PHYTOCHEMICAL ANALYSIS Phytochem. Anal. 10, 161–170, (1999) Styryl-Lactones from Goniothalamus Species— A Review M. Amparo Blázquez*, Almudena Bermejo, M. Carmen Zafra-Polo and Diego Cortes Departament de Farmacologia, Farmacognosia y Farmacodinamia, Facultat de Farmàcia, Universitat de València, 46100 Burjassot, Valencia, Spain Thirty-one bioactive styryl-lactones, with six different basic skeletons, have been isolated from Goniothalamus species. Aspects of their isolation, structural elucidation, biogenesis and biological activity are reviewed. Copyright # 1999 John Wiley & Sons, Ltd. Keywords: Annonaceae; Goniothalamus; styryl-lactones; isolation; biogenesis; biological activities. INTRODUCTION The family Annonaceae has been reviewed from the point of view of the frequent presence of isoquinoline alkaloids, and more recently on the basis of the restrictive existence of a very active class of natural products, the acetogenins, which are inhibitors of the mitochondrial respiratory chain complex I (Cavé et al., 1997; ZafraPolo et al., 1998). However, this family also produces a wide range of compounds belonging to various phytochemical groups: for example, terpenoid compounds cooccur with isoquinoline alkaloids in some genera, while a group of secondary metabolites commonly named styryllactones have been reported mainly within the genus Goniothalamus (Fig. 1). The first styryl-lactone, the styryl-pyrone goniothalamin (1.1), found within the family Annonaceae was isolated from several species of Goniothalamus (Jewers et al., 1972). This compound had been previously identified from the bark of Cryptocarya caloneura (Lauraceae) (Hlubucek and Robertson, 1967). Indeed, the styryl-pyrone skeleton is most important in a number of primitive Angiosperm families, such as the Lauraceae, Piperaceae, Ranunculaceae, Zingiberaceae and Equisetaceae. Five years later, a novel furano-pyrone derivative (altholactone, 5.1) was identified for the first time in the Annonaceae, from the bark of an unnamed Polyalthia species (Loder and Nearn, 1977). A large number of studies have been carried out to date to isolate new styryllactones, some of which have cytotoxic activity against tumour cells. Within the Annonaceae, the sustained interest in the genus Goniothalamus is due to the presence of a large number of bioactive styryl-lactones which appear to be mainly restricted to this genus. These secondary * Correspondence to: Dr. M. A. Blázquez, Dept. de Farmacol., Farmacog, y Farmacodinamia, Facultat de Farmàcia, Universitat de València, 46100 Burjassot, Valencia, Spain. E-mail: blazquea@uv.es Contract/grant sponsor: Spanish CICYT; Contract/grant number: SAF97-0013. CCC 0958–0344/99/040161–10 $17.50 Copyright # 1999 John Wiley & Sons, Ltd. metabolites include linear, epoxy and cyclic styryllactone derivatives originating from mixed biogenesis involving the shikimic acid and acetate pathways (Fig. 2). The aim of this review is to summarize the current knowledge of the isolation, stereochemistry, biogenesis and biological activity of styryl-lactones in the genus Goniothalamus. The classification is based on the structural characteristics of the six different skeletons as shown in Fig. 1. The identified compounds are presented according to their basic skeleton in Tables 1– 6, followed by the chronological order of identification or, in the case of type 3 structures, by structural analogies with the compound type. Table 7 summarizes the botanical sources from which the styryl-lactones have been isolated. ISOLATION AND STRUCTURAL ELUCIDATION Plant material such as leaves, stem bark, roots or whole plant are typically extracted by maceration with methanol or ethanol at room temperature. Isolations are performed by partitioning the initial extract with hexane, chloroform or dichloromethane and ethyl acetate, followed by repeated silica gel chromatography using flash columns, preparative TLC, Chromatotron1 separations and filtering on gel columns. On TLC layers, compounds may be detected by UV light (254 nm) and spraying with anisaldehyde–sulphuric acid, phosphomolybdic acid or Kedde’s