NO供体型吉西他滨衍生物的设计、合成及其抗肿瘤活性

Synthesis and Biological Evaluation of Nitric Oxide-releasing Hybrids of Gemcitabine and Phenylsulfonyl Furoxans as Anti-tumor Agents

在吉西他滨(gemcitabine)的N4位偶联上不同的二醇取代的苯磺酰基呋咱氮氧化物,设计合成了10个新型NO供体型吉西他滨衍生物9a^9e和10a^10e。体外抗肿瘤活性结果表明,化合物9b^9d和10b^10d显示较强的抗肿瘤活性,尤其化合物10c不仅对Hep G2、HCT116和SW620抗增殖活性(IC50=2.44~3.57μmol·L-1)强于吉西他滨(IC50=3.87~7.52μmol·L-1),而且释放出高浓度的NO。然而,加入NO清除剂后10c的抗肿瘤活性降低了近50%,提示NO供体型衍生物的抗肿瘤作用与NO释放有关。

A series of novel gemcitabine derivatives 9a-9e and 10a-10 e were designed and synthesized by coupling phenylsulfonyl furoxans with gemcitabine through various diol linkers, and their biological activities were evaluated in vitro.Compounds 9b-9d and 10b-10 d exhibited more potent anticancer activities. Especially, compound10 c showed excellent anti-proliferative activities(IC50=2.44-3.57 μmol·L-1) which were better than gemcitabine(IC50=3.87-7.52 μmol·L-1). However, the inhibitory rates of 10 c partially reduced by pre-treatment with hemoglobin, demonstrating that their anticancer activities were associated with their NO release.