Biotransformation of the fungistatic sesquiterpenoid patchoulol by botrytis cinerea

Biotransformation of the fungistatic sesquiterpenoid patchoulol (1) by the fungus Botrytis cinerea affords the 5-, 7- and (8R)-hydroxy (2, 3, and 5) derivatives as the major metabolites, together with a number of minor metabolites (4, 6-9) arising from hydroxylation at C-2, C-3, C-5, C-9, C-13, and C-14.     

Characterization of an abeo-taxane: brevifoliol and derivatives

Brevifoliol is a natural diterpene isolated from Taxus baccata Nutt. A series of brevifoliol 1 derivatives, 2-8 and 10, were prepared for characterization and semisynthesis purposes and included the introduction of acetyl, Troc, and TES groups at C-5 and C-13. Derivatives 16-20 of 5-acetylbrevifoliol 2 were obtained via esterification with cinnamic acid, with both 2S-(-)- and 2R-(+)-3-phenyllactic acid, and with N-benzoyl-(2'R,3'S)-3'-phenylisoserine at C-13. Brevifoliol compounds 12, 13, and 15 with either 2S-(-)-phenyllactate moieties at C-5 and C-13 or an N-benzoyl-(2'R,3'S)-3'-phenylisoserinyl at C-13 were also prepared. An abeo-taxane structure for 1 was clearly defined from the (13)C NMR analysis of the 5-acetyl-13-oxo derivative 8 and from the conversion of 1 into 10, a conformationally restrained compound having a C-13, C-15 oxygen bridge. The biological activity of each of these derivatives is being studied.     

A distinctive structural twist in the aminoimidazole alkaloids from a calcareous marine sponge: isolation and characterization of leucosolenamines A and B

Bioassay-guided fractionation of Papua New Guinea collections of Leucosolenia sp. resulted in the isolation of the novel compounds leucosolenamines A (5) and B (6) and the known compound thymidine (7). Compound 5 contains a 2-aminoimidazole core substituted at C-4 and C-5 by an N,N-dimethyl-5,6-diaminopyrimidine-2,4-dione and a benzyl group, respectively. Compound 6 retains the same core structure; however C-4 is substituted by a 5,6-diamino-1,3-dimethyl-4-(methylimino)-3,4-dihydropyrimidin-2(1H)-one moiety. This substitution pattern is unique and has never been observed in calcareous imidazole alkaloid chemistry. Leucosolenamine A (5) was mildly cytotoxic against the murine colon adenocarcinoma C-38 cell line.     

Lepadins F-H, new cis-decahydroquinoline alkaloids from the Australian ascidian Aplidium tabascum

Chemical investigation of a Great Barrier Reef ascidian, Aplidium tabascum, has resulted in the isolation of three new cis-decahydroquinoline alkaloids, lepadins F-H (4-6). The three new compounds differ from the previously isolated lepadins A-C (1-3) in that they contain a fully saturated 5-hydroxyoctyl side chain attached at C-5, an unsaturated eight-carbon ester moiety attached to C-3, and opposite stereochemistry at C-5 and C-3. Lepadins G (5) and H (6) are epimers at C-2. NMR and molecular modeling studies indicated that the three new compounds adopt a chair-chair conformation in which the nitrogen equatorially substitutes the cyclohexyl ring. This contrasts with lepadins A-C (1-3), which adopt a chair-chair conformation in which the nitrogen axially substitutes the cyclohexyl ring.     

A study of the trypanocidal activity of triterpene acids isolated from Miconia species

Triterpene acids, including ursolic acid (1), urjinolic acid (4) and oleanoic acid (5) along with a mixture of 2alpha-hydroxyursolic acid (2) and maslic acid (3) were isolated from methylene chloride extracts of the Miconia sellowiana and M. ligustroides species and their activities against the trypomastigote blood forms of Trypanosoma cruzi were evaluated. The potassium salt derivative of ursolic acid (1a) was also tested. The in vitro assays showed that compounds 1, 5 and 1a were the most active (IC(50) 17.1 microm, 12.8 microm and 8.9 microm, respectively). In contrast, a mixture of 2 plus 3, that exhibit a hydroxyl at C-2 and C-3, is much less potent than a mixture of 1 and 5 (IC(50) 48.5 microm and 11.8 microm, respectively). In the same manner, compound 4, that differs from 5 by two additional hydroxyl groups (at C-2 and C-23) displayed weak trypanocidal activity (IC(50) 76.3 microm) when compared with the other triterpenes. These results suggest that the free hydroxyl at C-3 and the polarity of C-28 are the most influential structural features for determining the in vitro trypanocidal activity of triterpenes. In vivo assays were also undertaken for the most active compounds 1, 1a and the mixture of 1 plus 5. The most significant reduction in parasite number in the parasitemic peak were obtained for compound 1 and its salt derivative 1a (75.7% and 70.4%, respectively). Moreover, the survival time was increased for all the treated animals.     

