Applied Microbiology and Biotechnology https://doi.org/10.1007/s00253-018-9329-2 MINI-REVIEW Marine-derived Phoma—the gold mine of bioactive compounds Mahendra Rai 1 & Aniket Gade 1 & Beata Zimowska 2 & Avinash P. Ingle 1,3 & Pramod Ingle 1 Received: 31 May 2018 / Revised: 12 August 2018 / Accepted: 13 August 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract The genus Phoma contains several species ubiquitously present in soil, water, and environment. There are two major groups of Phoma, viz., terrestrial and marine. After 1981 researchers all over the world have focused on marine-derived Phoma for their bioactive compounds. The marine Phoma are very rich sources for novel bioactive secondary metabolites, which could potentially be used as drugs. Recently, a large number of structurally unique metabolites with potential biological and pharmacological activities have been isolated from the marine Phoma species particularly Phoma herbarum, P. sorghina, and P. tropica. These metabolites mainly include diterpenes, enolides, lactones, quinine, phthalate, and anthraquinone. Most of these compounds possess antimicrobial, anticancer, radical scavenging, and cytotoxic properties. The present review has been focused on the general background of Phoma, current approaches used for its identification and their limitations, difference between terrestrial and marine Phoma species. In addition, this review summarizes the novel bioactive compounds derived from marine Phoma and their biological activities. Keywords Phoma . Marine . Secondary metabolites . Bioactive compounds . Biological and pharmacological activities Introduction In recent years, the main goal of both pharmaceutical and agrochemical industries is the discovery of new natural products, which can be used as medicine as well as environmental friendly agrochemicals. From 1981 to 2006, about 68% of antibacterial compounds and 34% of chemotherapeutical agents used in cancer therapy were either natural compounds or their derivatives (Newman and Cragg 2007). These products are naturally derived metabolites from microorganisms, plants, or animals (Garr et al. 2000). This encouraged many investigators to discover structurally novel and/or biologically active compounds. Fungi have been considered as a rich * Mahendra Rai mahendrarai@sgbau.ac.in; pmkrai@hotmail.com 1 Department of Biotechnology, S.G.B. Amravati University, Amravati, Maharashtra 444602, India 2 Department of Plant Protection, Institute of Plant Pathology and Mycology, University of Life Sciences in Lublin, 7 K. St. Leszczyńskiego Street, 20-068 Lublin, Poland 3 Department of Biotechnology, Engineering School of Lorena, University of Sao Paulo, Lorena, Sao Paulo, Brazil source of interesting new natural bioactive compounds from many decades, mainly due to their highly developed and diverse secondary metabolism. Being rich in bioactive secondary metabolites, fungi have attracted a great deal of attention from the researchers (Elissawy et al. 2015). The genus Phoma Sacc. emend. Boerema & G.J. Bollen (Pleosporales) is a ubiquitously distributed taxon belonging to Coelomycetes and always considered to be one of the largest fungal genera (Aveskamp et al. 2008). Initially, it included more than 3000 species (Monte et al. 1991). Such a large number of species described within Phoma were related to the use of nomenclature mainly based on the characteristics of the host plant and the marginalization of micro-morphological properties (Aveskamp et al. 2008). Dutch mycologists studied the comparative morphology of different species of Phoma on different culture media in constant conditions since 1992 led to their division into nine sections (Boerema 1997). As a consequence of 40 years of taxonomic research based on the morphological and cultural characteristics of Phoma species, the number of species was reduced to 223 (Boerema et al. 2004). The highly phylogenetic heterogeneity of the species in the Phoma sections result negated the existing division of the genus into sections and generated the necessity to re-classify (De Gruyter et al. 2009, 2010, 2012; Aveskamp et al. 2010). Nowadays, the genus Phoma sensu lato has been divided into clades rose to the rank of genera Appl Microbiol Biotechnol that comprise species with similar levels of relationships and accommodated within Didymellaceae (Aveskamp et al. 2010; Chen et al. 2015). The terrestrial fungi belonging