reagent. Analytical methods for the quantitative determination of styryl-lactones from Goniothalamus have not yet been reported. The structural elucidation methods most often reported have been one-dimensional 1H- and 13C-NMR, MS, IR and X-ray crystallography. In addition, two-dimensional NMR experiments involving COSY, COSY-45, HMQC, HMBC and NOESY spectra have been applied. The formation of chemical derivatives has often been used to confirm structural data employing, for example, acetylation by treatment with pyridine and acetic anhydride at room temperature, hydrogenation under an atmosphere of Received 9 November 1997 Accepted 10 April 1998 162 M. AMPARO BLÁZQUEZ ET AL. Figure 1. Styryl-lactone skeletons isolated from the genus Goniothalamus. hydrogen in the presence of an excess of palladium– carbon catalyst at room temperature (Bermejo et al., 1995), and alkoxylation by addition of methanol, ethanol or propanol in sulphuric acid medium (Bermejo et al., 1997). Moreover, Mosher ester derivatives have recently been utilized in determining the absolute stereochemistry of the C-3 chiral centre in styryl-lactones from Goniothalamus (Bermejo et al., 1997). Furthermore, total syntheses have been carried out in order to establish or refine the absolute configuration. dioxygenated styryl-pyrones or goniodiol type; and type 4 — saturated styryl-pyrones or garvensintriol type (Table 1). Goniothalamin (1.1) was identified using an MS degradation sequence and 1H-NMR spectroscopy to compare it with the compound originally isolated from the bark of Cryptocarya caloneura. Although a 6S absolute configuration was originally assigned, the synthesis of 6R (‡) and 6S (ÿ) goniothalamin by several methods (O’Connor and Just, 1986; Bennett et al., 1991) has demonstrated that the natural compound has a 6R configuration. Compound 1.2 was reported to be 5-acetyl goniothalamin (Ahmad et al., 1991), but is more probably 5acetoxy goniothalamin in agreement with data reported from the acetylation of 5-hydroxy goniothalamin (1.3) isolated from the stem bark of G. dolichocarpus and semi-synthesized, together with its diastereoisomer, by reacting 1.1 with selenium dioxide and refluxing with dioxan (Goh et al., 1995). Taking the absolute configuration of 1.1 as 6R, equivalent to 6S in a 5-oxygenated derivative, the absolute configurations of 1.2 and 1.3 are 5S and 6S. In the type 2 styryl-pyrones, goniothalamin oxide (2.1) was assigned a 6S, 7R, 8R configuration by spectral data and based upon the previous 6S assignment of 1.1 (Sam et al., 1987). The results of syntheses of 6R and 6S goniothalamin and the Drieding model suggest that 2.1 probably has a 6R, 7S, 8S configuration. Compound 2.2 could therefore be assigned as 5S, 6S, 7R, 8R and not 7S as previously recorded (Hasan et al., 1994). The absolute stereochemistries of a series of oxygenated goniothalamin homologues (type 3) have been revised because these were also deduced on the basis of goniothalamin having a 6S configuration. The absolute configuration of 3.1 was established by total synthesis (Tsubuki et al., 1992; Surivet et al., 1996) and from circular dichroism studies of the diol and its dibenzoate (Talapatra et al., 1997). The stereochemistry of 3.2 was CLASSIFICATION OF STYRYL-LACTONES Styryl-pyrones The first member of this class, goniothalamin (1.1), has been isolated from barks, roots and the whole plant material of G. andersonii, G. fulvus, G. giganteus, G. macrophyllus, G. malayanus, G. scortechinii, G. sesquipedalis, G. tapis and G. uvaroides (Jewers et al., 1972; El-Zayat et al., 1985; Muhammad et al, 1989; Ahmad et al., 1991; Hasan et al., 1995). This compound can be considered as a biogenetic precursor of the other groups of styryl-lactones. Because of the number of identified compounds and of the species that contain them, styrylpyrones represent to date the most important group of styryl-lactones. The most significant structural differences occur in the degree of oxidation of their aliphatic chain and in the saturation of the pyrone moiety. These characteristics permit the group to be classified under four types: type 