Antiproliferative cardenolides from Pentopetia androsaemifolia Decne. from the Madagascar rain forest.

Plant natural products have historically been very important to drug discovery and development, particularly in the anticancer field. This is illustrated by a discussion of the structures and activities of camptothecin and its analogues, paclitaxel (Taxol), the vinca alkaloids vinblastine and vincristine, and podophyllotoxin and its analogues. A description of the isolation of one new and three known cardenolides from the Madagascar plant Pentopetia androsaemifolia is then provided as an example of this approach to drug discovery. The paper concludes with a brief discussion of betulinic acid, an old compound which is being developed into an anticancer and anti-HIV agent, and ipomoeassin F, an interesting antiproliferative compound isolated from a plant collected in Suriname.

Tambouranolide, a new cytotoxic hydroxybutanolide from a Tambourissa sp. (Monimiaceae).

A new cytotoxic hydroxybutanolide, tambouranolide, has been isolated by solid phase extraction from an ethanol extract of the dried roots of a species of Tambourissa (Monimiaceae) from the Madagascar rainforest. The structure was elucidated through the interpretation of spectral data and its comparison to data reported in the literature for related molecules. The compound showed moderate in vitro cytotoxicity with an IC50 of 8 micro g mL(-1) in the A2780 human ovarian cancer cell line assay.

Cytotoxic diterpenoids from Podocarpus madagascariensis from the Madagascar rainforest.

Bioassay-directed fractionation of an extract of the root and bark of Podocarpus madagascariensis resulted in the isolation of a new totarol diterpenoid (1) in addition to the three known cytotoxic diterpenoids 19-hydroxytotarol (2), totaradiol (3), and 4beta-carboxy-19-nor-totarol (4). The structure of the new compound 1 was established as methyl-13-hydroxy-14-isopropyl-9(11),12,14(8)-podocarpatriene-19-oate on the basis of 1D and 2D NMR spectroscopic interpretation and methylation of 4. All the compounds exhibited cytotoxic activity against the A2780 ovarian cancer cell line.

Cytotoxic compounds of Physena madagascariensis from the Madagascar rain forest paragraph sign.

Two new flavanones, remangiflavanones D and E (1 and 2), were isolated from an extract of the twigs, leaves, and flowers of Physena madagascariensis together with three known flavanones, remangiflavanones A-C (3-5), and (E)-N-feruloyltyramine (6). The structures of the new compounds 1 and 2 were established on the basis of one-dimensional and two-dimensional NMR spectroscopic data interpretation. All compounds were evaluated for their cytotoxicity in the A2780 human ovarian cancer cell line. Compound 5 was the most active with an IC50 value of 2.5 microg mL-1.

An antiproliferative xanthone of Symphonia pauciflora from the Madagascar rainforest.

Investigation of a Malagasy endemic plant identified as Symphonia pauciflora Baker (Clusiaceae) for antiproliferative activities against the A2780 ovarian cancer cell line led to the isolation of a new compound identified as 2-(3,3-dimethylallyl)-7-methoxy-l,5,6-trihydroxy-2",2"-dimethylpyrano(6",5":3,4) xanthone (1) and the two known guttiferones A (2) and I (3). The structure elucidation of 1 was based on the analysis of its 1D and 2D NMR and mass spectral data. Compound 1 showed good antiproliferative activity with an IC50 value of 3.8 microM against the A2780 human ovarian cancer cell line, while the known guttiferone analogues (2 and 3) exhibited moderate activities with IC50 values of 8.3 microM and 7.8 microM, respectively.

A new labdane diterpene from Vitex cauliflora Moldenke from the Madagascar rainforest.

Fractionation of an antiplasmodial ethanolic extract from the aerial parts of Vitex cauliflora led to the isolation of the new labdane diterpene 1 together with the known triterpene uvaol. The structure of the new compound 1 was established as 3-oxo,15,17,18-triacetoxy-labda-7,13E-diene on the basis of spectroscopic data (1D and 2D NMR, MS).

Euphane triterpenoids of Cassipourea lanceolata from the Madagascar rainforest.

Fractionation of an ethanol extract of a Madagascar collection of the leaves and fruit of Cassipourea lanceolata Tul. led to the isolation of three euphane triterpenoids 1-3. The (1)H and (13)C NMR spectra of all compounds were fully assigned using a combination of 2D NMR experiments, including COSY, TOCSY, HSQC (HMQC), HMBC and ROESY sequences. The three compounds showed weak antiproliferative activities against the A2780 human ovarian cancer cell line, with IC(50) values of 25, 25 and 32 microM, respectively.