to Phoma sensu lato are well known phytopathogens, including quarantine species that cause significant loss in commercial crops (Rai and Misra 1981, Smith et al. 1992; Mendes-Pereira et al. 2003; Zimowska 2012; Kövics et al. 2014; Zimowska et al. 2018). These fungi produce structurally diverse secondary metabolites including highly selective as well as less specific (Pedras et al. 1999; Pedras and Biesenthal 2000; Rai et al. 2009). Moreover, within Phoma spp. there are endophytes, which are considered as a rich source of pharmacologically active metabolites (Strobel et al. 2004; Wang et al. 2012; Nicoletti and Fiorentino 2015). Furthermore, Phoma sensu lato complex comprises species and varieties that are recognized as saprophytes (Morgan-Jones and Burch 1988), pathogens of humans (H og et al. 2000; Balis et al. 2006; Rai et al. 2009, 2015), and other vertebrates such as cattle and fish (Costa et al. 1993; Faisal et al. 2007). Different Phoma species occur on land and marine environment. A number of facultative marine species have been reported to produce novel natural products (Sugano et al. 1991, 1994, 1995; H ller et al. 1999; Osterhage et al. 2000; Yarden et al. 2007; Mohamed et al. 2009; Rai et al. 2013). Pawar et al. (1967) described three species of Phoma, viz., P. multipora, P. capitulum, and P. ostiolata from the backish water salt-marsh sediments near Bandra, Bombay coast, India, where mangrove plants like Rhizophora mucronata Lamk., Pemphis acidula Forst. and Avicennia sp. grows. Estuarine sediment inhabitants P. glomerata (Corda) Wollenw. & Hochapfel and P. hibernica Grimes, O’Connor & Cummins were also studied by Borut and Johnson (1962). The intent of this review is to provide insights on the concept of identity, difference between terrestrial and marine Phoma species, and most importantly on the production of bioactive compounds by marine-derived Phoma species. Current concept in identity of Phoma Taxonomically, Phoma has always been considered as one of the most problematic fungal genus by mycologists. As mentioned earlier, initially, the taxonomy was based on host with combination of micromorphological features, mainly shape and size of pycnidia and pycnospores (Saccardo 1880, 1884; Aveskamp et al. 2010). This approach has resulted in the fact that the systematics of the genus has been never fully understood (Aveskamp et al. 2008, 2010). In an attempt to improve the classification, Boerema et al. (2004) proposed to divide the genus into nine sections based on cultural and morphological characteristics of strains, which were studied on three standard media, including the biochemical test (Dorenbosch 1970; Noordeloos et al. 1993). Such a conventional system of identification based on morphological features in vitro conditions is still valid but insufficient because micromorphological features depend on strains, place of origin, and host plants. This results in misidentifications and sometimes creates confusion in determination of identity. Therefore, for the authentic identification of Phoma sensu lato, molecular tools including analysis of nucleotide sequences, protein profiling, and secondary metabolites are considered as most important techniques (Aveskamp et al. 2008, 2010; Rai and Tiwari 2014). The sequencing tools were used to distinguish Boeremia strasseri (Moesz) Aveskamp, Gruyter & Verkley (Basionym Phoma strasseri Moesz) and Boremia exigua (Desm.) Aveskamp, Gruyter & Verkley (Basionym Phoma exigua var. exigua Desm.) isolated from medicinal and aromatic plants in Poland (Zimowska et al. 2018). These two species were primarily based on Boeremean classification and belonged to Phyllostictioides section (De Gruyter et al. 2002). B. exigua var. exigua is a plurivorous, cosmopolitan wound and weakly parasitic fungus, which has been reported on more than 300 hosts (Aveskamp et al. 2009). B. strasseri is a causal agent of black stem-rot of rhizomes and stems of peppermint (Boerema et al. 2004; Zimowska 2012). Based on the assumption of the relatively strict host specificity, appearance on standard media, and minute morphological differences in vitro (de Gruyter et al. 2002; Boerema et al. 2004), it was difficult to distinguish these two species. Both taxa form thin-walled pycnidia, glabrous but sometimes with hyphal outgrowths, usually with a predominated opening or ostiole. Conidia are mainly aseptate, but sometimes twocelled conidia