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目的:研究穿心莲内酯(AD)及其3,19-缩醛(酮)衍生物(3~15)、14-脱氧-11,12-二脱氢穿心莲内酯(ADD)C-15取代(16~28)及其复合8,17环氧化(31~34)等衍生物的体外抗肿瘤活性,用于指导抗肿瘤候选药物的合成。方法:以人食管癌Ec9706、人肺腺癌A549为模型,采用MTT法评价衍生物的活性,并进行初步的构效关系研究。结果:化合物3~15对2株肿瘤细胞的细胞毒活性较AD显著提高,其中化合物6对Ec9706的IC50为4.7μmol.L-1,而AD的IC50为81.7μmol.L-1。ADD的肿瘤细胞毒活性低于AD。不同的C-15取代基导致化合物16~28和31~34活性差异很大。AD的羟基乙酰化产物(35~37)活性比AD高,ADD的羟基乙酰化产物(38,39)活性比ADD低。结论:对AD的C-3,C-14,C-19羟基进行修饰、ADDC-15取代或C-15取代复合C-8,17双键环氧化可获得一系列体外抗肿瘤活性显著提高的衍生物。
Objective: To investigate the effects of andrographolide (AD) and its derivatives of 3,19-acetal (3-15), 14-deoxy-11,12-didehydroandrographolide 16-28) and their derivatives 8,17 epoxidation (31-34) and other derivatives in vitro antitumor activity, used to guide the synthesis of anti-tumor drug candidates. Methods: Human esophageal carcinoma Ec9706 and human lung adenocarcinoma A549 were used as the models. The activity of the derivatives was evaluated by MTT method and the preliminary structure-activity relationship was studied. Results: The cytotoxic activity of compound 3-15 against two tumor cells was significantly higher than that of AD. The IC50 of compound 6 to Ec9706 was 4.7μmol.L-1, while the IC50 of AD was 81.7μmol.L-1. Tumor cytotoxicity of ADD is lower than that of AD. Different C-15 substituents result in very different activities of compounds 16-28 and 31-34. AD hydroxy acetylation products (35-37) activity than AD, ADD hydroxy acetylation products (38,39) activity than ADD low. CONCLUSIONS: A series of in vitro antitumor activities were significantly improved by modification of C-3, C-14 and C-19 hydroxyl groups in AD, epoxidation of ADDC-15 or C-8 substituted C-8,17 double bonds Derivatives.