新型熊果酸喹啉衍生物的合成及抗肿瘤活性

以自然界中广泛存在的五环三萜类天然产物熊果酸为原料合成了一系列新型的熊果酸喹啉酰肼衍生物3a～3f和1,3,4-？f二唑衍生物4a～4f。采用1H NMR、13C NMR、IR、ESI-MS、元素分析等方法对化合物3a～3f和4a～4f进行结构表征和分析。通过MTT法测试了化合物3a～3f和4a～4f对MDA-MB-231、HeLa和SMMC-7721 3种肿瘤细胞株的增殖抑制活性。结果表明:化合物3a～3c对所测试3种细胞株均表现出显著的抑制活性。其中,化合物3a～3c对MDA-MB-231细胞的IC50值为1.16～1.84 μM,对HeLa的IC50值为0.83～1.18 μM,对SMMC-7721的IC50值为17.48～19.41 μM,强于阳性对照依托泊苷。根据抗肿瘤活性结果,初步分析化合物的抗肿瘤构效关系,发现在熊果酸分子中引入喹啉基并将羧基修饰为酰肼基和1,3,4-？f二唑基能够显著增强其抗肿瘤活性,且侧链为酰肼的衍生物活性优于？f二唑的衍生物。这一结果可为今后熊果酸的进一步结构优化,寻找具有更强抗肿瘤活性的衍生物提供依据。
A series of novel quinoline derivatives of ursolic acid(3a-3f, 4a-4f)bearing hydrazide and 1,3,4-oxadiazole moieties were synthesized by using ursolic acid, a kind of pentacyclic triterpenoid compounds, as the starting material. The structures of compounds 3a-3f and 4a-4f were characterized by IR, ESI-MS, NMR and elemental analysis. The antitumor activities of compounds 3a-3f and 4a-4f against MDA-MB-231, HeLa and SMMC-7721 cell lines were evaluated by MTT method. The resutls showed that compounds 3a-3c displayed significant antiproliferative activity. The IC50 values of compounds 3a-3c against MDA-MB-231, HeLa and SMMC-7721 cell lines were 1.16-1.84 μM, 0.83-1.18 μM and 17.48-19.41 μM, respectively, which were stronger than those of the positive control etoposide. According to the antitumor activity results, the antitumor structure-activity relationship of the compounds was preliminary analyzed. It was found that the incorporation of quinolinyl groups into the ursolic acid molecule and the modification of the carboxyl group into hydrazide groups and 1,3,4-oxadiazolyl groups could significantly enhance the antitumor activity of the ursolic acid, and that the activities of hydrazide derivatives were superior to the oxadiazole derivatives. The results of this study would provide substantial basis for the future structure modification of ursolic acid and the screening for derivatives with better antitumor activities