Antiproliferative compounds of Helmiopsis sphaerocarpa from the Madagascar rainforest.

Bioassay-directed separation of an ethanol extract of the leaves of Helmiopsis sphaerocarpa L.C. Barnett (Sterculiaceae) led to the isolation of the new compound 14alpha,15alpha-epoxy-3beta-hydroxytaraxerane (1) and the four known compounds taraxerol (2), stigmast-5-en-3-ol (3), 5alpha,8alpha-epidioxy-24(S)-methylcholesta-6,22-dien-3beta-ol (4), and 24xi-hydroperoxy-24-ethylcholesta-4,28(29)-dien-3-one (5). The structure of the new compound 1 was established on the basis of interpretation of its 1D and 2D NMR spectroscopic data. All the compounds were tested against A2780 human ovarian cancer cell lines, and compounds 4 and 5 showed mild antiproliferative activity, with IC(50) values of 16 and 7 microg mL(-1), respectively.

Antiproliferative cassane diterpenoids of Cordyla madagascariensis ssp. madagascariensis from the Madagascar rainforest.

Bioassay-guided fractionation of an ethanol extract of a Madagascar collection of the fruits of Cordyla madagascariensis ssp. madagascariensis led to the isolation of the four new cassane diterpenoids 1-4. The 1H and 13C NMR spectra of all compounds were fully assigned using a combination of 2D NMR experiments, including COSY, HSQC, HMBC, and ROESY sequences. All of the isolates were tested against the A2780 human ovarian cancer cell line, and compounds 1 and 2 showed mild antiproliferative activity with IC50 values of 10 and 36 microM, respectively.

Antiproliferative limonoids of a Malleastrum sp. from the Madagascar rainforest.

Bioassay-guided fractionation of an ethanol extract of a Malleastrum sp. afforded three new limonoids, malleastrones A-C ( 1- 3), respectively. Each limonoid contained a rare tetranortriterpenoid skeleton. Structure elucidation of the isolates was carried out by analysis of one- and two-dimensional NMR and X-ray diffraction data. The novel isolates 1 and 2 were tested for antiproliferative activity against a panel of cancer cell lines and exhibited IC 50 values ranging from 0.19 to 0.63 microM.

Cytotoxic clerodane diterpenoids and their hydrolysis products from Casearia nigrescens from the rainforest of Madagascar.

Bioassay-guided fractionation of the cytotoxic leaf and flower extract of Casearia nigrescens led to the isolation of four new clerodane diterpenoids, designated caseanigrescens A-D (1-4). These compounds were subject to hydrolysis to dialdehydes when stored in CDCl3. The structures of compounds 1-4 were determined using 1D and 2D NMR spectroscopy. All four compounds showed moderate cytotoxicity to the A2780 human ovarian cancer cell line, with an IC50 range of 0.83-1.4 microM.

Antiproliferative xanthones of Terminalia calcicola from the Madagascar rain forest.

A bioassay-guided fractionation of the EtOH extract of the Madagascan plant Terminalia calcicola led to the isolation of two new cytotoxic xanthones, termicalcicolanone A (1) and termicalcicolanone B (2). The structures of the new compounds were established on the basis of one- and two-dimensional NMR spectroscopic data. Both compounds showed modest antiproliferative activity toward the A2780 human ovarian cancer cell line.

Antiproliferative prenylated stilbenes and flavonoids from Macaranga alnifolia from the Madagascar rainforest.

Bioassay-guided fractionation of an extract of the fruit of Macaranga alnifolia from Madagascar led to the isolation of four new prenylated stilbenes, schweinfurthins E-H (1-4), and one new geranylated dihydroflavonol, alnifoliol (5). The known prenylated stilbene vedelianin (6) and the known geranylated flavonoids bonanniol A (7), diplacol (8), bonannione A (9), and diplacone (10) were also isolated. All 10 compounds were tested for antiproliferative activity in the A2780 human ovarian cancer cell line assay. Vedelianin (IC50 = 0.13 microM) exhibited the greatest activity among all isolates, while schweinfurthin E (IC50 = 0.26 microM) was the most potent of the new compounds.

Cytotoxic triterpenoid saponins of Albizia gummifera from the Madagascar rain forest.

Bioassay-guided fractionation of an EtOH extract obtained from the roots of the Madagascan plant Albizia gummifera led to the isolation of three new cytotoxic oleanane-type triterpenoid saponins, gummiferaosides A-C (1-3). The structures of these new compounds were elucidated using 1D and 2D NMR experiments and mass spectrometry. Compounds 1-3 showed cytotoxicity against the A2780 human ovarian cancer cell line with IC50 values of 0.8, 1.5, and 0.6 microg/mL, respectively.

