Design,Synthesis And SARs Study Of Novel Anti-tumor Vinblastines & Applications Of The Green Catalyst In Organic Synthesis

The whole thesis consists of two parts.1):design, synthesis and SARs study of novel anti-tumor vinblastines. And 2):Applications of the green catalyst in organic synthesis.Vinblastine (VBL) and vincristine (VCR), members of tubulin-binding agents of the vinca alkaloids family, were isolated from the periwinkle plant Cantharanthus roseus in the late 1950s. However, the small difference in structure between VBL and VCR significantly affected their oncolytic and toxicity profile. Therefore, since the early 1970s, numerous research groups have been actively engaged in searching for new vinca alkaloids analogues with the aim of identifying more active and less toxic compounds exhibiting a wider spectrum of antitumor efficacy.Based on the study of the SARs of vinblastines and the X-ray structure of vinblastine bound to tubulin, we designed and synthesized five series of vinblastine analogues substituted at the vindoline moiety of C-3, C-4 and/or C-16 site and, evaluated for their proliferation inhibition against two tumor cell lines (HeLa and A549 cell) in vitro and anti-tumor activity in vivo (human A549-F1 cell-transplanted tumor in nude mice). The results showed that three vinorelbine analogues displayed similar anti-tumor potency compared to the positive control NVB. Besides, we further studied the vindoline C-16 substituent effects on the biomimetic coupling reaction and optimized the method of Polonovski biomimetic coupling reaction.As an inorganic catalyst, HClO4-SiO2 has been widely used in organic synthesis due to the advantages of simple operation, eco-friendly technology, atom-economic reaction and recyclable catalyst. So, in the second part of this thesis (part 2.1), we reported an efficient and clean procedure for the N-alkylation of amides by direct condensation of alcohols with primary amides in the presence of silica perchloric acid (HClO4-SiO2). Moreover, quinoxalines represent an important class of heterocycles, and gain more and more attention in recent years. So, developing an efficient and simple method for the synthesis of quinoxalines was very important. In the part 2.2 thesis, we reported one-step method for the synthesis of quinoxalines by condensation of a-hydroxyketones and 1,2-diamines using FeCl3 and morpholine as a co-catalyst.