Synthesis and biological evaluation of N-(arylsulfanyl)carbonyl analogues of paclitaxel (taxol).

Four new N-(arylsufanyl)carbonyl paclitaxel analogues (2a-d) were prepared from 7-(triethylsilyl)-protected baccatin III (5). Their cytotoxicities against human ovarian (A2780) and prostate cancer (PC3) cell lines, as well as their tubulin-assembly activities, were determined. In these assays, the new compounds showed rather weak activities, one two orders of magnitude below those of paclitaxel (taxol; 1). The known 3'-N-[(thiophen-2-yl)carbonyl] paclitaxel analogue 3 was also prepared. As previously reported, 3 exhibited strongly improved cytotoxicities and tubulin-assembly activities as compared to paclitaxel (1).

Cytotoxic diterpenoids from two lianas from the Suriname rainforest.

Bioassay-guided fractionation of the MeOH and EtOAc fractions of extracts of two lianas collected in Suriname has led to the isolation of five new diterpenoids, humirianthone 1, 1-hydroxy-humirianthone 2, 15R-humirianthol 3, patagonol 4, and patagonal 5, and the five known diterpenoids, humirianthol 7, annonalide 8, acrenol 9, icacinol 10, and the oxidized annonalide 11. All 10 diterpenoids showed cytotoxic activity against the A2780 human ovarian cancer cell line, and compounds 1, 3, 8, and 9 also showed activity against phytopathogenic fungi.

New eudesmane derivatives from Melampodium camphoratum from the Suriname rainforest.

Bioassay-guided fractionation of an EtOAc extract of the leaves of Melampodium camphoratum using an assay for inhibitors of the degradation of hemin resulted in the isolation of six new eudesmane sesquiterpenes (1-6) and the known 6-epi-beta-verbesinol coumarate (7). The structures of compounds 1-6 were established as 6alpha-(4'-O-methyl-7'E-coumaryloxy)eudesm-4(14)-ene (1), 6alpha-({4'-O-stearyl}-7'E-coumaryloxy)eudesm-4(14)-ene (2), 6alpha-({4'-O-palmityl}-7'E-coumaryloxy)eudesm-4(14)-ene (3), 6alpha-({4'-O-[9' 'Z-hexadecenoyl]}-7'E-coumaryloxy)eudesm-4(14)-ene (4), 6alpha-(7'Z-coumaryloxy)eudesm-4(14)-ene (5), and 6alpha-({4'-acetoxy}-7'Z-coumaryloxy)eudesm-4(14)-ene (6). Compounds 1-4 showed weak activity in the hemin degradation assay, while compounds 5-7 were inactive.

Syntheses and bioactivities of macrocyclic paclitaxel bis-lactones.

Five macrocyclic paclitaxel bis-lactones and their corresponding open chain taxoids were synthesized as models of the tubulin-binding conformation of paclitaxel. Macrocyclic lactones with a 19-21-membered ring underwent isomerization to form smaller rings. The lactones were evaluated for cytotoxicity and tubulin-polymerization ability. All five macrocyclic paclitaxel lactones were active, but less so than paclitaxel, while the rearranged macrocyclic lactones and the corresponding open-chain taxoids were much less active or inactive.

New cytotoxic alkyl phloroglucinols from Protorhus thouvenotii.

Two new cytotoxic alkylene phloroglucinols and one known compound were isolated through chromatographic separation from the methanolic extract of the dried fruits of Protorhus thouvenotii (Anacardiaceae). The compounds showed marginal in vitro cytotoxicity in the A2780 ovarian cancer cell line assay with an IC50 of 11 microg/mL.

New cytotoxic terpenoids from the wood of Vepris punctata from the Madagascar Rainforest.

Continuation of the chemical examination of the cytotoxic constituents of the wood of Vepris punctata resulted in the isolation of the two new terpenoids 1 and 2 and eight known compounds, glechomanolide (3), isogermafurenolide, (E,E)-germacra-1(10),4,7(11)-triene, alpha-amyrin, lupeol, lupeyl acetate, taraxerol, and 3-epi-taraxerol, in addition to the alkaloids reported reported previously. The structures of the two new compounds were established on the basis of 1D and 2D NMR spectroscopic data interpretation and chemical modifications. All the isolated compounds were tested against the A2780 human ovarian cancer cell line; the four sequiterpenoids showed moderate cytotoxic activity, while the six triterpenoids were inactive.

Cytotoxic compounds from Mundulea chapelieri from the Madagascar Rainforest.

