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The biological activity of natural and semisynthetic lupane triterpenoids is discussed in a two-part review. The first part is devoted to the pharmacological properties of natural lupane triterpenoids. Betulinic acid has proven to be the most effective antitumor agent among more than fifty natural lupanes.
The discussion of lupane triterpenoids as prospective medicinal preparations is continued, and semisynthetic triterpenoids are being discussed. Acyl derivatives that mainly exhibit high anti-HIV, antitumor, and organo-protective activities are described. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2006, vol. 32, no. 3; see also http://www.maik.ru.
Bioassay-directed fractionation of a methyl ethyl ketone extract of Solidago canadensis L. (Asteraceae), using an assay to detect the lyase activity of DNA polymerase beta, resulted in the isolation of the four new lupane triterpenoids 1-4 and the seven known compounds lupeol, lupeyl acetate, ursolic acid, cycloartenol, cycloartenyl palmitate, alpha-amyrin acetate, and stigmasterol. The structures of the new compounds were established as 3beta-(3R-acetoxyhexadecanoyloxy)-lup-20(29)-ene (1), 3beta-(3-ketohexadecanoyloxy)-lup-20(29)-ene (2), 3beta-(3R-acetoxyhexadecanoyloxy)-29-nor-lupan-20-one (3), and 3beta-(3-hetohexadecanoyloxy)-29-nor-lupan-20-one (4), respectively, on the basis of extensive 1D and 2D NMR spectroscopic interpretation and chemical modification studies. All 11 compounds were inhibitory to the lyase activity of DNA polymerase beta.
Cellular screening of various synthetic triterpenoid compounds formally derived from lupane has identified a number of analogues as potential anticancer drug candidates. Here we describe the synthesis and structure-activity relationships of betulin and betulinic acid derivatives containing an E-ring modified with different oxygen functions. Thus compounds containing the lup-18-en-21-one, lup-18-ene-21,22-dione, 18,19-secolupane, and the highly oxygenated 18,19-secolupane systems, as well as des-E-lupane derivatives, were prepared from the readily available natural pentacyclic triterpene betulin using oxidative procedures. These compounds were named betulinines. We demonstrate that only selected compounds, particularly those containing a lupane E-ring-derived unsaturated ketone or diketone function, possessed in vitro cytotoxic activity against tumor cell lines, suggesting a structure-activity relationship.
The weak hydrosolubility of betulinic acid (3) hampers the clinical development of this natural anticancer agent. In order to circumvent this problem and to enhance the pharmacological properties of betulinic acid (3) and the lupane-type triterpenes lupeol (1), betulin (2), and methyl betulinate (7), glycosides (beta-D-glucosides, alpha-L-rhamnosides, and alpha-D-arabinosides) were synthesized and in vitro tested for cytotoxicity against three cancerous (A-549, DLD-1, and B16-F1) and one healthy (WS1) cell lines. The addition of a sugar moiety at the C-3 or C-28 position of betulin (2) resulted in a loss of cytotoxicity. In contrast, the 3-O-beta-D-glucosidation of lupeol (1) improved the activity by 7- to 12-fold (IC50 14-15.0 microM). Moreover, the results showed that cancer cell lines are 8- to 12-fold more sensitive to the 3-O-alpha-L-rhamnopyranoside derivative of betulinic acid (IC50 2.6-3.9 microM, 22) than the healthy cells (IC50 31 microM). Thus, this study indicates that 3-O-glycosides of lupane-type triterpenoids represent an interesting class of potent in vitro cytotoxic agents.
The cytotoxicities of 11 lupane series triterpenes against 3 human leukemias, 2 melanomas, 2 neuroblastomas and normal fibroblast cells were examined. Lupane triterpenes with a carbonyl group at C-17 (7-11) showed inhibitory effects on leukemia, melanoma and neuroblastoma cell growth. Lup-28-al-20(29)-en-3-one (8) markedly inhibited the cell growth of 3 leukemias to a greater extent than the other human cancers and normal lung fibroblast cells. The cytotoxicity profiles of 8 against human cancer cells showed that its cytotoxic effect against 3 lung cancer cell lines was strong and the cytotoxic effects against osteosarcoma, breast cancer and urinary bladder cancer cells were very weak. The morphological observations of leukemia nuclei and the gel electrophoresis analysis of DNA extracted from 8-treated leukemia cells revealed that 8 induced leukemia cell apoptosis. Furthermore, we investigated the cytotoxic effects of 8 on adriamycin (ADM)- and vincristine (VCR)-resistant K562 (K562/ADM and K562/VCR) cells. K562/ADM and K562/VCR cells showed greater resistance toward ADM and VCR when compared to parent K562 cells. However, 8 inhibited the drug-resistant K562 cell growth to the same extent as K562 cells by the induction of apoptosis.