also occur. Furthermore, application of alkaline reagents (KOH, NaOH) on fresh cultures in order to test production of metabolites turned out to be not informative, since in case of B. strasseri as well as B. exigua var. exigua, some strains show positive E+ reaction while some react negatively. Comparison of internal transcribed spacers (ITSs) region sequence, which is widely used in taxonomy and molecular phylogeny (Balmas et al. 2005; Aveskamp et al. 2009; Rai and Tiwari 2014), showed insignificant nucleotide differences in case of B. strasseri and B. exigua var. exigua isolates. The internal transcribed spacers (ITSs) of the rDNA operon ITS (Druzhinina et al. 2005) have been proposed as standard loci for use in DNA barcoding in fungi. However, various studies, including Polish one, indicated on the low discriminatory potency of ITS sequences within the Phoma sensu lato comlex (Abeln et al. 2002). Therefore, the multilocus DNA sequence typing approach was performed, in three additional loci, LSU (partial large subunit DNA 28S), tub 2 (gene region of β-tubulin), and act (gen region of gamma-actin) to enhance the phylogenetic analysis. The most accurate barcode to identify B. strasseri and B. exigua var. exigua was actin (Zimowska et al. 2018), Appl Microbiol Biotechnol which according to Aveskamp et al. (2009) has also been shown to be useful in discriminating among closely related Phoma taxa. Although the molecular techniques can greatly contribute to the taxonomy of Phoma species, the secondary metabolite profiling should also be evaluated as one of the relevant factors, which could be useful to distinguish fungi within Phoma sensu lato complex (Rai and Tiwari 2014). A great number of metabolites isolated from terrestrial species of Phoma have been described as phytotoxins, antimicrobials and mycoherbicides (Aldridge et al. 1967; Sugawara and Strobel 1986; Pedras and Biesenthal 2000; Cimmino et al. 2008; Wang et al. 2012; Rai and Tiwari 2014). Leptosphaeria maculans Ces. & De Not (Basionym Phoma lingam (Tode) Desm), the causal agent of blackleg disease of oilseed rape produces phytotoxic compounds. Up to eight siredosmins have been detected in culture fluids of this fungus (Koch et al. 1989), among which siredosmin Pl (SPL) was the main component (Koch et al. 1989; Pedras and Sguin-Swartz 1992). Siredosmins are non-host-selective and cause chlorotic lesions on leaves and inhibit root growth of host and non -host-plants of L. maculans (Badaway and Hoppe 1989a, 1989b). This species produces a hostselective toxin phomalide (Pedras and Biesenthal 2000), and stress-inducing metabolies, i.e., leptomaculins A and B, diacetyl-leptomaculins A-E, and deacetylsirodesmin PL (Pedras et al. 2008), which have already demonstrated antimicrobial activity. Phoma herbarum Westend, has been typified for genus Phoma (Boerema 1964) and synthesizes brefeldin A, which has been reported as cytotoxic, antiviral, and antifungal agent (Betina 1992). Moreover, two other phytotoxic metabolites— herbarumin I and herbarumin II have been isolated (RiveroCruz et al. 2000). Phytotoxic Phomin and dehydrophomin have been detected in culture filtrate of B. exigua var. exigua. The fungus also produces other cytochalasins i.e., deoxaphomin, proxiphomin, protophomin, p-hydroxybenzaldehyde, cytochalasin A, B, F, Z2 and Z3 and ascosonchine, which were found to be effective herbicidal agents (Scott et al. 1975; El-Kady and Mostafa 1995; Cimmino et al. 2008). Although, B. exigua var. exigua was reported from more than 300 plant species as an opportunistic pathogen, it is continuously being reported as a potential biocontrol agent of different weeds such as Taraxacum officinalis (dandelion) (Stewart-Wade and Boland 2004), Gaultheria shallon (salal) (Zhao and Shamoun 2006), and Cirsium arvense (Scop.) (Canada thistle) (Bithell and Stewart 2001). Furthermore, the isolation of cytochalasins from cultures of Phoma exigua var. heteromorpha (Schulzer & Sacc.) Noordel. & Boerema (Vurro et al. 1997), Coniothyrium multiporum (V.H. Pawar, P.N. Mathur & Thirum.) Verkley & Gruyter (Basionym Phoma multipora V.H. Pawar, P.N. Mathur & Thirum P. (Zhori and Swaber 1994), and Phoma spp. demonstrated these metabolites to be typical for some species of Phoma sensu lato complex. Plenodomus lindquistii (Frezzi) Gruyter, Aveskamp & Verkley (Basionym Phoma macdonaldii Boerema) causes black stem of the sunflower, a widely