吉西他滨类似物的设计、合成及体外抗肿瘤活性

吉西他滨是临床一线治疗恶性肿瘤的药物,但其4-位氨基(N4)易与脱氧胞苷脱氨酶(CDA)作用而失活,导致代谢稳定性差,严重影响了临床治疗效果。以吉西他滨为起始原料,经3步反应合成了N4保护的脂溶性吉西他滨衍生物(3a和3b),其结构经1H NMR,13C NMR和HR-MS(ESI)表征。体外活性测试结果显示:化合物3a对多种肿瘤细胞的抗增殖作用均强于临床药物吉西他滨(P<0.05)。酶稳定性实验结果表明:3a几乎不受CDA影响,代谢稳定性显著高于原药吉西他滨。

Design and Synthesis of Gemcitabine Analogues and Their Antitumor Activities in vitro

Gemcitabine(Gem)is a first line anticancer agent for treating a wide range of solid tumors.However,its poor stability due to quickly metabolized by cytidine deaminase(CDA)severely limits its medical applicability.In this study,a synthetic strategy for preparing gemcitabine derivatives which possess high metabolic stability was developed.The N4 protected lipophilic gemcitabine derivatives(3 a and 3 b)were synthesized by a three-step reaction using Gem as starting material.The structures were characterized by 1H NMR,13C NMR and HR-MS(ESI).Further evaluation of anticancer activities showed that compound 3 a had much stronger antiproliferative effects than Gem on several different kinds of tumor cells in vitro(P<0.05).Moreover,enzyme stability data displayed that 3 a was not affected by CDA,confirming that the stability of 3 a to CDA was significantly higher than Gem.