and germacrene B (7.1%)
Gammarth: α-Eudesmol
(12.3%), caryophyllene
oxide (5.5%), α-pinene
(5.0%), ar-curcumene
(5.0%), γ-cadinene (5.0%)
and γ-terpinene (5.0%)
Soliman:
Sabinene (58.7%), α-pinene
(15.4%), β-pinene (8.5%),
terpinen-4-ol (3.9%),
eremophilene
(1.4%), 2-himachalen-7-ol
(1.3%), and trans-sabinene
hydrate (1.0%)
Myristicin (67.9%), and
elemicine (0.8%)
Myrcene (34.3%), limonene
(30.1%), sabinene (16.5%),
β-phellandrene (7.0%), αpinene (2.5%), and β-pinene
(1.6%)
β-Pinene (36.9%), α-pinene
(29.3%), sabinene
(8.1%),bicyclogermacrene
(5.5%), myrcene (3.9%),
germacrene D (3.2%), and
(3E,5Z)-1,3,5-undecatriene
(2.0%)
β-Pinene (50.1%), α- pinene
(14.9%), δ-3-Carene
0.11
OS
0.022
SH
0.38
SH
Leaves
HD
GC-MS
Leaves
28
94.7
53
88.9
54
78.70
Tunisia
0.22
OS
59
75.5
0.11
OS
97
98.7
0.7
MH
52
98
Stems
21
96.6
Leaves
29
100
Umbels + seeds
HD
0.02
GC and GC-MS
NH
0.1
MH
HD
GLC-MS
0.4
NR
Kazakhstan
MH
HD
GC-MS
109
Resins
Iran
(Schepetkin et al.,
2016)
(Sharopov et al.,
2016)
Tajikistan
Roots
(Rahali et al.,
2016)
33
99.4
17
98
(Fatemikia et al.,
2017)
Boiss.
F.
gummosa
Boiss.
F. tingitana L.
F. iliensis Krasn.
ex Korov
F.
tunetana
Pomel ex Batt.
(6.7%), α-thujene (3.3%),
sabinene (3.1%), and alloocimene (2.9%)
β-Pinene (31.8%), α-pinene
(11.4%), β-eudesmol
(8.9%), and
caryophyllenol (7.4%)
β-Pinene (23.9%), α-pinene
(13.0%), β-eudesmol
(8.4%), and α-bisabolol
(6.7%)
β-Pinene (36.3%), α-pinene
(16.3%), limonene (3.7%),
and α-bisabolol (3.6%)
β-Pinene (20.2%), α-pinene
(8.9%), bornyl acetate
(9.9%), and fenchyl acetate
(8.4%)
β-Pinene (38.6%), α-pinene
(13.0%), β-eudesmol
(7.5%), and fenchyl acetate
(6.9%)
α-Thujene (13.5%), elemol
(8.9%), and cadinol (2.2%)
Cadinol (13.8%), eudesmol
(9.7%), elemol (8.3%), and
α-thujene (2.3%),
(E)-Propenyl sec-butyl
disulfide (15.7-39.4%) and
(Z)-propenyl sec-butyl
disulfide (23.4-45.0%) ap
α-Pinene (39.8%), β-pinene
(11.5%), and (Z)-β-ocimene
(7.5%)
0.22
Roots
31
97.9
0.36
Stems
35
94.2
33
90.9
1.2
MH
HD
GC-MS
Flowers
Iran
0.1
Leaves
34
90.2
14.7
Galbanum
32
98.4
Flowers
28
0.06
OS
HD
GC-MS
(Elghwaji et al.,
2017)
Libya
Leaves
(Najafabadi et al.,
2017)
0.1
OS
NR
NH aq
HD
GC-MS
Dried plant
material
Kazakhstan
25-46
8491.7
(Özek et al., 2017)
0.12
MH
HD
GC, GC-MS and
13C-NMR
Seeds
Tunisia
18
84.6
(Znati et al., 2017)
a
32
YEO: Yield of essential oil; b MH: Monoterpene hydrocarbon; c HD: Hydrodistillation; d NH: Non-terpene hydrocarbon; e OS: Oxygenated sesquiterpene; f EO: Essential oil;
EE: Etheric extract; h PE: Petrolic extract; i ME: Methanol extract; j OM: Oxygenated monoterpene; k NR: Not reported; l Over run 1-9; m SFE: Supercritical fluid extraction; n
Syn. F. khorasanica Rech. F. et Aell. and F. microloba Boiss.; o SH: Sesquiterpene hydrocarbon; p Formerly considered as a subspecies of F. communis; q From Gonabad,
Iran; r From Tabas, Iran; s From Razavi Khorsan Province, Iran (Tabas); t From Kohsorkhe-Kasmar, Iran; u SDSE: Steam distillation solvent extraction method; v OGR: Oleogum-resin; w ADHP: Air-dried herbal parts; x From Pathani, India; y From Irani, India; z SFME: Solvent free microwave extraction; aa MWHD: Microwave hydrodistillation; ab