Cytotoxic cardenolide glycosides of Roupellina (Strophanthus) boivinii from the Madagascar rainforest.

Bioassay-guided fractionation of an ethanol extract of Roupellina (Strophanthus) boivinii from the rainforest of Madagascar afforded the six new cardenolide glycosides boivinides 1-6, as well as the four known cardenolide glycosides digitoxigenin 3-O-[beta-D-glucopyrananosyl-(1-->4)-alpha-L-acofriopyranoside], corotoxigenin 3-O-beta-D-boivinoside, 17alpha-corotoxigenin 3-O-beta-D-sarmentoside, and uzarigenin 3-O-alpha-L-rhamnoside. The structures of these compounds were elucidated by various 1D and 2D NMR techniques. All new compounds showed significant antiproliferative activity against the A2780 human ovarian cancer cell line, with boivinide A being the most active at IC50 = 0.17 microM.

Cytotoxic compounds of Schizolaena hystrix from the Madagascar rainforest.

Bioassay-guided fractionation of a crude ethanol extract from a Madagascar collection of Schizolaena hystrix afforded the two new long-chain compounds, 3 S-acetoxyeicosanoic acid ethyl ester ( 1) and 3 S-acetoxydoeicosanoic acid ( 2), and the known long-chain compound 3 S-acetoxyeicosanoic acid ( 3). In addition, the long-chain alcohol 1-hydroxydodecan-2-one ( 7), as well as the new flavonoid schizolaenone C ( 4) and the two known flavonoids diplacol ( 5) and 3'-prenylnaringenin ( 6) were isolated from a methanol extract of the same plant. Isolation and structure elucidation of the novel compounds and the cytotoxicities of all the isolates are reported.

Two new cytotoxic naphthoquinones from Mendoncia cowanii from the rainforest of Madagascar.

Bioassay-guided fractionation of the root and stem extracts of Mendoncia cowanii led to the isolation of two new and two known naphthoquinones. The structures of the new compounds, avicequinones D and E (1 and 2), were determined using 1D and 2D NMR spectroscopy and by chemical conversion of compound 1 to 2. The new compounds were active in the A2780 human ovarian cancer cell line with IC50 values of 7.4 - 50 microM, respectively, and 1, 3, and 4 were subsequently found to be weakly active in an assay for inhibition of the kinase Akt.

Cytotoxic diterpenes from Cassipourea madagascariensis from the Madagascar rainforest.

Bioassay-directed fractionation of ethanol extracts of the roots and leaves of the plant Cassipourea madagascariensis resulted in the isolation of the two new terpenoids cassipourol (1) and cassipouryl acetate (2) in addition to the three known compounds, 3beta,30-dihydroxylup-20(29)-ene (3), 30-hydroxylup-20(29)-en-3-one (4), and combretol (5). The structures of the two new compounds were established on the basis of 1D and 2D NMR spectroscopic data and chemical conversion. All the isolated compounds were tested against the A2780 human ovarian cancer cell line; the two diterpenes (1 and 2) showed moderate cytotoxic activity, while the three known compounds (3-5) were weakly active.

Cytotoxic and other compounds from Didymochlaena truncatula from the Madagascar rain forest.

Bioassay-guided fractionation of the EtOH extracts obtained from a plant identified as Didymochlaena truncatula led to the isolation of two cytotoxic alkaloids, camptothecin and 9-methoxycamptothecin. A second plant collection yielded three lignan derivatives, didymochlaenone A (1), didymochlaenone B (2), and (-)-wikstromol, one stilbene, (E)-3-methoxy-5-hydroxystilbene, and two stigmasterol derivatives, stigmast-4-en-3beta-ol and stigmast-4-en-3-one, but no camptothecins, and it is probable that a coding error led to a mistaken identification of the original extract. The structures of the new compounds 1 and 2 were established on the basis of extensive interpretation of one- and two-dimensional NMR spectroscopic data.

Cytotoxic sesquiterpene lactones from Vernonia pachyclada from the Madagascar rainforest.

Bioassay-guided fractionation of the cytotoxic leaf extract of Vernonia pachyclada Baker led to the isolation of three new sesquiterpene lactones, designated glaucolides K-M (1-3). The structures of the new compounds were determined using 1D and 2D NMR spectroscopy, and the structure and stereochemistry of 1 were confirmed by single-crystal X-ray diffraction. Compound 3 showed moderate activity in the A2780 human ovarian cancer cell line, with an IC50 of 3.3 microM.