observed sunflower disease in many countries responsible for economic damage to early-drying sunflower plants (Roustaee et al. 2000). The fungus produces zinniol, a phytotoxin responsible for sunken, discolored lesion on leaves and stems of sunflower (Sugawara and Strobel 1986). Didymella macrostoma (Mont.) Qian Chen & L. Cai (Basionym Phoma macrostoma Mont.) strain 94-44B was isolated from Canada thistle causing shoot and root growth inhibition and severe chlorosis (also called photobleaching) of the foliar parts of many broad-leaved plant species (Bailey et al. 2010). The most susceptible plants belonged to Asteraceae, Brassicaceae, and Fabaceae; whereas, the most resistant plant families were Poaceae, Pinaceae, and Linaceae (Bailey et al. 2011). This fungal strain was targeted for development as a bioherbicide to control broadleaved weeds such as turfgrass in agriculture and agroforestry due to its ability to synthesize thaxtomin A, specific phytotoxin which represents high toxicity to the wide spectrum of weed species (Wolfe et al. 2016). Phoma sensu lato is currently considered as one of the most prominent groups of endophytes and abundant source of novel bioactive compounds with potential for application in medicine, agriculture, and industry (Nisa et al. 2015). So far, several bioactive compounds from endophytic Phoma spp. have been reported. An endophytic Phoma species from guinea (Saurauia scaberrinae) showed to produce important metabolites such as usnic acid, phomodione, and cercosporamide in the culture broth. These compounds demonstrated remarkable activity against Staphylococcus aureus, Pythium ultimum, Sclerotinia sclerotiorum, and Rhizoctonia solani (Hoffman et al. 2008). Elissawy et al. (2015) surveyed literature from 2010 to 2014 for the biologically active secondary metabolites including terpenoids and prenylated polyketides, i.e., meroterpenes obtained from marine-derived fungi. Cytochalasin derivatives and cytochalasin B were isolated from Phoma sp. recovered from jellyfish (Nemopilema nomurai) which showed cytotoxic activity against human solid tumor cell lines (A549, SKOV-3, SK-MEL-2, XF 498, and HCT15) and HeLa cell line, respectively (Kim et al. 2012). The endophytic Phoma species ZJWCFOO6 isolated from Arisaema erubescens in China produce different metabolites that possess strong and moderate antifungal and cytotoxic activities. A compound (3 S)-3,6,7-trihydroxy-α-tetralone, showed antifungal activities, while cercosporaminde, β – Sitosterol trichodermin possess broadspectrum of antifungal and antitumor activities (Wang et al. 2012). Appl Microbiol Biotechnol Difference between terrestrial and marine Phoma and their bioactive compounds Terrestrial Phoma spp. A chemotaxonomic investigation of this genus showed that marine-derived Phoma spp. differ significantly from the terrestrial counterparts with respect to their secondary metabolites (Osterage et al. 2002). Rai et al. (2009) reviewed different secondary metabolites secreted by terrestrial Phoma spp. and discussed their biomedical applications. Some species of Phoma, viz., P. sorghina, P. herbarum, P. exigua var. exigua, P. macrostoma, P. glomerata, P. macdonaldii, P. tracheiphila, P. proboscis, P. multirostrata, and P. foveata secrete weedicidal compounds such as phytotoxin and anthraquinone pigments, and can be used for the formulation of mycopesticides, agrophytochemicals, and dyes. Singh et al. (1998) elucidated the structure of pharmaceutically important metabolites including phomenoic acid, sirodesmins, Phomenolactone, phomactin A, phomasetin, phomadecalins, squalestatin-1 (S1), and squalestatin-2 (S2). The secondary metabolites such as equisetin and phomasetin extracted from Phoma species were evaluated for their antitumor, antimicrobial, and anti-HIV activities (Singh et al. 1998). Moreover, another metabolite, brefeldin A with potential phytotoxic property was isolated from several fungi including P. herbarum. Chemically, it is macrocyclic lactone exhibited broad spectrum antifungal, antiviral, and cytotoxic activity. In addition, it was also observed that Brefeldin A is a significant inhibitor of intracellular protein transport, which plays an important role in structure and function of the Golgi apparatus in animal cells (Betina 1992; Cole et al. 2000). It also acts as inhibitor of protein trafficking in endomembrane system of mammalian cells (Sciaky et al. 1997). Phoma