新型紫杉烷类衍生物的制备及生物活性评价

多药耐药性问题是导致第一代紫杉烷药物在临床化疗失败的主要原因。本文对紫杉醇C7、C10、C14、C3′多个位点的取代基进行改造,针对合成的6个新型的紫杉烷化合物,在体外考察其对多药耐药肿瘤细胞株以及人结肠癌HCT-116干细胞的增殖抑制活性,实验结果表明6个化合物的抗多药耐药活性均优于紫杉醇。采用P-gp高表达的犬肾细胞MDCK-MDR1进一步研究高活性候选化合物JT-3与P-gp的相互作用。以此研发抗多药耐药型的新一代紫杉烷类药物,对开发扩大抗癌新适应症的新一代紫杉烷类抗癌药意义重大。

Synthesis and Biological Activity Evaluation of Novel Taxane Derivatives

It has been shown that multidrug resistance (MDR) is the main reason for the failure of first-generation taxane drugs in clinical chemotherapy, and mediated by P-gp and metabolized by CYP3A4 enzymes. Accordingly, the substituents at C7, C10, C14, and C3" of paclitaxel were modified, and six new taxane compounds were designed and synthesized to investigate their biological activities in multidrug-resistant tumor cell lines and human colon cancer stem cells HCT-116 in vitro. All of these novel toxoids exhibited remarkable cytotoxicity against extremely drug-resistant cancer cell lines, as compared to paclitaxel, indicating that these new toxoids can overcome MDR caused by the overexpression of P-gp. The interaction of the candidate compound JT-3 with P-gp was evaluated using Madin-Darby canine kidney (MDCK)-multidrug resistance-1 (MDR1). Therefore, the development of a new generation taxoid anticancer agents with superior efficacy against drug-resistant cancers, is highly promising and significant to develop the new generation of taxane anticancer drugs that expand new anticancer indications.