An efficient conversion of taxinine to taxinine NN-1, an anticancer agent and a modulator of multidrug-resistant tumor cells

Taxinine NN-1 (1), which shows significant activities as a modulator of multidrug-resistant cancer cells and as an anticancer agent in an in vitro assay based on a HCC panel, was synthesized in order to obtain sufficient material for a higher order bioassay from easily available taxinine (2). The synthesis was achieved via intermediate 8, which was derived from 2 by the stepwise protection of a 9,10-dihydroxyl group as acetonide and a 2-hydroxyl group as a MOM protecting group. The temporary elimination of a cinnamoyl group at C-5 of 8 and successive reduction of a C-13 carbonyl group of the resulting 9 gave 10 and the undesired 13-epimer 11. The latter was recycled to 9 by oxidation with MnO(2). Stepwise acetylation and cinnamoylation at C-13 and C-5 of 10 and successive deprotection of the acetonide protecting group at C-9,10 of the resulting 13 gave diol 14. Diacetylation of 14 and deprotection of the MOM protecting group at C-2 of the resulting 15 gave 1. The overall yield of 1 was 45% in 11 steps from 2.     

1-deoxypaclitaxel and abeo-taxoids from the seeds of Taxus mairei

A new paclitaxel derivative and two new 2(3-->20)-abeo-taxoids were isolated from a methanol extract of the seeds of Taxus mairei, and their structures were established as 1-deoxypaclitaxel (1), 7beta,10beta-diacetoxy-2alpha,5alpha,13alpha-trihydroxy-2(3-->20)-abeo-taxa-4(20),11-dien-9-one (2), and 2alpha,13alpha-diacetoxy-10beta-hydroxy-2(3-->20)-abeo-taxa-4(20),6,11-triene-5,9-dione (3) on the basis of spectroscopic data analysis. Taxane 1 is the first example of a paclitaxel analogue with a C-1beta hydrogen substituent. Taxane 3 is an 2(3-->20)-abeo-taxane with a rare C-5 ketone and C-6 double bond.     

Antidiabetic complications and anti-Alzheimer activities of sophoflavescenol, a prenylated flavonol from Sophora flavescens, and its structure-activity relationship

It was previously reported that prenylated flavonols from Sophora flavescens are inhibitors of rat lens aldose reductase (RLAR), human recombinant aldose reductase (HRAR), advanced glycation endproducts (AGE), β-secretase (BACE1) and cholinesterases (ChE). Based upon structure-activity relationships, 3,4'-dihydroxy flavonols with a prenyl or lavandulyl group substitution at the C-8 position, and a hydroxy group at the C-5, are important for such inhibition. In our ongoing study to isolate active principles from S. flavescens by an activity-guided isolation procedure, further detailed phytochemical investigations of the CH(2)Cl(2) fraction were conducted via repeated chromatography over silica gel and Sephadex LH-20 columns. This ultimately resulted in the isolation of a promising active sophoflavescenol with higher inhibitory activities among the current prenylated flavonols isolated from S. flavescens against RLAR, HRAR, AGE, BACE1 and ChEs. The results further support that 3,4'-dihydroxy flavonols with a prenyl or lavandulyl substitution at the C-8 position and a methoxy group at C-5 represent a new class of RLAR, HRAR and AGE inhibitors. Nevertheless, the C-5 hydroxyl group of prenylated flavonoids is important for inhibition of BACE1 and ChEs, indicating that the hydroxyl group at C-5 might be the main contributor to the augmentation and/or modification of prenylated flavonol activity.     

Taxoids from Taxus chinensis

Two new taxoids, 13,15-epoxy-13-epi-taxayunnasin A (1) and taxchinin N (2), were isolated from the leaves and stems of Taxus chinensis. Compound 2 is the first taxoid to be reported with an alpha,beta-unsaturated lactone at C-4, C-5, C-20, and C-2. The structure of 1 was elucidated by spectroscopic analysis and confirmed by semisynthesis from taxayunnasin A, while 2 was determined structurally using spectroscopic methods and by single-crystal X-ray diffraction.     