HS-SPME: Headspace-solid phase microextraction; ac FF: Fresh flowers; ad DF: Dry flowers; ae FS: Fresh stems; af DS: Dry stems; ag S1: From Koohpaye, Iran; ah S2: From
g
110
Jangale Ghaem, Iran; ai S3: From Joopar, Iran; aj S4: From Khomroot, Iran; ak S5: From Pabdana, Iran; al S6: From Rayen, Iran; am S7: From Sardoo, Iran; an S8: From Sirjan,
Iran; ao S9: From Shahr Babak, Iran; ap From flowers, leaves, stems, roots in the flowering period as well as seeds and umbels (fruits) together with roots in the fruiting period;
aq
Mainly composed of sulfur-containing compounds
111
Fig. 1. The photographs taken from F. assa-foetida L., A: in the marginal parts of Semnan
province, Iran; B: separated leaves and flowers; C: fresh aerial parts.
112
Fig. 2. A: Photograph of F. assa-foetida L. taken by E. Karimi (PhD candidate in agriculture)
in the full flowering stage, B and C: local foods prepared by dried stems and aerial parts of F.
assa-foetida L.
113
Fig. 3 Sulfur-containing, aliphatic, cyclic and aromatic compounds identified in the essential oils
of 18 Ferula species: (Z)-1-(sec-butyl)-2-(prop-1-en-1-yl)disulfane (1), 2,3,4-trimethylthiophene
(2), (E)-1-(sec-butyl)-2-(prop-1-en-1-yl)disulfane (3), 2-methyloctane (4), (1R,5R)-4,6,6trimethylbicyclo[3.1.1]hept-3-en-2-one (5), 2,5-diethylthiophene (6), 1,3-dimethyltrisulfane (7),
4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-ol (8), 1,2-di((E)-but-2-en-2-yl)disulfane (9), 2-ethyl3,6-dimethoxybenzaldehyde (10), 3,7-dimethyloct-6-en-1-yl propionate (11) and (E)-hex-1-en-1yl(phenethyl)sulfane (12) (Kanani et al., 2011).
114
Fig. 4. Eight bioactive hemiterpene coumarin derivatives, fesumtuorin A-H (13-20),
separated from F. sumbul (Kauffm.) Hook.f. (Zhou et al., 2000).
115
Fig. 5. The molecular structures of the isolated ferulagol A (21) and ferulagol B (22) in the
extract of F. assa-foetida L. (roots) (El-Razek et al., 2001).
116
Fig. 6. The characterized sesquiterpenoids pallidones A-F (23-28) and isolated in the ethyl
acetate extract obtained from F. pallida Korovin roots (Su et al., 2000).
117
Fig. 7. The molecular structures of the isolated assafoetidnol A (29) and assafoetidnol B (30)
in the extract of F. assa-foetida L. (roots) (Abd El-Razek et al., 2001).
118
Fig. 8. The main bioactive compounds (31-36) separated from F. fukanensis K.M.Shen
(Motai et al., 2004).
119
Fig. 9. The molecular structures of the four sesquiterpene coumarins (37-40) obtained from
the 80% aqueous methanol extract of the roots of F. fukanensis K.M.Shen (Motai and
Kitanaka, 2004).
120
Fig. 10. The molecular structure of saradaferin (41) separated from the EtOAc extract of F.
assa-foetida L. (OGR) (Bandyopadhyay et al., 2006).
121
Fig. 11. The sesquiterpenoid coumarins (42-44) isolated from the ethanol extract obtained
from F. teterrima Kar. & Kir. and F. sinkiangensis K. M. Shen roots (Yang et al., 2006).