1 — 7,8-olefinic styryl-pyrones (C7=C8) or goniothalamin type; type 2 — 7,8-epoxidic styrylpyrones or goniothalamin oxide type; type 3 — 7,8Copyright # 1999 John Wiley & Sons, Ltd. Figure 2. Hypothetical biogenetic pathways to the styryllactones in Goniothalamus. Phytochem. Anal. 10: 161–170 (1999) STYRYL-LACTONES FROM GONIOTHALAMUS SP. 163 Table 1. Styryl-pyrones from Goniothalamus Substituents 1 1.1 7,8-Ole®nic styryl-pyrones, ªgoniothalamin typeº Goniothalamin R=H 1.2 1.3 5-Acetoxy-goniothalamin 5-Hydroxy-goniothalamin Absolute con®gurationa Molecular formula M‡ Goniothalamus sp. (reference) 6R C13H12O2 200 5S, 6S 5S, 6S C15H14O4 C13H12O3 258 216 G. andersonii (Jewers et al., 1972) G. borneensis (Cao et al., 1998) G. fulvus (Muhammad et al., 1989) G. giganteus (El-Zayat et al., 1985) G. macrophyllus (Jewers et al., 1972) G. malayanus (Jewers et al., 1972) G. scortechinii (Muhammad et al., 1989) G. sesquipedalis (Hasan et al., 1995) G. tapis (Muhammad et al., 1989) G. uvaroides (Ahmad et al., 1991) G. uvaroides (Ahmad et al., 1991) G. dolichocarpus (Goh et al., 1995) 2 2.1 2.2 7,8-Epoxidic styryl-pyrones, ªgoniothalamin oxide typeº Goniothalamin oxide R=H 6R, 7S, 8S C13H12O3 5-Acetoxy-isogoniothalamin R=OAc 5S, 6S, 7R, C15H14O5 oxide 8R 216 274 G. macrophyllus (Sam et al., 1987) G. sesquipedalis (Hasan et al., 1994) 3 3.1 7,8-Dioxygenated styryl-pyrones, ªgoniodiol typeº 6R, 7R, 8R Goniodiol R1=R2=R3=H C13H14O4 234 3.2 7-Acetyl-goniodiol R1=R3=H; R2=Ac 6R, 7R, 8R C15H16O5 276 3.3 3.4 8-Acetyl-goniodiol Goniodiol diacetate R1=R2=H; R3=Ac R1=H; R2=R3=Ac 6R, 7R, 8R 6R, 7R, 8R C15H16O5 C17H18O6 276 318 G. giganteus (Fang et al., 1991a) G. gri®thii (Talapatra et al., 1985) G. sesquipedalis (Talapatra et al., 1985) G. amuyon (Wu et al., 1991) G. gri®thii (Talapatra et al., 1985) G. sesquipedalis (Talapatra et al., 1985) G. amuyon (Wu et al., 1992) G. gri®thii (Talapatra et al., 1985) G. sesquipedalis (Talapatra et al., 1985) 3.5 Goniotriol R1=OH; R2=R3=H 5S, 6R, 7R, 8R C13H14O4 250 3.6 8-Acetyl-goniotriol 3.7 Etharvendiol R1=OH; R2=H; 5S, 6R, 7R, C15H16O6 R3=Ac 8R R1=OEt; R2=R3=H 5S, 6R, 7R, C15H18O5 8R 4 4.1 Saturated styryl-pyrones, ªgarvensintriol typeº Garvensintriol Ð a R=OAc R=OH 5S, 6R, 7S, C13H16O5 8S 292 G. amuyon (Wu et al., 1992) G. giganteus (Alkofahi et al., 1989) G. sesquipedalis (Talapatra et al., 1985) G. giganteus (Fang et al., 1990) 278 G. arvensis (Bermejo et al., 1998) 252 G. arvensis (Bermejo et al., 1998) For de®nitive absolute con®gurations see references given in the text Copyright # 1999 John Wiley & Sons, Ltd. Phytochem. Anal. 10: 161–170 (1999) 164 M. AMPARO BLÁZQUEZ ET AL. Table 2. Furano-pyrones from Goniothalamus Substituents Absolute con®gurationa Molecular formula M‡ 5 a,b-Unsaturated furano-pyrones, ªaltholactone typeº 5.1 Altholactone (= goniothalenol) Ð 2R, 3R, 3aR, 7aS C13H12O4 232 G. G. 5.2 Isoaltholactone Ð 2S, 3S, 3aR, 7aS C13H12O4 232 G. G. G. G. 5.3 2-Epi-altholactone Ð 2S, 3R, 3aR, 7aS C13H12O4 232 G. 6 Saturated furano-pyrones, ªgoniofupyrone typeº 6.1 Goniofupyrone R=OH 6.2 Goniotharvensin 6.3 Etharvensin R=H R=OEt 6.4 Arvensin R=OH a 2R, 3R, 3aS, 7aS, 7R* 2R, 3R, 3aR, 7aS 2R, 3R, 3aS, 7aS, 7R 2R, 3R, 3aS, 7aR, 7R Goniothalamus sp. (reference) arvensis (Bermejo et al., 1995) giganteus (El-Zayat et al., 1985) arvensis (Bermejo et al., 1995) malayanus (Colegate et al., 1990) montanus (Colegate et al., 1990) tapis (Colegate et al., 1990) arvensis (Bermejo, 1997) C13H14O5 250 G. giganteus (Fang et al., 1991b) C13H14O4 234 G. arvensis (Bermejo et al., 1995) C15H18O5 278 G. arvensis (Bermejo et al., 1997) C13H14O5 250 G. arvensis (Bermejo, 1997) For de®nitive absolute con®gurations see references given in the text. Table 3. Furano-furones from Goniothalamus Substituents 7 Furano-furones, ªgoniofufurone typeº 7.1 Goniofufurone Ð 7.2 8-Epi-goniofufurone Ð a Absolute con®gurationa Molecular formula M‡ Goniothalamus sp. (reference) 4R, 5S, 6S, 7R, 8R C13H14O5 250 G. arvensis (Bermejo et al., 1998) G. borneensis (Cao et al., 1998) G. giganteus (Fang et al., 1990) 4R, 5S, 6S, 7R, 8S C13H14O5 250 G. giganteus (Fang et al., 1991a) For