Synthesis And Biological Evaluation Of Oleanolic Acid Saponins And Synthesis Of Hydroxycamptothecin Glycoconjugates

1. Synthesis and Biological Evaluation of Oleanolic Acid SaponinsSaponins are complex glycosides of steroids and triterpenes, with significant pharmacological activities, and widely distributed in natural products. It is noteworthy that more than half of the triterpene saponins are oleanane-type saponin, The isolation of each individual saponin from a plant species presents a formidable task, which hinders the further development of this important group of natural products. The mechanical studies of the bioactivities of saponins can't be favourably developed because of that. Chemical synthesis could remove this bottle-neck.1) Synthesis of flaccidosideⅡFlaccidosideⅡis the main bioactive fraction of Chinese folk medicine Di Wu which is used for detoxication, expelling wind-evil, releasing wetness-evil and represents good curative effect for rheumatoid arthritis. In addition, it was reported that flaccidosideⅡshowed significant in vitro antitumor activities. Flaccidoside is a glycoside of oleanolic acid with one sugar chain being attached through an ether linkage at C-3, and another through an ester linkage at C-28 (a so-called bidesmosidic saponin"), its chemical structure was elucidated as 3-O-α-L-rhamno pyranosyl-(1→2)-β-D-xylopyranosyloleanolic acid 28-O-α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside. The structural complexity, especially having a 2'-OH branched sugar chain on C-3 of oleanolic acid, has hindered the chemical synthesis of this type of bidesmosidic triterpene saponin. Because of its highly activities and unique chemical structure, flaccidoside II was chosen as our target molecule. We successfully synthesized the natural product flaccidoside II by the tactic of linear strategies glycosylation, and the key block 2-4 was beautifully assembled in 76% yield by two successive glycosylations without any intermediate separation,2) Design, Synthesis and Biological Evaluation of two series of Oleanolic Acid Saponin DerivativesThe inhibition of Protein tyrosine phosphatase 1B (PTP1B) has attracted much attention in recent years due to its potential of treating non-insulin-dependent diabetes mellitus (type 2 diabetes). According to the research of Lihong Hu etc., oleanolic acid and its derivatives showed significant PTP1B inhibition activity. Two series of oleanolic acid saponin derivatives were synthesized by coupling a series of sugars to oleanolic acid derivatives 3-5 and 3-12 at C-3, evaluated spectrophotometrically for inhibition of a-glucosidase, a-amylase and PTP1B. Compound 3-24 showed highly inhibitory activitiy against PTP1B with IC50 19.1 nmol/mL.2. Design and Synthesis of Hydroxycamptothecin GlycoconjugatesCamptothecins are a kind of pentacylic alkaloid first isolated from the Chinese tree Camptotheca acuminata. This brightly fluorescent compound was found to be a potential inhibitor of the growth of leukemia cell by a unique mechanism:inhibition of DNA topoisomerase I. But its widely application was limited for its negligible water solubility and serious side toxicity. Significant attention has been paid to the equilibrium between the lactone and its ring-opened carboxylate form, which influences its antitumor ability. The chemical modification of camptothecin is an available way to improve antitumor and solubility, decreasing side toxicity. Among these, the study of glycoconjugate of camptothecin is a new and promising aspect.To improve biological profile of 10-hydroxycamptothecin, a series of 20-O-linked hydroxylcamptothecin glycoconjugates has been designed for enhanced solubility and stabilization of the E lactone ring. The bulky side chain of valine linked to hydroxycamptothecin via 20-ester bond is crucial for hydrolytic stability of these conjugates.Eight 20-O-glycoconjugates of hydroxycamptothecin were successfully synthesized by using D-galactose, D-glucose, D-mannose,2-acetylamino-2-deoxy glucose and D-lactose as targeting moiety, and valine as linker.