122
Fig. 12. The main sesquiterpene derivatives (45-47) characterized in the methanol extract
from the roots of F. gummosa Boiss. (Iranshahi et al., 2010a).
123
Fig. 13. The molecular structures of three newly characterized sesquiterpenoid coumarins,
ferulin A-C (48-50), extracted from the roots of F. ferulaeoides (Steud.) Korov (Meng et al.,
2013a).
124
Fig. 14. The structures of sesquiterpene coumarins (51-52) from F. narthex Boiss (Bashir et
al., 2014a).
125
Fig. 15. The structures of the three sesquiterpenoid coumarins (53-55) separated from the
roots of F. ferulioides (Steud.) Korovin (Liu et al., 2015).
126
Fig. 16. The molecular structures of newly characterized disesquiterpene coumarins (56-57)
separated from F. pseudalliacea Rech.f. (Dastan et al., 2012).
127
Fig. 17. The molecular structure of sinkiangenorin D (58) as a newly characterized
sesquiterpene coumarin separated from the seeds of F. sinkiangensis K. M. Shen (Li et al.,
2015a).
128
Fig. 18. The sesquiterpene coumarins (59-60) isolated from F. sinkiangensis K. M. Shen (Li
et al., 2015b).
129
Fig. 19. The main bioactive compounds (61-62) separated from F. sinkiangensis K. M. Shen
(Xing et al., 2017).
130
Fig. 20. The molecular structures of characterized coumarin esters derivatives (63-64)
separated from F. orientalis L. (Razavi et al., 2016).
131
Fig. 21. The molecular structure of ferulone C (65), a ester coumarin, isolated from roots of
F. persica Wild (Razavi and Janani, 2015).
132
Fig. 22. The molecular structures of the two dihydrofuranocoumarin esters obtained from the
roots of F. lutea (Poir.) Maire, (−)-5-hydroxyprantschimgin (66) and (−)-5-hydroxydeltoin
(67) (Ben Salem et al., 2013).
133
Fig. 23. The molecular structures of kuhistanols A-D (68-71) from F. kuhistanica Korovin
(Chen et al., 2000a).
134
Fig. 24. The molecular structures of the farnesyl hydroxybenzoic acid derivatives (72-75) in
the F. kuhistanica Korovin MeOH extract of roots (Chen et al., 2001).
135
Fig. 25. The main sesquiterpene chromone derivatives (76-80) separated from a watermethanol extract of F. fukanensis K.M.Shen (roots) (Motai and Kitanaka, 2005a).
136
Fig. 26. The molecular structures of the two sesquiterpene chromone derivatives, ferulin D,E
(81-82) extracted from the roots of F. ferulaeoides (Steud.) Korov (Meng et al., 2013a).
137
Fig. 27. The molecular structures of five daucane-type sesquiterpenes (83-87) characterized
in the methanolic extract of F. kuhistanica Korovin (stems and roots) (Chen et al., 2000b).
138
Fig. 28. The molecular structures of the eudesmanolide (88) and carotene (89) derivatives in
the organic extract of F. sinaica Boiss. (Ahmed et al., 2001).
139
Fig. 29. The molecular structure of (1S,4S,5R,6S,7S,10S)-5,10,11-cadinanetriol (90)
separated from an acetone extract of the air-dried ground roots of F. communis L (Appendino
et al., 2001).
140
Fig. 30. The molecular structure of 2,3-α-epoxyjaeschkeanadiol-5-benzoate (91) separated
from a methylene chloride extract of F. hermonis Boiss (roots) (Diab et al., 2001).
141
Fig. 31. The main daucane esters (92-93) separated from a hexane extract of F. hermonis
Boiss (roots) (Galal et al., 2001).
142
Fig. 32. The main daucane esters (94-96) separated from an EtOAc extract of F. kuhistanica
Korovin. (dried fruits) (Tamemoto et al., 2001).
143
Fig. 33. Seventeen bioactive sesquiterpene compounds (97-113) separated from F.
penninervis Regel and Schmalh (Shikishima et al., 2002).