Anxiolytic effect of natural galphimines from Galphimia glauca and their chemical derivatives

The anxiolytic effects of galphimine B (1), galphimine A (2), and galphimine E (3), natural nor-secofriedelanes isolated from Galphimia glauca, as well as derivatives obtained by acetylation (4), hydrogenation of the C-1/C-2 double bond (5), basic hydrolysis followed by hydrogenation of the C-1/C-2 double bond (6), and deacetylation (7) of galphimine E (3), were evaluated on ICR mice exposed to the elevated plus-maze test. This study also included the evaluation of a galphimines-rich fraction (GRF) with a known concentration of 1-3, obtained from the dry leaves of G. glauca. Intraperitoneal administration of 15 mg/kg of 1, 2, 6, and GRF (1 h before testing) caused an anxiolytic-like effect in the animals, increasing significantly (p <0.001) the percentage of time of permanence and the number of crossings toward the open arms of the plus-maze. No activity was detected after administration of compounds 3, 4, 5, and 7. These results showed that GRF had activity similar to the most active pure galphimines (1 and 2) and that, like for the spasmolytic activity previously reported, the main determining factor responsible for the anxiolytic activity of the compounds was the presence of free hydroxyl groups at C-4, C-6, and C-7 and the presence of the double bond in the A ring.     

The antiproliferative effect of acridone alkaloids on several cancer cell lines

Fifteen acridone alkaloids were examined for their antiproliferative activity toward monolayers and suspension of several types of cancer and normal human cell lines. As a result, atalaphyllidine (9), 5-hydroxy-N-methylseverifoline (11), atalaphyllinine (12), and des-N-methylnoracronycine (13) showed potent antiproliferative activity against tumor cell lines, whereas they have weak cytotoxicity on normal human cell lines. The structure-activity relationship established from the results revealed that a secondary amine, hydroxyl groups at C-1 and C-5, and a prenyl group at C-2 played an important role for antiproliferative activities of the tetracyclic acridones.     

Chiral decalins: preparation from oleanolic acid and application in the synthesis of (-)-9-epi-ambrox

A novel and versatile process was developed to prepare the trans-decalins Delta9(11)-3beta-acetoxysclareolide (2) and Delta9(11)-3beta-acetoxy-8-epi-sclareolide (3), respectively, with 4a-methoxycarbonyl-2,7,7-trimethyl-1-oxo-cis-decalin-2-ene (4) and its C-3 hydroxyl derivative 5 from oleanolic acid (3beta-hydroxyolean-12-en-28-oic acid, 1). Three key steps were (a) introduction of the AcO-12 group and the C-9,C-11 double bond at ring C of methyl 3beta-acetoxyolean-12-en-28-oate (8) to afford the diene, methyl 3,12-diacetoxyolean-9(11),12-dien-28-oate (11); (b) photolytic cleavage of the C-8,C-14 bond in the diene to give an acetoxy-substituted triene 14; and (c) oxidative cleavage of the triene or its hydrolyzed alpha,beta-unsaturated ketone product with m-CPBA/TsOH to give the cis- and trans-decalins 2-5. Delata9(11)-3beta-Acetoxysclareolide (2) was stereospecifically reduced to give 3beta-acetoxy-9-epi-sclareolide (23), from which (-)-9-epi-ambrox (7) was synthesized.     

Five novel highly oxygenated diterpenes of Orthosiphon stamineus from Myanmar

Five novel highly oxygenated diterpenes, orthosiphols K (1), L (2), M (3), and N (4) and norstaminone A (5), were isolated from the aerial part of Orthosiphon stamineus, together with three known diterpenes, orthosiphols A (6) and B (7) and neoorthosiphol A (8). Orthosiphol L (2) is an isopimarane-type diterpene with a hydroxyl group at C-12, which supports the biogenesis of staminane-type diterpenes, i.e., migration of a vinylic group from C-13 of isopimarane to C-12. Norstaminone A (5) has a staminane carbon framework and supports the biosynthetic pathway from staminols to norstaminols via staminolactones. All the isolated compounds showed mild to weak antiproliferative activities toward highly liver metastatic colon 26-L5 carcinoma and human HT-1080 fibrosarcoma cell lines.     

Two new 26,27-cyclosterols from the marine sponge Strongylophora corticata

Two novel steroids with a cyclopropane ring at C-25 and C-26, 7-oxopetrosterol (1) and 7alpha-hydroxypetrosterol (2), along with two known compounds, petrosterol (3) and 23,24-dihydrocalysterol (4), have been isolated from the Japanese marine sponge Strongylophora corticata. The structures of 1 and 2 were determined as 26, 27-cyclo-24,27-dimethyl-3beta-hydroxycholest-5-en-7-one and 26, 27-cyclo-24,27-dimethylcholest-5-en-3beta,7alpha-diol on the basis of spectroscopic investigations.     

Phytotoxic withanolides from Jaborosa rotacea

Twelve new withanolides were isolated from the aerial part of Jaborosa rotacea: five had a spiranoid delta-lactone (1-5); one contained a 26,12-delta-lactone and a C-12-C-23 bond (6); five corresponded to trechonolide-type withanolides with configuration at C-23 opposite of those previously isolated (7, 8, 10-12); two of these have an additional oxido-bridge between C-21 and C-24; finally a withanolide with a hemiketal ring formed between a 21-hydroxyl and a 12-ketone (13) and the closely related jaborosalactone R were also isolated. New compounds were fully characterized by a combination of spectroscopic methods (1D and 2D NMR and MS). The structures of the spiranoid withanolide and of the epimer of trechonolide A were confirmed by X-ray diffraction studies. Compounds 4, 5, 6, and 8 showed selective phytotoxicity toward monocotyledoneous and dicotyledoneous species.     