betae isolated from Smallanthus sonchifolius of Asteraceae family produces bioactive diterpenes like aphidicolin (Ichihara et al. 1984; Lin et al. 2003) which inhibits DNA polymerase (Gallo et al. 2008). Shibazaki et al. (2004) isolated a bioactive compound YM-215343 from strain of Phoma QNO4621, which showed fungicidal activity against Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus (MIC values 2–16 μg/mL) as well as cytotoxicity against HeLa S3 cells (IC50 of 3.4 μg/mL). The culture filtrates of Phoma sorghina caused necrosis when spotted on pokeweed leaves and eight other weed species, indicating a non-specific nature (Venkatasubbaiah et al. 1992). Sordarin type diterpene glycosides isolated from various terrestrial Phoma species showed potential efficacy towards inhibition of fungal protein synthesis thereby interacting with the elongation factor 2 (EF2), but only occasionally it was found in marine-derived fungi (Ebel 2010). Benzoic acid derivative (altersolanol A and 2-hydroxy- 6methyl benzoic acid) produced by Phoma sp. recovered from Taxus wallachiana (Himalayan Yew), Singhe-To, Khatmandu, Nepal, showed activity against Bacillus subtilis (Yang et al. 1994). Kong et al. (2014) studied endophytic Phoma sp. OUCMDZ-1847 isolated from the fruits of the mangrove plant Kandelia candel (Rhizophoraceae) occurring in Wenchan, Hainan Province, China. The secondary metabolites (thiodiketopiperazinoids) obtained from Phoma sp. OUCMDZ-1847 showed cytotoxicity against the K562, HL60, and HCT-116 tumor cell lines by the MTT method and against the A549 and MGC-803 tumor cell lines by the SRB method. The authors concluded the necessity of α,β-unsaturated ketone moiety for cytotoxicity and the development of potent thiodiketopiperazinoid anticancer agents. The structurally diverse secondary metabolites such as phytotoxic depsipeptide phomalide, and dioxopiperazines were described by Pedras and Taylor (1993) and (Pedras and Biesenthal 2001), respectively. Further, host-specific sesquiterpene phomalairdenone from terrestrial Phoma sp. which are less common in marine environment were reported (Pedras et al. 1999). This differentiation between marine and terrestrial Phoma sp. and their metabolite contents were confirmed by an HPLC study (Osterhage et al. 2000). Marine Phoma The phylogenetic studies on Phoma spp. have provided evidence of vast differences in marine-derived fungi and their terrestrial counterparts (Vijaykrishna et al. 2006; Jones et al. 2009). Morphological and cultural studies showed that the marine fungi and their terrestrial partners are taxonomically related (Höller et al. 2000; Raghukumar 2008; Wang et al. 2008; Jones et al. 2009). Nonenolides herbarumin I and herbarumin II (Fig. 1(I, II), with 10-membered heterocyclic ring were isolated from Phoma herbarum (West.) which inhibited growth of Amaranthus hypochondriacus (RiveroCruz et al. 2000). Phytotoxic activity of cell-free culture filtrate of P. herbarum FGCC#75 was reported by Vikrant (2002) and Vikrant et al. (2006), against Parthenium hysterophorus, which is due to a chemical 3-nitro-1,2-benzenedicarboxylic acid (3-nitrophthalic acid). In another study, Phomactins (diterpenes) were isolated from a marine Phoma sp. These novel diterpenes inhibited the binding of platelet activating factor (PAF) with its receptors at low concentration (Chu et al. 1992, 1993). Severe phytotoxicity with symptoms of chlorosis, curling, and finally complete collapse of leaves after 2 days of treatment was noted on Lantana camara using cell-free filtrate of P. herbarum FGCC#3 and 4. Highest phytotoxicity was recorded with the benzene extracted thermostable and thermotolerant compounds from P. herbarum FGCC#3 (Kalam et al. 2014). Zhang et al. (2013) studied the proliferative response of IgM antibodies in B-cells by YCP (YCP is the acronym of Yancheng and polysaccharide), a Appl Microbiol Biotechnol Fig. 1 Chemical structures of bioactive compounds recovered from P. herbarum. (I) Herbarumin I and (II) Herbarumin II homogeneous polysaccharide, derived from mycelium of marine fungus Phoma herbarum YS4108. Direct, saturable, and reversible binding of YCP to murine splenic B cells through Toll-like receptors, i.e., TLR2 and TLR4 were reported. This activates intracellular ERK, p38, and JNK along with the nuclear translocation of NF-kB. This study demonstrated the efficient immunomodulatory function of YCP in oncological