Three known saponins, chiisanoside, 11-deoxyisochiisanoside, and isochiisanoside, and one novel saponin, 3,4-seco-4(23),20(29)-lupadiene-3,28-dioic acid 28-O-alpha-l-rhamnopyranosyl (1-->4)-beta-d-glucopyranosyl (1-->6)-beta-d-glucopyranoside, referred to as sessiloside, were isolated from a hot water extract of Acanthopanax sessiliflorus leaves. All of these saponins were lupane-type triterpene triglycosides, and their concentrations were 4.1, 1.0, 0.5, and 0.4% (w/w) of the total extract, respectively. Sessiloside and chiisanoside inhibited pancreatic lipase activity in vitro, and addition of the saponin-rich fraction to a high-fat diet suppressed the body weight gain of mice. The possibility of application of the lupane-type saponins from A. sessiliflorus leaves to the treatment of obesity is discussed.
Chloroform-soluble extracts of the stems and of the mixed stems and stem bark of Lophopetalum wallichii were found to be inhibitory in a farnesyl protein transferase (FPTase) bioassay system. During the course of activity-guided fractionation, the known lupane-type triterpenes, ochraceolide A (1), ochraceolide B (2), betulin, and lupeol and the new lupane lactone, dihydro ochraceolide A (4), were isolated. The stereochemistry of the epoxide group of ochraceolide B (2) was determined by preparation of both epoxide isomers [2, and the new semisynthetic derivative, 20-epi-ochraceolide B (3)] from 1. The structure of 4 was established by reduction of 1 with sodium borohydride. Compounds 1 and 2 exhibited significant inhibitory activity in the FPTase assay (IC50 values of 1.0 and 0.7 microgram/mL, respectively). Lupeol was found to be weakly active (IC50 65.0 micrograms/mL) in this test system, whereas no significant inhibition was detected for betulin or compounds 3 or 4. When evaluated against a panel of human cancer cells in culture, compounds 1 and 4 were modestly cytotoxic. Compounds 2 and 3 were not active in the panel.
Four known lupane-type triterpenoids, glochidonol (1), glochidiol (2), lup-20(29)-ene-1beta,3beta-diol (3) and glochidone (3) were isolated from the stem bark of Glochidion zeylanicum. Previously, lupeol (5), lup-20(29)-ene-3beta,24-diol (6) and betulin (7) were isolated from the stem bark of Phyllanthus flexuosus. This study reports the assays of these lupane-type triterpenoids: all isolates 1-7 and synthetic analogues, glochidonyl acetate (1a), lup-20(29)-ene-1,3-dione (1b) and lup-20(29)-ene 3beta,24-diacetate (6a) were tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA). Among them, the effects of compounds 2 (IC50 = 290 mol ratio/32 pmol TPA) and 3 (IC50 = 300) were stronger than the others. In addition, compound 2 exhibited a strong inhibitory effect on mouse skin tumor promotion in an in vivo mouse two-stage carcinogenesis test.
Six known lupanes lupenone ( 1), 3- epi-lupeol ( 2), glochidone ( 4), glochidonol ( 5), glochidiol ( 6) and lup-20(29)-ene-1beta,3beta-diol ( 7) were isolated from the roots and stem wood of Glochidion eriocarpum and three, 5, 6 and lup-20(29)ene-3alpha,23-diol ( 3), were isolated from the roots and stem wood of Glochidion sphaerogynum. Compounds were identified by (1)H- and (13)C-NMR techniques. Triterpenes 2 - 7 were tested against the growth of three human tumor cell lines, MCF-7, NCI-H-460 and SF-268. Lupanes 3, 5, and 6 exhibited strong inhibitory effects against all three; thus GI (50) values for 3 were 12.7 +/- 3.7, 17.9 +/- 1.1 and 17.9 +/- 0.5, for 5 9.0 +/- 3.7, 4.9 +/- 0.2 and 9.8 +/- 0.5, and for 6 6.63 +/- 0.7, 7.5 +/- 0.5 and 9.7 +/- 0.3.3. Epilupeol was less active, with GI (50) values of 75.6 +/- 11.7, 86.1 +/- 12.4 and 80.9 +/- 2.6 while 7 was moderately active only against MCF-7 (GI (50) = 79.2 +/- 2.4). Additional studies indicated that triterpenes 5 and 6 exerted their antiproliferative activity through the involvement of apoptosis while triterpene 3 did not.
