For the purpose of surveying naturally occurring precursors of oestrogenic substances, and their metabolic processes, to mammalian lignans such as enterodiol (END) and enterolactone (ENL), many plant lignans have been studied. Trachelogenin, an aglycone of tracheloside, occurring in the seeds of Carthamus tinctorius L. (safflower), was demonstrated to transform to seven metabolites, including (−)-ENL, by anaerobic incubation with a human faecal bacterial mixture, when the reaction was monitored by LC/MS. The structures of the metabolites were determined by spectroscopic means after a large-scale incubation and purification of the respective metabolites. Moreover, the ligand-binding affinity of these metabolites to oestrogen receptors (ERs) α and β was measured in comparison with that of (+)-ENL. (−)- and (+)-ENL were found to significantly bind to both ERα and β, in which an appreciable difference in affinity was observed between (+)- and (−)-ENL for ERβ, but not for ERα.Highlights► Trachelogenin was converted to enterolactone by human intestinal bacteria. ► The metabolites of trachelogenin were isolated and identified. ► The enterolactone converted from trachelogenin was (−)-enantiomer. ► The ligand binding affinity of the compounds to oestrogen receptors was evaluated.

Enterolactone (ENL) and enterodiol are mammalian lignans. Several plant lignans have been reported as precursors of mammalian lignans. However, asarinin (AS), a furofuran type lignan which occurs in medicinal plants and foods, has not been reported as mammalian lignan precursor to date. After the incubation of AS with human intestinal microflora, AS was converted to not only ENL, but also two more metabolites (mono-demethylenated and ring-cleaved compounds). Under the same conditions, sesamin (SM) was converted to ENL. Furthermore, chiral HPLC analysis showed that ENL produced from AS and SM was (−)-ENL. This is the first report which shows that AS is a mammalian lignan precursor.

Flavan-3-ol oligomers from the stems of Cynomorium songaricum were found to show potent SOD-like activity with one of the dimers being most potent. The flavan-3-ols also showed inhibitory activity on α-glucosidase, implying the beneficial effects of this herb on diabetes patients. The total (extractable and non-extractable) tannin content of this herb was found to be as high as 18.3%. The contents of catechin, flavan-3-ol oligomers and extractable tannins using 70% acetone, methanol or water were analysed. It was found that 70% acetone was the most efficient extract solvent amongst these three solvents, especially for higher flavan-3-ol oligomers.

New derivatives of caffeic acid and quinic acid were synthesized and their anti-fungal and inhibitory activities on fungal 1,3-β-glucan synthase were determined in comparison with those of the corresponding chlorogenic acid derivatives. All the chlorogenic, quinic and caffeic acid derivatives that were coupled with an H2N-orn-4-(octyloxy) aniline group (1, 1b and 1c) displayed potent activities in both anti-fungal and inhibition of 1,3-glucan synthase assays. Compounds 1 and 1c inhibited the fungal membrane enzyme with the potency comparable to that of a known 1,3-β-d-glucan synthase inhibitor, aculeacin A. The results revealed that the anti-fungal activity of the chlorogenic acid derivative with a free amino group was at least partly due to inhibition of the fungal 1,3-β-glucan synthase. These results suggest that further investigation on caffeic acid derivatives may lead to the discovery of novel anti-fungal agents with drug-like properties.

In our continued research on chlorogenic acid analogues and derivatives with improved bioactivity, we have synthesized some caffeoyl 5,6-anhydroquinic acid derivatives. The 1,7 acetonides of chlorogenic acid (15), and of the mono-caffeoyl 5,6-anhydroquinic acids (7–8) showed appreciable anti-HIV activity. The 3,4-dicaffeoyl 5,6-anhydroquinic acid (12) exhibited an anti-HIV activity twice as that of 3,5-dicaffeoylquinic acid (22). The caffeoyl 5,6-anhydroquinic acid derivatives displayed potent anti-oxidant activities. The mono-caffeoyl 5,6-anhydroquinic acids (10–11) were more than twice stronger than chlorogenic acid (21) on SOD-like activity.

2,3-Seco-dioic acids derived from four different triterpene skeletons were prepared and evaluated for their anti-HIV-1 protease activity. Two A-seco derivatives showed potent inhibitory activity against HIV-1 protease (3c and 3e, IC50 5.7 and 3.9 μM, respectively), while four other derivatives showed moderate to weak inhibition (3a, 3b, 3d and 3f, IC50 15.7–88.1 μM). The combination of a 2,3-seco-2,3-dioic acid functional group in ring A and a free acid group at C-28 or C-30 significantly enhanced HIV-1 protease inhibitory activity (3a, 3c–3e, IC50 3.9–17.6 μM). On the other hand, all A-seco derivatives were found to be very weak inhibitors of HCV, renin and trypsin proteases (IC50 > 80 μM). These findings indicate that A-seco triterpenes with a carboxyl group at C-28 or C-30 are novel and highly selective HIV-1 protease inhibitors.The 2,3-seco-dioic acid derivatives of different triterpene skeletons were prepared, two of which showed potent inhibitory activity against HIV-1 protease (3c and 3e). The combination of a 2,3-seco-2,3-dioic acid functional group in ring A and a free acid group at C-28 or C-30 significantly enhanced the activity against HIV-1 protease.

A new farnesyl hydroquinone, ganomycin I (1), was isolated along with ganomycin B (2) from the chloroform extract of the fruiting bodies of the Vietnamese mushroom Ganoderma colossum. These compounds inhibited HIV-1 protease with IC50 values of 7.5 and 1.0 μg/mL, respectively. Kinetic studies using Zhang−Poorman and Lineweaver plots revealed that compound 2 competitively inhibited the active site of the enzyme, whereas the tetracyclic triterpene schisanlactone A, previously isolated from the same fungus, was a dimerization inhibitor, with an IC50 value of 5.0 μg/mL. The previous findings were also confirmed by the virtual docking of both compounds with HIV-1 protease crystal structure.