Bioassay-guided fractionation of methanolic extracts of Mundulea chapelieri resulted in the isolation of two new flavonoids, isomundulinol (1) and 3-deoxy-MS-II (2), in addition to the eight known flavonoids 8-(3,3-dimethylallyl)-5,7-dimethoxyflavanone, MS-II, mundulinol, mundulone, munetone, rotenolone, rotenone, and tephrosin, and one known sesquiterpenoid, 8alpha-acetoxyelemol. The structures of the new flavonoids 1 and 2 were determined by 1D and 2D NMR experiments. All the isolated compounds were tested for cytotoxicity against the A2780 human ovarian cancer cell line; rotenolone and rotenone were the most potent compounds isolated, with IC(50) values of 0.5 and 0.7 microg/mL, respectively.

Design, synthesis, and bioactivities of steroid-linked taxol analogues as potential targeted drugs for prostate and breast cancer.

The female steroid hormone 3,17beta-estradiol (2) was selected as an agent to target taxol (1) to estrogen receptor (ER) positive breast cancer cells. Estradiol-taxol conjugates (ETC) were synthesized through linkages from the 11- or 16-position of estradiol to the 2'-, 7-, or 10-position of taxol. All conjugates were cytotoxic to the A2870 ovarian cancer cell line, although less so than taxol. The MCF-7 breast cancer cell line (ER-alpha positive) and MDA-MB-231 breast cancer cell line (ER-alpha negative) were also used to evaluate the selectivity and cytotoxicity of these conjugates. One conjugate showed some selectivity for ER positive cells, but it was less potent than taxol. Two ETC hemisuccinates were also prepared to improve the solubility of the conjugates. The corresponding Na and triethanolammonium salts were slightly more cytotoxic than the acid form but were much less cytotoxic than the corresponding ETC.

Highly hydroxylated triterpenes from Salvia kronenburgii.

The three new triterpenes (1-3) and five known triterpenes and a sterol were isolated from the acetone extract of a Turkish collection of Salvia kronenburgii. The structures of the new triterpenes were established as 1beta,2alpha-dihydroxy-3beta-acetoxy-11-oxours-12-ene (1), 2alpha,20beta-dihydroxy-3beta-acetoxyurs-9(11),12-diene (2), and 1beta,2alpha-dihydroxy-3beta-acetoxyurs-9(11),12-diene (3) on the basis of spectral analyses, including 1D and 2D NMR and mass spectroscopy. It is probable that compounds 2 and 3 are artifacts from dehydration of the corresponding allylic alcohols. 1beta,2alpha,3beta,11alpha-Tetrahydroxyurs-12-ene (5), the most abundant compound in the extract, was found to be highly cytotoxic to renal, non-small cell lung, and breast cancer cell lines.

New cytotoxic oleanane saponins from the infructescences of Polyscias amplifolia from the Madagascar rainforest.

Bioassay-guided fractionation of an ethanolic extract of the infructescences of Polyscias amplifolia resulted in the isolation of two new oleanolic acid saponins, polyfoliolides A (1) and B (2), in addition to the two known saponins 3-O-beta-D-galactopyranosyloleanolic acid (3) and 3-O-beta-D-galactopyranosyl-(1-->4)-beta-D-galactopyranosyloleanolic acid (4). The structures of the two new compounds were established as 3-O-beta- D-galactopyranosyl-(1-->4)-beta-D-xylopyranosyloleanolic acid (1) and 3-O-beta-D-galactopyranosyl-(1-->4)-alpha-L-arabinopyranosyloleanolic acid (2) on the basis of extensive 1D and 2D NMR spectroscopic data interpretation and chemical conversions. All the isolated compounds showed weak cytotoxicity against A2780 human ovarian cancer cell line, with IC50 values in the range 6.7 to 10.8 microg/mL.

New cytotoxic triterpene acids from aboveground parts of Manihot esculenta from the Suriname rainforest.

Two novel triterpene acids, esculentoic acid A ( 1) and B ( 2) as well as the seven known compounds 3 - 9 were isolated from an EtOAc extract of leaves, stems, and twigs of Manihot esculenta by bioassay-guided fractionation for cytotoxic activity. The structures of the two new compounds were established as 3alpha-hydroxytaraxer-14-en-29-oic acid ( 1) and 3-oxotaraxer-14-en-29-oic acid ( 2) on the basis of 1D and 2D NMR spectroscopic data interpretation and chemical conversions. The two new compounds 1 and 2 showed moderate cytotoxicity against the A2780 human ovarian cancer cell line.

New cytotoxic indole alkaloids from Tabernaemontana calcarea from the Madagascar rainforest.

