摘要
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.
Our previous studies have found that diaryl-β-lactam derivative （S）-4-（3-hydroxy-4-methoxyphenyl）-3-methylene- 1-（3,4,5-trimethoxyphenyl）azetidin-2-one （3a） possesses potent antitumor activity and its mechanism of action was confirmed as a tubulin aggregation inhibitor. In this paper, 22 novel analogs were synthesized through modifications of the phenolic hy- droxyl group in B ring of compound 3a. The structures of all target compounds were characterized by 1H NMR, 13C NMR and HRMS data. The inhibition against proliferation of A2780, MDA-MB-231, SKOV-3 and Hela cells were tested by thiazolyl blue tetrazolium bromide （MTT） assay, and the bioassay results demonstrated that most of these derivatives showed good anti- proliferative activities. Among them, （S）-1-（3,4,5-trimethoxypheny1）-4-（3-（4-nitrobenzoyloxyl）-4-methoxyphenyl）-3-meth- ylene-azetidin-2-one （Sn） exhibited most potent activities against the above four cancer cells with the corresponding IC50 val- ues of 0.055, 0.105, 0.084 and 0.102 μmol/L, respectively, indicating that these type of compounds merit further investigation.
出处
《有机化学》
SCIE
CAS
CSCD
北大核心
2017年第3期683-690,共8页
Chinese Journal of Organic Chemistry
基金
国家自然科学基金(Nos.21472025
81302257)资助项目~~