de®nitive absolute con®gurations see references given in the text. determined by spectroscopic and crystallographic analysis (Wu et al., 1991). The R configurations at positions 6, 7, 8 and that of 5S were also determined by several methods for compounds 3.3–3.6 (Alkofahi et al., 1989; Fang et al., 1990; Shing and Zhou, 1992; Wu et al., 1992; Yang and Zhou, 1995; Talapatra et al., 1997). The recently isolated compound etharvendiol (3.7) has the same configuration as 3.5 (Bermejo et al., 1998), but with an unusual ethoxylated group in the lactone moiety. Moreover, this is the first time that this substituent has been found in a compound with a styryl-pyrone skeleton. It is remarkable that the type 3 styryl-pyrones show a Copyright # 1999 John Wiley & Sons, Ltd. high coupling constant between H-7 and H-8 (J7–8 = 7.9– 8.6 Hz), characteristic of a 7,8 erythro-diol configuration. Finally, the first saturated styryl-pyrone type compound, garvensintriol (4.1), has recently been isolated from the stem bark of Goniothalamus arvensis and has been shown to be a 3,4-dihydro-7,8-diepigoniotriol (Bermejo et al., 1998). Furano-pyrones The first such compound (5.1) of this group was initially identified from Polyalthia (Loder and Nearn, 1977) and Phytochem. Anal. 10: 161–170 (1999) STYRYL-LACTONES FROM GONIOTHALAMUS SP. 165 Table 4. Pyrano-pyrones from Goniothalamus Substituents 8 8.1 8.2 8.3 Pyrano-pyrones, ªgoniopypyrone typeº Goniopypyrone R=OH 5-Deoxygoniopypyrone R=H Leiocarpin-A R=H Absolute con®guration 4S, 5S, 6R, 7R, 8S 4R, 6R, 7S, 8S 4R, 6R, 7S, 8R Molecular formula M‡ Goniothalamus sp. (reference) C13H14O5 250 G. giganteus (Fang et al., 1990) C13H14O4 234 G. giganteus (Fang et al., 1991a) C13H14O4 234 G. leiocarpus (Mu et al., 1996) Table 5. Butenolides from Goniothalamus Substituents Absolute con®guration Molecular formula M‡ 9 Butenolides, ªgoniobutenolide-A typeº 9.1 Goniobutenolide-A Ð 7S, 8R C13H12O4 232 9.2 Goniobutenolide-B Ð 7S, 8R C13H12O4 232 Goniothalamus sp. (reference) G. borneensis (Cao et al., 1998) G. giganteus (Fang et al., 1991b) G. borneensis (Cao et al., 1998) G. giganteus (Fang et al., 1991b) Table 6. Heptolides from Goniothalamus Substituents 10 10.1 10.2 10.3 10.4 a Heptolides, ªgonioheptolide-A typeº Gonioheptolide-A R1=OH; R2=Me Gonioheptolide-B R1=OH; R2=Et Almuheptolide-A R1=OEt; R2=Et Almuheptolide-B R1=H; R2=Et Relative relationships Molecular formula M‡ c-c-t-ta c-c-t-t t-c-t-t c-t-t C14H18O6 C15H20O6 C17H24O6 C15H20O5 282 296 324 280 Goniothalamus sp. (reference) G. G. G. G. giganteus (Fang et al., 1993) giganteus (Fang et al., 1993) arvensis (Bermejo, 1997) arvensis (Bermejo, 1997) c = cis; t = trans. Copyright # 1999 John Wiley & Sons, Ltd. Phytochem. Anal. 10: 161–170 (1999) 166 M. AMPARO BLÁZQUEZ ET AL. Table 7. Species of Goniothalamus containing styryl-lactones Species Organ G. amuyon Leaf G. andersonii G. arvensis Whole plant Stem bark G. borneensis Bark G. dolichocarpus G. fulvus G. giganteus Stem bark Ð Stem bark G. gri®thii Bark G. leiocarpus G. macrophyllus Uncited Whole plant Root Stem bark/root Stem bark Stem bark/leaves Ð Stem bark G. malayanus G. montanus G. scortechinii G. sesquipedalis Leaf/root G. tapis G. uvaroides Ð Root Root 3.2 3.3 3.5 1.1 3.7 4.1 5.1 5.2 5.3 6.2 6.3 6.4 7.1 10.3 10.4 1.1 7.1 9.1 9.2 1.3 1.1 1.1 3.1 3.5 3.6 5.1 6.1 7.1 7.2 8.1 8.2 9.1 9.2 10.1 10.2 3.1 3.2 3.4 8.3 1.1 2.1 1.1 5.2 5.2 1.1 1.1 2.2 3.1 3.2 3.4 3.5 1.1 5.2 1.1 1.2 Compounds Reference 7-Acetyl-goniodiol 8-Acetyl-goniodiol Goniotriol Goniothalamin Etharvendiol Garvensintriol Altholactone Isoaltholactone 2-Epi-altholactone Goniotharvensin Etharvensin Arvensin Goniofufurone Almuheptolide-A Almuheptolide-B Goniothalamin Goniofufurone Goniobutenolide-A Goniobutenolide-B 5-b-Hidroxygoniothalamin Goniothalamin Goniothalamin Goniodiol Goniotriol 8-Acetyl-goniotriol Altholactone Goniofupyrone Goniofufurone 8-Epi-goniofufurone Goniopypyrone 5-Deoxy-goniopypyrone Goniobutenolide-A Goniobutenolide-B Gonioheptolide-A Gonioheptolide-B Goniodiol 7-Acetyl-goniodiol Goniodiol diacetate Leiocarpin-A Goniothalamin Goniothalamin oxide Goniothalamin