immunotherapy through TLR-mediated activation of signaling pathways like MAPK and NF-kB (Zhang et al. 2013). YCP, purified from the mycelium of marine P. herbarum YS4108, was responsible for induction of NO production in macrophages through binding of YCP to TLR 4 and CR3 pathways (Chen et al. 2009). Anticancer activity of diphenyl ether analogues and their derivatives derived from marine Phoma sp. CDZ F-11 were evaluated against H1975 cells. Sugano et al. (1991) identified PAF antagonistic activities of Phomactin A (l-O-alkyl-2(R)-(acetyIglyceryl)-3phosphorylcholine) (Fig. 2(I)) present in Phoma sp. (SANK 11486) isolated from the shell of a crab Chionoecetes opilio and collected from the coast of Fukui prefecture, Japan. PAF is responsible for platelet aggregation, chemotaxis and degranulation of polymorphonuclear leukocytes, smooth muscle Fig. 2 Chemical structures of bioactive metabolites recovered from marine Phoma species. (I) Phomactin A. (II) Phomactin B & B1. (III) Phomactin B2. (IV) Phomactin C. (V) Phomactin D Appl Microbiol Biotechnol Fig. 3 Chemical structures of bioactive metabolites recovered from marine Phoma species. (I) Phomactin E (II) Phomactin F. (III) Phomactin G contraction, vascular permeability, and hypotension. They have also reported other PAF-antagonists such as Phomactins B, B1, B2, C, and D (Fig. 2(II–V)) (Sugano et al. 1994) and Phomactins E, F and G (Fig. 3(I–III)) (Sugano et al. 1995). A vast range of secondary metabolites have been isolated from marine Phoma spp. with antimicrobial potential. These include phomadecalins A, B, C, and D, phomapentenone A (Fig. 4(I–III)) (Che et al. 2002), 5-hydroxyramulosin (C 1 0 H 1 2 O 4 ), and 7-methoxycoumarin (C 1 0 H 1 2 O 4 ) (Osterhage et al. 2002), YM-202204 (Fig. 5(I)) (Nagai et al. 2002), Dibutyl phthalate and ono (2ethylhexyl) phthalate (Fig. 5(II–III)) (Bhimba et al. 2012), (7-(γ,γ)-dimethylallyl oxymacrosporin) (Fig. 5(IV)) (Huang et al. 2017), etc. have been recovered. In addition, certain other metabolites having herbicidal activity (e.g., herbarumin I and herbarumin II) (Rivero-Cruz et al. 2000), phagocytic activity (e.g., YCP) (Yang et al. 2005), cytotoxic activity [e.g., epoxyphomalin A and B (Fig. 6(I–II)); phomazines A, B, and C; (Fig. 6(III–V)] (Mohamed et al. 2009; Kong et al. 2014) and PAF antagonistic activities (Sugano et al. 1991, 1994, 1995; Goldring and Pattenden 2004), etc., were also isolated from various marine Phoma species. Moreover, Liu et al. (2003) reported novel metabolites with promising bioactivities from marine Phoma spp. (strain CNC-651). These secondary metabolites mainly include phomoxin, phomoxide, and eupenoxide (Fig. 7(I– III)). Nenkep et al. (2010) also reported the easy recovery of different haloquinones and benzoquinones (e.g., bromochlorogentisylquinones A and B; chlorogentisyl alcohol and gentisyl alcohol; Fig. 8(I–III)) from marine P. herbarum having potential radical scavenging activity. Recently, another secondary metabolite, Cyperin-2-O-®-Dglucoside (Fig. 8(IV)) was isolated from marine Phoma sp. CZD F-11 which showed promising anticancer and antiaromatase activities (Wu et al. 2018). The mangrove endophytic fungus Phoma sp. L28 produces a new anthraquinone, 7-(γ, γ)-dimethylallyloxymacrosporin, along with five known analogues, macrosporin, 7-methoxymacrosporin, tetrahydroaltersolanol B, altersolanol L, and ampelanol, which were isolated for the first time from Phoma sp. L 28. These bioactive secondary metabolites demonstrated remarkable antifungal Fig. 4 Chemical structures of bioactive compounds isolated from marine Phoma sp. NRRL 25697. (I) Phomadecalins A, B & D. (II) Phomadecalin C. (III) Phomapentenone A Appl Microbiol Biotechnol Fig. 5 Chemical structures of secondary bioactive metabolites isolated from marine Phoma sp. Q60596: (I) YM-202204; from P. herbarum VB7: (II) Dibutyl phthalate (III) Mono (2ethylhexyl) phthalate, and from Phoma sp. L28 (IV) 7-(γ,γ)-dimethylallyl oxymacrosporin activity against Colletotrichum musae (Berk. & M. A. Curtis) Arx., Fusarium graminearum Schw., C. gloeosporioides (Penz) Sacc., Penicillium italicum Wehme, F. oxysporum Schlecht. f. sp. lycopersici (Sacc.) W.C. Snyder & H. N. Hansen, and Rhizoctonia solani Kuhn (Huang et al. 2017). Table 1 summarizes the secondary metabolites secreted by different marine Phoma spp. and their wide array of habitats and bioactivities. Mechanism of synthesis of some secondary