Synthesis Of Oleanolic Acid, 18β-glycyrrhetinic Acid And Ursolic Acid Derivatives And Primary Research On Their Cytotoxic Activities

Malignant neoplasm, called cancer, is general and frequently-occurring disease which threatens human health seriously. It leads the second morality rate, inferior to cardiovascular disease. Many scientists over the world are very interested in that the natural products as lead compounds are modified to synthesis novel anti-tumor agents.Oleanolic acid, 18β-glycyrrhetinic acid and ursolic acid, as pentacyclic triterpenoids, are ubiquitous in the plant kingdom and exhibit various biological activities. Their structures are very similar and they are all potential anti-tumor promoters and cytotoxic agents against tumor cells, inhibiting proliferation, inducing apotosis and preventing invasion. Oleanolic acid and ursolic acid are also inhibitors of nitric oxide production induced by interferon-γ (IFN-γ) in mouse macrophages, which is also closely related mechanistically to carcinogenesis. Therefore oleanolic acid, 18β-glycyrrhetinic acid and ursolic acid are potential cancer chemproventive agents.To study the further cytotoxic activity-structure relationship of these three triterpenoids, five series of their analogues were designed and synthesized, using oleanolic acid, 18β-glycyrrhetinic acid and ursolic acid as starting materials. The enone frame was introduced into ring A and/or C in the first series of synthetic compounds (IO, IG, IU). The common moiety in the second series of analogues (IIO, IIG) was the homoannular diene or heteroannular diene in ring C and D. These compounds (IIIO, IIIG, IIIU) contained enone and allylic alcohol functionalities. There was at least one hydroxyl group in the forth series (IV). Both the enone group of the first series of derivatives and the polyhydroxyl moiety of the fourth ones were involved into the products (VO, VG, VU). Altogether 122 intermediates and target moleculars were synthesized including 70 novel compounds.The cytotoxic activities of these analogues against seven cultured tumor cells (i.e. PC-3, CNE, KB, A549, BEL-7404, HL-60, Hela) were evaluated and cisplatine (DPP) was the positive control. It came to the conclusion that some of these synthesized derivatives showed potent inhibitory effect on the growth of these tumor cells. A few compounds were even more active than cisplatine, such as compound FengKB-009.