A novel lupane-triterpene glycoside, called wujiapioside B (1), was isolated from the leaves of Acanthopanax gracilistylus (Araliaceae) together with three known lupane-triterpene glycosides, acankoreoside C (2), acantrifoside A (3) and 3-epibetulinic acid 28-O-alpha-L-rhamnopyranosyl-(1-->4)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl ester (4). Based on spectroscopic data, the chemical structure of 1 was determined as 3alpha,23-dihydroxy-lup-20(29)-en-28-oic acid 28-O-alpha-L-rhamnopyranosyl-(1-->4)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl ester. Compounds 2-3 were obtained for the first time from this plant and compound 4 has not been isolated from Acanthopanax genus yet.
A new lupane type triterpenoid, 3beta, 11alpha-dihydroxy-30-norlupan-20-one and 6 known lupane triterpenoids were isolated from the petroleum ether (60-90 degrees C) extract of the whole plant of Salvia roborowskii Maxim. Their structures were elucidated by means of spectral methods including NMR and MS techniques.
The isolation and NMR data of seco-lupane triterpenes and coumarins from Platypodium elegans are reported.
A new seco-ring A lupane triterpene derivative (1), along with lupenone, lupeol, beta-sitosterol, ursolic acid, and stigmasterol 3-O-beta-d-glucoside, were isolated from a methanol extract of mature stems of Lasianthus gardneri, a shrub from the family Rubiaceae growing in Sri Lanka. The structure and stereochemistry of the new compound were determined using a combination of (13)C and (1)H homo- and heteronuclear 2D NMR experiments and from mass spectral data. The structure of 1 was confirmed by partial synthesis from lupeol.
Three new compounds, ochraceolides A, B, and C, were isolated from nonpolar extracts derived from Kokoona ochracea stem bark. Based on spectroscopic data, their structures were determined to be the closely related lupane lactones: 3-oxolup-20(29)-en-30,21 alpha-olide, 20,29-epoxy-3-oxolupan-30,21 alpha-olide, and 3,6-dioxolup-20(29)-en-30,21 alpha-olide. Compounds 1 and 3 exhibited significant cytotoxic activity with cultured P-388 cells (ED50 values of 0.26 and 0.53 microgram/ml, respectively) but were at least tenfold less active with a variety of human tumor cell lines. Compound 2 was weakly active with cultured P-388 and KB-3 cells (ED50 values of 7.8 and 5.2 micrograms/ml, respectively), but no significant activity was observed with other human cancer cell types (ED50 values of more than 20 micrograms/ml).
We examined the differentiation-inducing effects of extracts of 49 wild plants, 25 types of seaweed and 26 mushrooms in Akita on the human leukemia cell line HL60 and a B16 mouse melanoma-derived sub-clone with high differentiation capability (B16 2F2). Differentiation inducers of HL60 cells such as retinoic acid, showed no effects on the differentiation of B16 2F2 cells. Furthermore, chemical compounds known to be inducers of B16 cells, did not induce differentiation of HL60 cells. Screening tests showed that the differentiation of HL60 cells was induced by extracts of 28 wild plants, 10 types of seaweed and 2 mushrooms, and melanogenesis of B16 2F2 cells was increased by extracts of 21 wild plants, 8 types of seaweed and 7 mushrooms. All of the alcoholic extracts of plants belonging to the subfamily Cichorioideae of the family Compositae caused cell differentiation of the melanoma cell line. The extracts of Chinese dandelion root, also inhibited cell growth and induced melanogenesis of B16 2F2 cells. We isolated the active compound from ethanol extracts of the crude drug. Chemical and physical data for the active compound were identical with those for lupeol, a lupane-type triterpene.
In a search for cancer chemopreventive agents from natural sources, four lupane-type and seven oleanane-type triterpenoids, and ten synthetic analogs were screened as potential anti-tumor promoters by using the in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein-Barr virus early antigen (EBV-EA) activation assay. Among them, 25-acetoxy-3alpha-hydroxyolean-12-en-28-oic acid (1) and 3beta,25-epoxy-3alpha-hydroxylup-20(29)-en-28-oic acid (2) were examined for anti-tumor promoting activity in a two-stage carcinogenesis assay on mouse skin with 7,12-dimethylbenz[a]anthracene (DMBA) and TPA as promoter. 25-Acetoxy-3alpha-hydroxyolean-12-en-28-oic acid (1) and 3beta,25-epoxy-3alpha-hydroxylup-20(29)-en-28-oic acid (2) showed moderate inhibitory activities.
A new 27-carboxylic lupane-type triterpene, tiarellic acid (1), was isolated from Tiarella polyphylla together with corosolic acid (2) and tormentic acid (3). Tiarellic acid was characterized as 3,23-dihydroxy-20(29)-lupen-27-oic acid and its NMR data were unambiguously assigned using 2-D NMR techniques.