metabolites Phomactin A A complete mechanism for the synthesis of phomactin A was proposed by Tang et al. (2009), which starts with the Fig. 6 Chemical structures of bioactive metabolites recovered from marine Phoma sp. (I) Epoxyphomalin A. (II) Epoxyphomalin B; and from Phoma sp. OUCMDZ-1847. (III) Phomazine A. (IV) Phomazine B. (V) Phomazine C Appl Microbiol Biotechnol Fig. 7 Chemical structures of bioactive metabolites recovered from marine Phoma spp. (strain CNC-651). (I) Phomoxin. (II) Phomoxide. (III) Eupenoxide intramolecular oxa-[3 + 3] annulation by construction of the ABD-tricycle. To date, two elegant total syntheses of (± ) and (+)-phomactin A have been reported (Goldring and Pattenden 2002; Diaper et al. 2003; Foote et al. 2003; Mohr and Halcomb 2003). They assembled the Diels-Alder cycloaddition reaction and communicated total synthesis of Phomactin A. Further, they were able to oxidize C3-3a olefin of ABD- tricycle and Diels-Alder cycloaddition for the singlet-oxygen, which was achieved selectively to give endoperoxide. Fig. 8 Chemical structures of secondary bioactive metabolites isolated from P. herbarum. (I) Bromochlorogentisylquinones A. (II) Bromochlorogentisylquinones B. (III) Chlorogentisyl alcohol and gentisyl alcohol; and from marine Phoma sp. CZD F-11. (IV) Cyperin2-O-®-D-glucoside Herbarumin I Fürstner et al. (2002) synthesized herbarumin I and II, which are effective herbicides with 10-membered ring lactone. Different marine Phoma derived secondary metabolites and their bioactivities S. Phoma spp N. Source of Phoma sp. Class of compound Bioactive compound and molecular formula Type of biological activity References 1 Marine Phoma spp. Shell of a crab Chionoecetes opilio, coast of Fukui prefecture, Japan Diterpenes Phomactins A, B, B1, B2, D, C, E, F, and G PAF antagonist Sugano et al. (1991, 1994, 1995) 2 P. herbarum Enolides 3 P. tropica Necrotic lesions on dandelion foliage, Zea mays, MichoacaÂn, Mexico, 1998 Inner tissues of marine brown alga Fucus spiralis Inhibition of radicle growth of (7S,8S,9R)-7,8-dihydroxy-9-propyl-5-nonen-9-olide (herbarumin I), seedlings of Amaranthus (2R,7S,8S,9R)-2,7,8-trihydroxy-9-propyl-5-nonen-9-olide (herbarumin hypochondriacus (herbicidal II) agents) Antimicrobial 5-hydroxyramulosin (C10H12O4) 7-methoxycoumarin, (C10H12O4) Osterhage et al. (2002) 4 Phoma sp. NRRL 25697 Isolated from the stromata of Hypoxylon stromata – Phomadecalins A, B, D and C Phomapentenone A Che et al. (2002) 5 Phoma sp. Q60596 – Lactone YM-202204 6 Marine Phoma spp. (strain CNC-651) Marine Phoma spp. Marine microbial mat Eleuthera Island Bahamas Synthetic Cyclic carbonates and oxygenated Polyketide Quinine Phomoxin (C15H22O6), Phomoxide (C14H20O4) Eupenoxide (C14H22O4) Phomactin G (2,3-Dichloro-5,6-dicyano-1,4-benzoquinone) 8 Phoma herbarum YS4108 – Mitogenic polysaccharide YCP (Yancheng and Polysaccharide), 2.4 × 103 kDa, EPS2 9 Marine Phoma sp. – Prenylated polyketides Epoxyphomalin A and B 10 P. herbarum From edible marine red alga Gloiopeitis tenax Haloquinones, benzoquinones Bromochlorogentisylquinones A and B (C7H4BrClO3), Chlorogentisyl alcohol and gentisyl alcohol 11 Phoma sp. SK3RW1M Roots of Avicennia marina Lactone and (Forsk.) Vierh. Of Xanthone Shankou mangrove, derivatives Guangxi, P. R. China 7 – Antibacterial against B. subtilis 200 lg/disk (18, 12, 10, 9 mm zones respectively) S. aureus 200 lg/disk (10, 8, 8 mm zones respectively) Antifungal Antibiotic – Rivero-Cruz et al. (2000) Nagai et al. (2002) Liu et al. (2003) Platelet activating factor (PAF) antagonist Goldring and Pattenden (2004) Increase phagocytic activity of mice Yang et al. in vitro and in vivo, i.e., (2005) immunomodulator, free radical scavenging (antioxidant) Cytotoxicity at nanomolar Mohamed concentrations et al. (2009) Radical scavenging activity 1,8-dihydroxy-10-methoxy-3-methyldibenzo[b,e] oxepine-6,11-dione Cytotoxic acitivity (C16H12O6, 300.0634), 1-hydroxy-8-(hydroxymethyl)-6-methoxy-3-methyl-9H-xanthen-9-one (C16H14O5, 286.0841), 1-hydroxy-8-(hydroxymethyl)-3-methoxy-6-methyl-9H-xanthen-9-one (C16H14O5, 286.0841) Nenkep et al. (2010) Pan et al. (2010) Appl Microbiol Biotechnol Table 1 Table 1 (continued) S. Phoma spp N. Source of Phoma sp. Class of compound Bioactive compound and molecular formula Type of biological activity References 12 Phoma herbarum VB7 From mangrove plant leaves Phthalate Dibutyl phthalate, mono (2ethylhexyl) phthalate (C16H22O4, 278 kDa) Antibacterial activity, weakly cytotoxic activity Bhimba et al. (2012) 13 Phoma sp. OUCMDZ-1847 Mangrove plant Kandelia Thiodiketopiperazines Phomazines Phomazine A (C19H18N2O3S), candel, Wenchan, Hainan Province, China Phomazine B (C20H22N2O3S2), Phomazine C (C18H20N2O8S2) Mangrove plant roots of Anthraquinone 7-(γ,γ)-dimethylallyl oxymacrosporin (C21H20O5) and derivatives Myoporum bontioides A derivative A & C inactive, B moderately cytotoxic Kong et al. (2014) Antifungal activity Huang et al. (2017) Anticancer and antiaromatase Wu et al. (2018) 14 Phoma sp. L28 15 Marine Phoma Zhoushan Archipelago, sp. CZD F-11 China Diphenyl derivative Cyperin-2-O-®-D-glucoside Appl Microbiol Biotechnol Appl Microbiol Biotechnol Usually, these pigments are secreted by P. herbarum. They selected the readily accessible D-ribonolactone acetonide derivative starting material, which was converted into tosylate. This tosylate was then treated with NaOMe in THF which leads to some intermediates, followed by trans-esterification and release of some molecules like oxygen and closure of ring structure. These intermediate products were then exposed to EtMgBr and CuBrâMe2S in THF giving about 60% yield of lactone. Finally, 90% yield of herbarumin I was obtained after the cleavage of acetyl group using dilute aqueous HCl. Herbarumin II Ribose-derived alcohol was used for the synthesis of herbarumin II. The precursor carboxylic acid synthon was prepared by Rhydroxylation of the sodium enolate derivative (Evans et al. 1985). Resulting acid was esterified with alcohol and ruthenium indenylidene complex as a catalyst in refluxing CH2Cl2. This resulted in the lactone about 79% yields. The final treatment of lactone with diluted aqueous HCl resulted in about 84% yield (Fürstner et al. 2002). 5-hydroxyramulosin and 7-methoxycoumarin Islam and colleagues (Islam et al. 2007) presented the concise and lucid description of the synthesis mechanism of isocoumarin derivatives. They further reported one pot synthesis of different isocoumarin derivatives including ramulosin. Esterification of (R,E)-5-hydroxyhex-2-enal with diketene was catalytically promoted by 4-(dimethylamino)pyridine to give β-keto ester at room temperature. The β-keto ester was then treated with potassium carbonate, and 18-crown-6 at room temperature, hemiacetal was obtained. The resulting bicyclic compound was formed after ring opening and aldol condensation. Finally, after the completion of the reactions (−)-mellein, (+)-ramulosin, (−)-Omethylmellein, (−)-6-hydroxymellein, (−)-6-methoxymellein, and (+)-6-hydroxyramulosin were synthesized in short steps as optically active forms. Phomactin G The mechanism of in vitro synthesis of phomactin G is not fully elucidated and therefore, biosynthesis by Phoma species may provide some clues about the underlying the mechanism. The first phase, i.e., cyclase phase of synthesis, where transformation of geranylgeranyl diphosphate (GGDP) into phomacta1(14),3,7-triene, was proposed by Tokiwano et al. (2004). The synthesis mechanism was based on the series of C-labelling experiments and DFT analysis. The reaction starts with the macrocyclization of GGPP to give carbocation, followed by series of methyl and hydride migrations, transforming carbocation into phomacta-1(14),3,7-triene. Transformation includes concurrent transannulation and elimination of carbocation. Conclusions The concept on taxonomy of the genus Phoma has been a problem. However, it has been always a very important genus not only in taxonomic point of view but also as excellent producer of bioactive secondary metabolites. Phylogenetically, the terrestrial Phoma spp. differs from their marine counterparts. There are many secondary metabolites secreted by marine fungi, which have already demonstrated antiviral, antifungal, antibacterial, antiprotozoal, and weedicide activities, and therefore, can be harnessed for the biological control of harmful weeds and also against different microbes. The secondary metabolites may be formulated for different microbial pathogens, and thus may open up new vistas in the field of biocontrol strategy. Funding information This review received financial assistance in the form of Basic Science Research Faculty Fellowship grant No F 18-1/ 2011 (BSR); 30/12/2016 from the University Grants Commission, New Delhi, India. 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