Bioassay-directed fractionation of the alkaloid portion of a CH(2)Cl(2)-MeOH extract of Tabernaemontana calcarea resulted in the isolation of the three new cytotoxic indole alkaloids, 1-3, and the 12 known alkaloids voacangine (4), isovoacangine (5), coronaridine (6), 11-hydroxycoronaridine (7), voacristine (8), 19-epi-voacristine (9), isovoacristine (10), ibogamine (11), 10-methoxyibogamine (12), 11-methoxyibogamine (13), heyneanine (14), and 19-epi-heyneanine (15). The structures of the new compounds 1-3 were elucidated on the basis of extensive 1D and 2D NMR spectroscopic interpretation. All the compounds exhibited cytotoxic activity against the A2780 ovarian cancer cell line.

New cytotoxic alkaloids from the wood of Vepris punctata from the Madagascar rainforest.

Bioassay-guided fractionation of a CH(2)Cl(2)/MeOH extract of the wood of Vepris punctata resulted in the isolation of three new furoquinoline alkaloids, 5-methoxymaculine (1), 5,8-dimethoxymaculine (2), and 4,5,6,7,8-pentamethoxyfuroquinoline (3), in addition to the four known alkaloids flindersiamine (4), kokusaginine (5), maculine (6), and skimmianine (7). The structures of the new alkaloids 1-3 were established on the basis of extensive 1D and 2D NMR spectroscopic data interpretation. All the isolated compounds were tested against the A2780 human ovarian cancer cell line, and all seven alkaloids showed weak cytotoxic activity.

New cytotoxic lupane triterpenoids from the twigs of Coussarea paniculata.

Bioassay-guided fractionation of a CH(2)Cl(2)-MeOH extract of the twigs of Coussarea paniculata using a yeast-based assay for potential DNA-damaging agents resulted in the isolation of three new lupane triterpenoids, 1-3, in addition to eight known triterpenoids, lupeol (4), lupeyl acetate (5), betulin (6), betulinic acid (7), 3-epi-betulinic acid (8), 3-epi-betulinaldehyde (9), oleanolic acid (10), and ursolic acid (11). The structures of the new compounds were established as lup-20(29)-en-3beta,25-diol (1), lup-20(29)-en-11alpha-ol-25,3beta-lactone (2), and 3-deoxybetulonic acid (3), on the basis of extensive 1D and 2D NMR spectroscopic data interpretation and chemical conversion.

New cytotoxic bis 5-alkylresorcinol derivatives from the leaves of Oncostemon bojerianum from the Madagascar rainforest.

Bioassay-directed fractionation of a CH(2)Cl(2)-MeOH extract of the leaves of Oncostemon bojerianum resulted in the isolation of eight new 5-alkylresorcinols, named oncostemonols A-H (1-8), and two known derivatives, (8'Z)-1,3-dihydroxy-5-[16'-(3' ',5' '-dihydroxyphenyl)-8'-hexadecen-1'-yl]benzene (9) and (8'Z)-1,3-dihydroxy-5-[14'-(3' ',5' '-dihydroxyphenyl)-8'-tetradecen-1'-yl]benzene (10). The structures of the new compounds 1-8 were elucidated on the basis of extensive 1D and 2D NMR spectroscopic interpretation and chemical derivatization. All the compounds exhibited cytotoxic activity against the A2780 ovarian cancer cell line.

Two new triterpene esters from the twigs of Brachylaena ramiflora from the Madagascar rainforest.

Bioassay-guided fractionation of a CH(2)Cl(2)/MeOH extract of the small twigs of Brachylaena ramiflora var. ramiflora resulted in the isolation of the two new triterpene esters 1 and 2 and five known triterpenoids, alpha-amyrin palmitate (3), beta-amyrin palmitate (4), beta-amyrin acetate (5), lupeyl acetate (6), and lupeol (7). The structures of the two new compounds were established as kairatenyl palmitate (1) and hopenyl palmitate (2) on the basis of 1D and 2D NMR spectroscopic data interpretation and chemical conversions. All the isolated compounds showed weak cytotoxicity against the A2780 human ovarian cancer cell line.

New cytotoxic coumarins and prenylated benzophenone derivatives from the bark of Ochrocarpos punctatus from the Madagascar rainforest.

Bioassay-guided fractionation of a CH2Cl2-MeOH extract of the bark of Ochrocarpos punctatus resulted in the isolation of seven new coumarins, ochrocarpins A-G (1-7), three new benzophenone derivatives, ochrocarpinones A-C (8-10), and five known coumarins, mammea A/AC cyclo F (11), mammea A/AD cyclo D (12), mammea A/AB cyclo F (13), mammea A/AA cyclo F (14), mammea A/AB cyclo D (15), and 15,16-dihydro-16-hydroperoxyplukenetione (16). The structures of compounds 1-10 were established on the basis of extensive 1D and 2D NMR spectroscopic data interpretation. All compounds exhibited cytotoxicity against the A2780 ovarian cancer cell line.