Isoaltholactone Isoaltholactone Goniothalamin Goniothalamin 5-Acetoxy-isogoniothalamin oxide Goniodiol 7-Acetyl-goniodiol Goniodiol diacetate Goniotriol Goniothalamin Isoaltholactone Goniothalamin 5-Acetoxy-goniothalamin Wu et al., 1991 Wu et al., 1992 Wu et al., 1992 Jewers et al., 1972 Bermejo et al., 1998 Bermejo et al., 1998 Bermejo et al., 1995 Bermejo et al., 1995 Bermejo, 1997 Bermejo et al., 1995 Bermejo et al., 1997 Bermejo, 1997 Bermejo et al., 1998 Bermejo, 1997 Bermejo, 1997 Cao et al., 1998 Cao et al., 1998 Cao et al., 1998 Cao et al., 1998 Go et al., 1995 Muhammad et al., 1989 El-Zayat et al., 1985 Fang et al., 1991a Alkofahi et al., 1989 Fang et al., 1990 El-Zayat et al., 1985 Fang et al., 1991b Fang et al., 1990 Fang et al., 1991a Fang et al., 1990 Fang et al., 1991a Fang et al., 1991b Fang et al., 1991b Fang et al., 1993 Fang et al., 1993 Talapatra et al., 1985 Talapatra et al., 1985 Talapatra et al., 1985 Mu et al., 1996 Jewers et al., 1972 Sam et al., 1987 Jewers et al., 1972 Colegate et al., 1990 Colegate et al., 1990 Muhammad et al., 1989 Hasan et al., 1995 Hasan et al., 1994 Talapatra et al., 1985 Talapatra et al., 1985 Talapatra et al., 1985 Talapatra et al., 1985 Muhammad et al., 1989 Colegate et al., 1990 Ahmad et al., 1991 Ahmad et al., 1991 named altholactone. Eight years later it was also isolated from the bark of Goniothalamus giganteus (El-Zayat et al., 1985) and reported under the different trivial name of goniothalenol (Table 2). Altholactone and all furanopyrones are biogenetically related to styryl-pyrones (Hlubucek and Robertson, 1967; Jewers et al., 1972). The furano-pyrone skeleton represents the second most abundant class of styryl-lactones in Goniothalamus. A Copyright # 1999 John Wiley & Sons, Ltd. number of these compounds, including the main styryllactone of the genus, are characterized by the presence of an a,b-unsaturated d-lactone moiety (type 5: altholactone type). However, there are three different stereochemistries based on the relative configurations at the 2 and the 3 positions. The configuration of the C-3 chiral centre was initially established from coupling constant values in the 1 H-NMR and demonstrated by crystallographic analysis. Phytochem. Anal. 10: 161–170 (1999) STYRYL-LACTONES FROM GONIOTHALAMUS SP. The coupling constants between H-3 and H-3a, and between H-2 and H-3 in 5.1 were reported to be 2.5 Hz (trans) and 5.8 Hz (trans), respectively, whereas in 5.2 the corresponding coupling constants were 5.5 Hz (cis) and 7.5 (trans); thus, 5.1 and 5.2 are 2,3 diepimers. The existence of compound 5.2 suggested that the different relative configurations at C-2 and C-3 could have their origin in an a- or b-epoxidation of the biogenetic intermediary 1.1. Thus b-epoxidation of 1.1 (goniothalamin) followed by an intramolecular cyclization may form (‡) altholactone (5.1), while a-facial formation of the corresponding epoxide could give rise to (‡) isoaltholactone (5.2). Altholactone (5.1) has been synthesized from several starting materials, such as carbohydrates (Gesson et al., 1987, 1989; Gillhouley and Shing, 1988; Mukai et al., 1997), optically active glyceraldehyde derivatives (Kang and Kim, 1989; Tsubuki et al., 1993) and natural diethyl L-tartrate (Somfai, 1994). The furano-pyrone 5.3 (Bermejo, 1997) is a new natural compound that has previously only been obtained by synthesis (Ueno et al., 1989). Another furano-pyrone group is represented by type 6 (goniofupyrone type) (Table 2). Examination of the coupling constant J3a–7a (5.0 Hz) in 6.1–6.3 indicated that H-3a and H-7a (fused bicyclic ring system) must be in the cis configuration (with a flexibility model the angle would be near zero), as occurs for furano-pyrone type 5. However, the low value found for this coupling constant in compound 6.4 presents strong evidence that H-3a and H-7a are in the trans configuration. The other two coupling constants in the tetrahydrofuran ring of 6.1–6.3 are very similar to those of altholactone, 5.1. That goniotharvensin, 6.2, is a 6,7-dihydro derivative of 5.1 was corroborated by hydrogenation of the latter over