目的:为增强喜树碱的抗肿瘤活性,设计并合成了9个新型喜树碱20(S)去甲斑蝥素酯衍生物.方法:以顺丁烯二酸酐与呋喃为原料,通过[4+2]环加成反应,立体选择性地得到5-烯去甲斑蝥素1;中间体1,2和3通过醇解得到相应的去甲斑蝥素单酸甲酯侧链4a-i;侧链4a-i与喜树碱在EDCI/DMAP条件下,缩合得到相应的喜树碱20-位去甲斑蝥素酯衍生物7a-i.采用CCK-8法考察了7a-i对4种肿瘤细胞株的体外抑制活性.结果:此类化合物对于BGC803和SW480具有与斑蝥素及喜树碱2个阳性对照药品相当的抑制活性,7b,7d,7f和7g对于HepG2或PANC-1具有很好的抑制活性.结论:喜树碱和斑蝥素的直接偶联产物保持了喜树碱的抗肿瘤特性,但是弱化了斑蝥素的抗肝癌活性,对于进一步的药物设计具有参考意义.%Objective: To improve the anticancer bioactivity of camptothecin, nine camptothecin 20-ester derivatives were designed and synthesized. Methods: Starting from maleic anhydride and furan, [4+2]cyclization addition reaction was conducted to obtain 5-ene-norcantharidin 1, followed by alcololysis to give the corresponding side chain 4a-i, which was then coupled with camptothecin in the condition of EDCI and DMAP to afford camptothecin 20-ester derivatives 7a-i. Inhibition activity against four kinds of tumor cell lines was investigated with CCK-8 method. Results: Compared to the two positive controls, cantharidin and camptothecin, all of the nine target compounds showed comparable inhibition against BGC803 and SW480, and compounds 7b, 7d, 7f and 7g exhibited potent inhibition against HepG2 or PANC-1. Conclusion: The direct coupling products of camptothecin with cantharidin keep the antitumor properties of camptothecin, but weaken the anti-hepatocarcinoma activity of cantharidin. This finding may provide reference for further drug design.
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