NO供体型呋咱类1-位氧代冬凌草甲素衍生物的合成及抗增殖活性

目的：为寻找新型一氧化氮（N0）供体型抗肿瘤候选药物，设计合成了一系列新型呋咱类1-位氧代冬凌草甲素衍生物。方法：首先合成不同呋咱类NO供体中间体（9a-i），再将它们与1-位氧代冬凌草甲素（2）的14-位羟基进行缩合，得到一系列NO供体型呋咱类1，位氧代冬凌草甲素衍生物；用Griess实验测试硝酸盐／亚硝酸盐的含量，从而间接测试了NO释放量；同时采用MTT法测定了目标化合物对4种人肿瘤细胞株增殖的抑制活性。结果：所有呋咱类N0供体衍生物在体外60min时间点上都能释放大于19μmol·L-1的NO。活性最好的目标化合物10h对Bel-7402细胞的增殖抑制活性IC50值达到0．74μmol·L-1，优于阳性对照药紫杉醇；获得了初步构效关系信息。结论：利用NO供体和活性天然产物形成孪药分子有望成为发现新型抗肿瘤药物的途径之一。

Synthesis of novel furozan-based nitric oxide-releasing derivatives of 1-oxo-oridonin with anti-proliferative activity

AIM： To search for novel nitric oxide （NO） releasing anti-tumor agents, a series of furoxan-based nitric oxide-releasing derivatives of 1-oxo-oridonin were designed and synthesized. METHOD： Different furozan-based NO donors （9a-i） were synthesized and conjugated with the 14-hydroxyl of 1-oxo-oridonin （2）. The level of nitrate/nitrite in the cell lysates was tested by Griess assay and the anti-proliferative activity of these derivatives against four human cancer cell lines was also determined. RESULTS： These furoxan-based NO-releasing derivatives could produce more than 19 μmol·L-1 of NO in vitro at the time point of 60 min. The most promising compound 10 h exhibited stronger activity than the positive control Taxol against the Bel-7402 cell line with an IC50 value 0.74 μmol·L-1. The structure-activity relationships were concluded based on the derived experimental data. CONCLUSION： These results suggested that NO-donor/natural product hybrids may provide a promising approach for the discovery of novel anti-tumor agents.