palladium–carbon (Bermejo et al., 1995). Etharvensin (6.3) was the first furano-pyrone to be described that has an ethoxylated group in the lactone moiety. The absolute stereochemistry of the C-3 chiral centre of 6.3 was established by preparing the (R)- and (S)-a(methoxy)-a-(trifluoromethyl)-phenyl acetic acid by Mosher’s ester method (Dale and Mosher, 1973) and was found to be identical to that of 6.1, which had previously been established by synthesis (Mukai et al., 1996a). Furano-furones Only two styryl-lactones with this skeleton have been described. Both were isolated from the stem bark of Goniothalamus giganteus (Fang et al., 1990, 1991a) and they differ only with respect to their stereochemistry at C8 (Table 3). Because highly oxygenated lactones may have significant potential as anti-tumour agents, these compounds have been the subject of numerous enantioselective syntheses from carbohydrates. The absolute configuration of natural 7.1 was confirmed on the basis of an unambiguous synthesis of its enantiomer from Dglycero-D-gulo-heptono-g-lactone (Shing and Tsui, 1992). Later it was reported that the absolute configurations of 7.1 and 7.2 coincide with those of their suggested biogenetic precursors (Gracza and Jäger, 1994), and recently a series of structural analogues of goniofufurone (7.1) have been synthesized from D-glucose as the starting material (Cagnolini et al., 1997). Copyright # 1999 John Wiley & Sons, Ltd. 167 Pyrano-pyrones Among the styryl-lactones isolated from G. giganteus (Fang et al., 1990), goniopypyrone (8.1) stands out as exhibiting very high, non-selective activity against human tumour cell lines. This compound, together with 5-deoxygoniopypyrone (8.2) and leiocarpin-A (8.3) (Table 4), are examples of pyrano-pyrone styryl-lactones. The structure and relative configuration of 8.1 were initially suggested by comparison of the 1H-NMR spectral data with that of altholactone (5.1), and were confirmed by X-ray crystallographic data which also indicated the existence of an intramolecular hydrogen bond between 5-OH and 7-OH (Fang et al., 1990). The synthesis of 8.1 and 8.2 (Tsubuki et al., 1992; Shing et al., 1993; Yang and Zhou, 1997; Friensen and Bissada, 1998) confirmed their structures and absolute configurations. Butenolides The two known butenolide compounds, 9.1 and 9.2, were originally isolated from G. giganteus (Fang et al., 1991b), but recently both metabolites have been obtained from the bark of G. borneensis (Cao et al., 1998) (Table 5). The structural elucidation was supported by comparison of the NMR spectral data with those of acetylmelodorinol, a closely related compound previously identified from Melodorum fruticosum bark (Annonaceae) the structure of which was proven by X-ray crystallography (Jung et al., 1990). The Z-configuration of the C5=C6 double bond in 9.1 and the E-configuration in 9.2 were suggested by comparison of the NMR data, and further proven by NOE experiments in which the olefinic proton H-6 was enhanced by irradiating the proton H-4 (Table 5). This suggested a closer distance between these two in the Z-configuration since no NOE effects were observed when irradiating either H-4 or H-6 in the E-configuration. The relative stereochemistry of the vicinal diol moiety was initially established as threo by comparing the coupling constant J7,8 (4.3 Hz) with those observed for related compounds. The first total syntheses of compounds 9.1 and 9.2, as well as their 8-epimers, reassigned the relative configuration of the vicinal diol moiety as erythro and established the absolute stereochemistries (Shing et al., 1994). The erythro relationship was also demonstrated by a selective asymmetric dihydroxylation (Xu and Sharpless, 1994); other authors (Ko and Lerpiniere, 1995; Shing et al., 1995; Surivet and Vatèle, 1996; Mukai et al., 1996b) also confirmed the erythro configuration for natural goniobutenolides-A and -B by several syntheses, and established the absolute configuration as 7S, 8R. Heptolides Compounds of this group contain an unusual, saturated eight-membered lactone moiety (z-lactone) (Table 6) related to