144
Fig. 34. The molecular structures of three daucane sesquiterpenes (1R,4R)-4-hydroxydauca7-ene-6-one (114), (1R,4R)-4-hydroxydauca-7-ene-6,9-dione (115), and (1R,3S,8S)-3-ethoxy8-angeloyloxydauca-4-en-9-one (116), separated from an hexane extract of F. hermonis Boiss
(roots) (Lhuillier et al., 2005).
145
Fig. 35. The molecular structures of the six sesquiterpene lactones (117-122) obtained from
from the roots of F. varia (Schrenk) Trautv. (Suzuki et al., 2007).
146
Fig. 36. The molecular structures of five characterized sesquiterpene derivatives (123-127)
separated from the dichloromethane extract of F. vesceritensis Coss. & Dur, organ: aerial
parts (Oughlissi-Dehak et al., 2008).
147
Fig. 37. The molecular structures of the two sesquiterpene esters obtained from the roots of
F. elaeochytris Korovin, 6-anthraniloyljaeschkeanadiol (elaeochytrin A) (128) and 4βhydroxy-6α-(p-hydroxybenzoyloxy)dauc-9-ene (elaeochytrin B) (129) (Alkhatib et al., 2008).
148
Fig. 38. The molecular structures of the sesquiterpene, badrakemonin (130), obtained from
the roots F. badrakema Koso-Pol (Iranshahi et al., 2009).
149
Fig. 39. The molecular structures of the four sesquiterpene lactones (131-134) obtained from
from the roots of F. diversivittata Regel & Schmalh. (Iranshahi et al., 2010b).
150
Fig. 40. Molecular structures of a characterized ester (135) and a coumarin sesquiterpene
derivative (136) from the roots of F. tunetana Pomel ex Batt (Jabrane et al., 2010).
151
Fig. 41. The molecular structures of three daucane sesquiterpenes (137-139) isolated from the
roots of F. communis subsp. communis (Dall’Acqua et al, 2011).
152
Fig. 42. The molecular structures of three daucane esters (140-142 and 141a) separated from
an n-hexane-ethyl acetate (1:1) extract of the ground seeds of F. hermonis Boiss (Auzi et al.,
2008; Ibraheim et al., 2012a).
153
Fig. 43. The components, sesquiterpene lactone glycosides (143-149), separated from the
water-soluble fraction obtained from the methanol extract of F. varia (Schrenk) Trautv. roots
(Kurimoto et al., 2012b).
154
Fig. 44. bioactive compounds (150-157) separated from a water extract of F. varia (Schrenk)
Trautv roots (Kurimoto et al., 2012a).
155
Fig. 45. The structures of the four sesquiterpene resacetophenones (158-161) separated from
the roots of F. ferulioides (Steud.) Korovin (Liu et al., 2015).
156
Fig. 46. The molecular structures of the four polysulphanes (162-165) isolated from the aerial
parts of F. behboudiana Rech. f. Esfand (Yousefi et al., 2010).
157
Fig. 47. The main bioactive sulfur-containing compounds (166-170) separated from a
dichloromethane extract of F. latisecta Rech.f. & Aellen (Soltani et al., 2018).
158
Fig. 48. The molecular structures of the isolated sulfur-containing compounds
foetithiophenes C-F (171-174) in the petroleum ether extract from the roots of F. foetida
Regel (Chitsazian-Yazdi et al., 2015).
159
Fig. 49. The main bioactive compound, a caffeic acid cinnamyl ester, namely (2E)-3,4dimethoxycinnamyl-3-(3,4-diacetoxyphenyl) acrylate (175) separated from F. assa-foetida L.
(Abd El-Razek, 2007).
160
Fig. 50. Eight bioactive sesquiterpenoids--ferulaeone A-H (176-183)—isolated from
aqueous-ethanol (5:95, v/v) extracts of the roots of F. ferulaeoides (Steud.) Korov (Meng et
al., 2013b).
161
Fig. 51. The molecular structure of the saponin (sandrosaponin XI) (184) isolated from the
root of F. hermonis Boiss. (Ibraheim et al., 2012b).
162
Fig. 52. The molecular structures of steroidal esters sinkiangenorin (185), sinkiangenorin B
(186) and sinkiangenorin C (187), isolated from the seeds of F. sinkiangensis K. M. Shen (Li
et al., 2014).
163
Fig. 53. Two compounds (188, 189) separated from F. lutea (Poir.) Maire (Znati et al., 2014).
164