摘要
目的:设计合成新型肉桂酰胺苯甲酰胺类化合物并测定其体外抗肿瘤活性。方法:采用药物设计拼合原理,将具有抗肿瘤细胞增殖活性的(取代)肉桂酰胺片段与组蛋白去乙酰化酶抑制剂CI-994融合设计化合物,以取代的肉桂酰胺为起始原料经过3步反应制备目标化合物5a^5q。结果:共设计合成17个未见报道的肉桂酰胺苯甲酰胺类衍生物,其结构均经1H-NMR和HRMS确证;体外HDAC1抑酶活性显示大部分化合物表现一定的抑酶活性,体外抗肿瘤活性研究表明化合物5q对HDAC1抑酶活性与阳性对照CI-994相当;体外抗肿瘤细胞增殖实验显示化合物5q对四株人源肿瘤细胞(Hut78,A549,U-937和PC-3细胞)抗增殖活性显著优于CI-994,同时对人正常胚肺细胞MRC-5(IC50>50μmol·L-1)无抑制活性。结论:化合物5q具有显著的抑酶活性及抗肿瘤增值活性,有进一步研究价值。
Objective： To synthesize novel cinnamamide-containing benzamides derivatives and evaluate their antitumor activities. Methods： Hybrids（5 a - 5 q） of CI-994 and cinnamamide analogues have been designed,and synthesized through 3 steps using substituted cinnamamides. Results： Seventeen designed compounds were synthesized and characterized by1 H-NMR and HRMS. In vitro biological studies showed that most of the compounds exhibited inhibitory activity against HDAC1, among which compound 5 q showed similar activity compared with CI-994. Antitumor cell proliferation experiment in vitro showed that compound 5 q with significant selectivity over MRC-5 human normal cell lines（IC50 50 μmol·L^-1） demonstrated better antiproliferative potency than CI-994 against Hut78 cells,A549 cells,U-937 cells and PC-3 cells. Conclusion： Compound 5 q which demonstrated significant antiproliferative potency against cancer cells and inhibitory activity against HDAC1 is worth of much more research.
出处
《中国新药杂志》
CAS
CSCD
北大核心
2018年第3期345-350,共6页
Chinese Journal of New Drugs
基金
上海市科委青年科技英才扬帆计划(14YF1412800)