cytotoxic metabolites isolated from a marinederived Actinomycete of the genus Streptomyces, namely octalactins-A and -B (Tapiolas et al., 1991). Gonioheptolides-A (10.1) and -B (10.2) were the first compounds of this class to be isolated from the stem bark of G. giganteus (Fang et al., 1993). It is interesting to note the presence of an ethoxy group in the lactone moiety in 10.2, as described for a styryl-pyrone (3.7) (Bermejo et al., Phytochem. Anal. 10: 161–170 (1999) 168 M. AMPARO BLÁZQUEZ ET AL. 1998) (see Table 1) and a furano-pyrone (6.3) (Bermejo et al., 1997) (see Table 2). The relative stereochemistry of gonioheptolides-A (10.1) and -B (10.2) is based on the NOESY spectrum of their triacetate derivatives. The NOEs observed between H-4, H-5, H-6 and H-8 are consistent with a cis relationship between them, whereas the trans configuration between H-5 and H-7 was suggested because no NOE cross peaks were observed. Recently two novel heptolides, almuheptolides-A (10.3) and -B (10.4), have been isolated from the stem bark of G. arvensis (Bermejo, 1997). Compound 10.3 is a 4,5-diethoxylated, 6,7-dihydroxylated heptolide whose relative configuration is different from that of 10.1 and 10.2. The NOEs observed between H-5/H-6 and H-5/H-8 in their diacetate derivatives are in agreement with cis relationships for H-5, H-6 and H-8, whereas the absence of NOE effects with H-4 and H-7 suggests a trans relationship between them. The co-occurrence of furanopyrones and heptolides in G. arvensis and G. giganteus suggests biosynthetic connectivities between the two types, particularly when chemical interconversions between them are considered (Bermejo, 1997). BIOGENETIC CONSIDERATIONS The styryl-lactones of Goniothalamus comprise a homogeneous and relatively reduced group of secondary metabolities, characterized by a basic skeleton of 13 carbon atoms that include in their structure a styryl or pseudo-styryl fragment linked to a lactone moiety (either a furanone or a pyranone). However, in the heptolide group, the z-lactone is directly attached to the aromatic ring. According to several authors (Fang et al., 1993; Shing et al., 1995), the biosynthesis of these compounds occurs via the shikimic acid pathway through phenylalanine to cinnamic acid (C6–C3 unit), followed by the incorporation of two acetate–malonate units (C4 unit) activated as coenzyme-A. Coupling of these two units followed by lactonization would generate the simplest styryl-pyrone, (‡) goniothalamin (1.1), as the key intermediate. Hydroxylations and various cyclizations would have to take place to form the different known skeletons (Fig. 2). Styryl-pyrones are common constituents in fungi, mainly in the Hymenochaetaceae (Basidiomycetes) (Fiasson, 1982). Their formation from aromatic amino acids and acetate units has been studied via feeding experiments with labelled precursors (Towers, 1969). Recently, a styryl-pyrone synthase has been identified in cell free extracts from gametophytes of Equisetum arvense (Beckert et al., 1997). This new enzyme catalyses the formation of styryl-pyrones from malonyl Co-A and hydroxycinnamoyl Co-A precursors, hence confirming the mixed biosynthetic origin of the styryllactones. a-Epoxidation of the double bond of goniothalamin (1.1), followed by trans opening of the epoxide at the benzylic carbon, and allylic hydroxylation gives goniotriol (3.5). Because of its reactivity, this compound has been considered the natural precursor of the other styryllactone groups. The rearrangement under basic conditions of goniotriol forms all g-lactones known in Goniothalamus, both unsaturated (butenolides) and saturated (furano-furones). The butenolide compounds Copyright # 1999 John Wiley & Sons, Ltd. must be generated by dehydration while furano-furone types could be a consequence of an intramolecular Michael-type ring closure (forming a new tetrahydrofuran ring). Styryl-pyrones with the opposite stereochemistry at the benzylic carbon (position 8) are expected to derive from epimerization. Therefore, 8-epi-goniotriol (not found in nature) could explain the existence through an intramolecular