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前期研究发现,二芳基-β-内酰胺类化合物(S)-1-(3,4,5-三甲氧基苯基)-4-(3-羟基-4-甲氧基苯基)-3-亚甲基氮杂环丁烷-2-酮(3a)具有显著抗肿瘤活性,作用机制研究证实为微管蛋白聚集抑制剂.本文以3a为先导,通过针对其B环酚羟基的结构改造,合成了22个衍生物,结构均经~1H NMR、~(13)C NMR和HRMS等确证.采用噻唑蓝(MTT)法测试了目标化合物对人卵巢癌细胞A2780和SKOV-3、人乳腺癌细胞MDA-MB-231和宫颈癌细胞Hela的增殖抑制活性.结果表明,大多数化合物显示了较好的增殖抑制活性,其中化合物(S)-1-(3,4,5-三甲氧基苯基)-4-(3-对硝基苯甲酰氧基-4-甲氧基苯基)-3-亚甲基氮杂环丁烷-2-酮(5n)活性明显优于化合物3a,对上述四种肿瘤细胞株均显示了较好的抑制活性,相应IC_(50)值分别为0.055、0.084、0.105和0.102μmol/L,说明该类化合物值得进一步深入研究.
Previous studies have found that the diaryl-β-lactams (S) -1- (3,4,5-trimethoxyphenyl) -4- (3-hydroxy-4- methoxyphenyl) 3-methylene azetidin-2-one (3a) has significant anti-tumor activity, and its mechanism of action is confirmed as a tubulin aggregation inhibitor.In this paper, 3a-led, Twenty-two derivatives were synthesized and their structures were confirmed by ~ 1H NMR, ~ (13) C NMR and HRMS, respectively. The target compounds were tested for the cytotoxicity on human ovarian cancer cells A2780 and SKOV-3 by MTT assay The inhibitory activity of breast cancer cell MDA-MB-231 and cervical cancer cell Hela were studied.The results showed that most of the compounds showed good proliferation inhibitory activity, in which the compound (S) -1- (3,4,5-trimethoxy- (3-p-nitrobenzoyloxy-4-methoxyphenyl) -3-methylene azetidin-2-one (5n) was significantly more active than the compound 3a, which showed good inhibitory activity against the above four tumor cell lines. The corresponding IC 50 values were 0.055, 0.084, 0.105 and 0.102 μmol / L, respectively, indicating that these compounds deserve further study.