Three new lanostane-type triterpenoids having farnesyl hydroquinone moieties, named ganosinensins A−C (1−3), were isolated from the fruiting body of Ganoderma sinense, together with three known lanostane triterpenes, ganodermanontriol, ganoderiol A, and ganoderiol D. The structures of compounds 1−3 were determined by spectroscopic data interpretation.

A human intestinal bacterium Ruminococcus (R.) sp. END-1 capable of oxidizing (−)-enterodiol to (−)-enterolactone, enantioselectively, was further investigated from the perspective of transformation of plant lignans to mammalian lignans; A cell-free extract of the bacterium transformed (−)-enterodiol to (−)-enterolactone through an intermediate, enterolactol. The bacterium showed not only oxidation but also demethylation and deglucosylation activities for plant lignans. Arctiin and secoisolariciresinol diglucoside were converted to (−)-dihydroxyenterolactone and (+)-dihydroxyenterodiol, respectively. Moreover, by coincubation with Eggerthella sp. SDG-2, the bacterium transformed arctiin and secoisolariciresinol diglucoside to (−)-enterolactone and (+)-enterodiol, respectively.

We synthesized dammarane-type triterpene derivatives and evaluated their ability to inhibit HIV-1 and HCV proteases to understand their structure–activity relationships. All of the mono- and di-succinyl derivatives (5a–5f) were powerful inhibitors of HIV-1 protease (IC50 < 10 μM). However, only di-succinyl (5e) and 2,3-seco-2,3-dioic acid (3b) derivatives similarly inhibited HCV protease (IC50 < 10 μM). A-nor dammarane-type triterpenes (4a and 4b, IC50 10.0 and 29.9 μM, respectively) inhibited HIV-1 protease moderately or strongly, but were inactive against HCV protease. All compounds that powerfully inhibited HIV-1 or HCV protease did not appreciably inhibit the general human proteases, renin and trypsin (IC50 > 1000 μM). These findings indicated that the mono-succinyl dammarane type derivatives (5a–5d) selectively inhibited HIV-1 protease and that the di-succinyl (5e, 5f) as well as 2,3-seco-2,3-dioic acid (3b) derivatives preferably inhibited both viral proteases.

Three artificial triterpenoids, (20R)-20,25-epoxy-dammaran-2-en-6α,12β-diol (1), (20R)-20,25-epoxy-3-methyl-28-nordammaran-2-en-6α,12β-diol (2) and isodehydroprotopanaxatriol (3), were isolated from an acidic hydrolysate of Panax ginseng C.A. Meyer, along with three known triterpenes, (20R)-panaxadiol (4), (20R)-panaxatriol (5) and oleanolic acid (6). Compounds 1–3 and 6 showed inhibitory activity against HIV-1 protease with IC50 of 10.5, 10.3, 12.3 and 6.3 μM, respectively. The results indicated that acid treatment of Ginseng extract could produce diverse structures with interesting bioactivity.Three artificial triterpenoids were isolated along with three known ones, from an acidic hydrolysate of Panax ginseng. Four of them showed inhibitory activity on HIV protease.

α-Glucosidases play important roles in the digestion of carbohydrates and biosynthesis of viral envelope glycoproteins. Inhibitors of α-glucosidase are promising candidates for the development of antitype II diabetics and anti-AIDS drugs. Here, we report the synthesis and α-glucosidase inhibitory activity of mono- and diketal/acetal derivatives of chlorogenic acid. The diketal derivatives showed more potent inhibitory activity than the monoketals. The 1,7-(5-nonanone) 3,4-(5-nonanone)-chlorogenic acid diketal showed remarkable inhibitory activity against α-glucosidases with potency better than that of 1-deoxynojirimycin hydrochloride. Four diasteremers of pelargonaldehyde diacetal and two of monoacetal derivatives of chlorogenic acid were synthesized in this study. They showed significant potent inhibition similar to or more potent than the ketal counterparts. Acetals with the alkyl chain oriented toward position 2 of chlorogenic acid showed more potent activity than those oriented toward position 6.

Four new lanostane triterpenes, colossolactone V (1), colossolactone VI (2), colossolactone VII (3), and colossolactone VIII (4), were isolated from the fruiting bodies of the Vietnamese mushroom Ganoderma colossum, together with the known compound colossolactone E (5). The structures of 1−4 were assigned on the basis of spectroscopic evidence, and their absolute configurations were determined by CD spectroscopy and the Mosher ester method. Compounds 1−5, as well as two previously isolated compounds [schisanlactone A (6) and colossolactone G (7)] from the same mushroom, were evaluated for inhibition of HIV-1 protease, with IC50 values for the most potent compounds ranging from 5 to 13 µg/mL.

Three triterpenoids, 16β-hydroxy-2,3-seco-lup-20(29)-ene-2,3-dioic acid (1), 3β,21β,24-trihydroxy-30-noroleana-12,20(29)-dien-28-oic acid (2) and 16β-hydroxylupane-1,20(29)-dien-3-one (3), along with eleven known triterpenes were isolated from stems of Stauntonia obovatifoliola Hayata subsp. intermedia (Y.C. Wu) T. Chen. Their structures were determined by analysis of HR-EI/FAB-MS and 1D and 2D NMR spectroscopic data and comparison with those in the literature. Ten of the compounds showed inhibitory activity against HIV-1 protease.Three triterpenoids were isolated along with 11 known ones from the stems of Stauntonia obovatifoliola. Ten of them showed inhibitory activity on HIV protease.