Halogenated boldine derivatives with enhanced monoamine receptor selectivity

(S)-(+)-Boldine (1) was brominated, chlorinated, and iodinated using molecular bromine in acetic acid or N-halosuccinimides in trifluoroacetic acid. Initial halogenation occurs at C-3, followed (in the cases of chlorine and bromine) by the less reactive C-8, to afford 3-haloboldines- and 3,8-dihaloboldines (2-5). Using a 2:1 ratio of N-iodosuccinimide to boldine, however, only the 3-iodo derivative 6 was obtained. Radioligand binding studies of these products showed that halogenation of boldine at C-3 favors affinity for D(1)- (vs D(2)-) dopaminergic receptors, attaining a low nanomolar IC(50) value in the case of 3-iodoboldine (6).     

New seco-prezizaane-type sesquiterpenes, jiadifenin with neurotrophic activity and 1,2-dehydroneomajucin from Illicium jiadifengpi

Two new seco-prezizaane-type sesquiterpenes, 1,2-dehydroneomajucin (1) and jiadifenin (2), were isolated from the methanol extract of the pericarps of Illicium jiadifengpi, indigenous to the southern part of China. Their structures were elucidated on the basis of NMR data. Compound 2, which is an equilibrated mixture of the epimers 2a and 2b on the C-10 acetal carbon, is the first example of a majucin-type seco-prezizaane with an oxo-function at the C-10 position. The proposed structure for 2 was unambiguously confirmed by chemical conversion of the known sesquiterpene (2S)-hydroxy-3,4-dehydroneomajucin (5) to 2. Compounds 2 and 5 were found to significantly promote neurite outgrowth in primary cultures of fetal rat cortical neurons at concentrations from 0.1 to 10 microM.     

Inhibitory effects of xanthones on platelet activating factor receptor binding in vitro

Nine naturally occurring xanthones were investigated for their platelet activating factor (PAF) receptor binding inhibitory effects using rabbit platelets. 2-(3-methylbut-2-enyl)-1,3,5-trihydoxyxanthone, macluraxanthone, 1,3,5-trihydroxy-6,6'-dimethylpyrano(2',3':6,7)-4-(1,1-dimethylprop-2-enyl)xanthone, 6-deoxyjacareubin and 2-(3-methylbut-2-enyl)-1,3,5,6-terahydroxyxanthone showed strong inhibition with IC50 values of 4.8, 11.0, 21.0, 29.0 and 44.0 microM, respectively. The prenyl group at C-2, the dimethylprop-2-enyl group at C-4 and the hydroxyl group at C-5 are all beneficial to the binding of xanthones to the PAF receptor. The results revealed that xanthones can represent a new class of natural PAF receptor antagonists.     

Nigerapyrones A-H, α-pyrone derivatives from the marine mangrove-derived endophytic fungus Aspergillus niger MA-132

Eight new α-pyrone derivatives, namely, nigerapyrones A-E (1-5) and nigerapyrones F-H (8-10), along with two known congeners, asnipyrones B (6) and A (7), were isolated from Aspergillus niger MA-132, an endophytic fungus obtained from the fresh tissue of the marine mangrove plant Avicennia marina. The structures of these compounds were elucidated on the basis of spectroscopic analysis. The undescribed geometries of the trisubstituted double bonds (C-9 and C-11) for asnipyrone B (6) have now been explicitly determined, while the incorrect placement of the methyl group at C-5 of asnipyrone A (7) has now been revised at C-3. The cytotoxic activities of the isolated α-pyrone derivatives against eight tumor cell lines as well as antimicrobial activities against two bacteria and four plant-pathogenic fungi of these compounds were evaluated. Compounds 2, 4, 5, and 7 showed weak cytotoxicity against some of the tested tumor cell lines.     

Anti-inflammatory triterpenes from the leaves of Rosa laevigata

Bioassay-guided fractionation of an EtOAc extract of the leaves of Rosa laevigata afforded two new 19-oxo-18,19-seco-ursane-type triterpenes (1 and 3), a new ursane-type nortriterpene (2), a new ursane-type triterpene lactone saponin (4), and two new oleanane-type triterpenoids (5 and 6), together with eight known triterpenoids (7-14). Compound 1, a 19-oxo-18,19-seco-28-norursane, possesses a conjugated diene between C-12 and C-17. Several of the isolated compounds (1, 5, 7, 11, and 13) exhibited moderate activities in anti-inflammatory assays in vitro.