Michael mechanism of the furano-pyrones and pyrano-pyrones types (Shing et al., 1993). Nevertheless, in a recent study on the total synthesis of (‡) 8-epigoniofufurone (7.2), Surivet and Vatèle 1997 report that the a-pyrone 8-epi-goniotriol does not isomerize to the afurone form, a precursor of 8-epi-goniofufurone (7.2). This refutes the above hypothesis that 8-epi-goniotriol could be one of the possible biogenetic precursors of 8epi-goniofufurone. On the other hand, other authors (Talapatra et al., 1985) have suggested that the biogenetic origin of the furano-pyrones may be as a derivative of several intramolecular cyclisations of epoxidic styryl-pyrones, and in addition considered that the stage of epoxidation is the one which limits the possible oxygenated and cyclic compounds. Finally, the heptolide compounds could originate directly from immediate lactonization following the coupling of the C6–C3 and C4 units (Fang et al., 1993). However, recent research shows that the heptolides can be obtained easily from furano-pyrones. Therefore, an enantioselective method for preparing penta-substituted eight-membered ring lactones from optically active altholactone (5.1) as starting precursor has been obtained (Bermejo, 1997). BIOACTIVITY OF STYRYL-LACTONES The styryl-lactones make up an interesting group from the pharmacological point of view. Styryl-lactones, despite their restricted occurrence in the plant kingdom, are reported to possess cytotoxic, anti-tumour, pesticidal, teratogenic and embryotoxic activities (Sam et al., 1987; Fang et al., 1991a, b). Significant anti-tumour and cytotoxic activities associated with styryl-lactones of Goniothalamus have promoted a detailed chemical investigation of the different styryl-lactones. Goniothalamin (1.1), the first styryl-lactone isolated, showed strong embryotoxicity, teratogenicity and toxicity in both the brine shrimp lethality assay and human epidermoid carcinoma of the nasopharynx (9-KB) cell line assays (Sam et al., 1987). The cytotoxic effect of 1.1 was evaluated on different cell lines, both cancerous (HeLa, human cervical carcinoma; PANC-1, pancreas carcinoma; HGC-27, gastric carcinoma; and MCF-7, breast carcinoma) and non-cancerous (3T3, mouse fibroblast), reflecting a non-selective mode of action. Nevertheless, the cytotoxicity appears to be more effective on dividing cells (Ali et al., 1997). The styryl-pyrone 7-acetyl-goniodiol (3.2) was demonstrated to have significant anti-tumour activity in the murine lymphocytic leukaemia (P-388) in vivo system as well as cytotoxicity against a cell culture 9-KB (Wu et al., 1991). Goniodiol (3.1) was found to be a selective cytotoxic agent against several human tumour cell lines, Phytochem. Anal. 10: 161–170 (1999) STYRYL-LACTONES FROM GONIOTHALAMUS SP. particularly human lung carcinoma A-549 (Talapatra et al., 1985). It is noteworthy that goniofufurone (7.1) showed significant cytotoxic activities against several human tumour cell lines, while 8-epi-goniofufurone (7.2) proved to be less active (Fang et al., 1991a; Wu et al., 1992). With respect to the pyrano-pyrone group, goniopypyrone (8.1) is one of the most active styryl-lactones of the Goniothalamus genus with similar cytotoxic activity (DE50 of ca. 0.67 mg/mL) against human breast carcinoma (MCF-7), human lung carcinoma (A-549) and human colon adenocarcinoma (HT-29) (Fang et al., 1990). Gonioheptolides-A (10.1) and -B (10.2) differ in their activity against human tumour cell lines. It is interesting to note that the DE50 value of 10.1 against A-549 is close to the value that is considered significant in the search for new anti-tumour drugs (Fang et al., 1993). The bioactivities of the styryl-lactones of Goniothala- 169 mus lead us to ask whether the cytotoxicity towards different human carcinoma cell-lines could be explained, as for Annonaceous acetogenins, by an action on the mitochondrial respiratory chain (Zafra-Polo et al., 1998). Thus, actimicin-A, a classical inhibitor of complex III, is structurally related to the styryl-lactones heptolide type. 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