Design, Synthesis And Structure-Activity Relationships Of New Anti-tumor Vinorelbine Derivatives

Vinblastine (VBL) and vincristine (VCR), isolated at the end of the1950s from the periwinkle plant Catharanthus roseus, were a group of antimitotic drugs inhibiting tubulin polymerization into microtubules and had been widely used in the clinic for more than50years. However, vinblastine and vincristine still exhibited significant dose-limiting toxicities and chemical unstability. Therefore, since the early1970s, numerous efforts in the fields of both chemistry and biology have been undertaken in an effort to obtain more effective and less toxic Vinca alkaloid-type analogues 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 focused on development of new derivatives based on vinorelbine (NVB), which shows higher antitumor activity and better chemical stability among the family of vinca alkaloids. As a result, we designed and synthesized a series of vinorelbine analogues (26compounds) substituted at the vindoline moiety of C-3site and, evaluated for their proliferation inhibition against two tumor cell lines (HeLa and A549cell) in vitro and anti-tumor activity in vivo (A549). Besides, we further studied the vindoline C-4substituent effects on the in vivo ADME. Furthermore, we have designed and synthesized four new pro-drugs with C-4ester derivatives.