六元内酰胺类化合物的合成及其抗肿瘤活性  

Synthesis and antitumor activity of δ-lactam compounds

作　　者：李宝力 郑新羽 王熳炯 包可婷 毛斐[1] LI Bao-li;ZHENG Xin-yu;WANG Man-jiong;BAO Ke-ting;MAO Fei(School of Pharmacy, East China University of Science and Technology, Shanghai 200237, Chin)

机构地区：[1]华东理工大学药学院,上海200237

出　　处：《中国药物化学杂志》2018年第3期173-183,共11页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(21222211)

摘　　要：目的设计合成六元内酰胺类衍生物并进行抗肿瘤活性测试。方法以2-巯基吡啶为起始原料,通过与溴乙酸甲酯反应,并用过硫酸氢钾氧化得到活性亚甲基的单酯化合物2-(吡啶-2-磺酰基)乙酸甲酯,该单酯与肉桂醛类似物进行Michael加成反应、取代伯胺还原胺化及成环反应得到目标化合物;采用MTT法测试化合物对人淋巴瘤Karpass299细胞的增殖抑制作用。结果合成了39个手性目标化合物:(3S,4S)-1-苄基-4-苯基-3-(吡啶-2-磺酰基)哌啶-2-酮及其类似物,其结构和纯度均经1H-NMR、MS谱确证。结论目标化合物表现出很好的抗肿瘤活性,其中,化合物6q具有明显的人淋巴瘤细胞增殖抑制活性(10μmol·L-1的抑制率为99%),是一个良好的抗淋巴癌先导化合物。This study focused on the synthesis and antitumor activity of the analogues of （3S,4S）-1-benzyl- 4-phenyl-3-（pyridin-2-ylsulfonyl） piperidin-2-one and designed a series of δ-lactam compounds to evaluate their antitumor activity. Intermediate methyl 2-（ pyridin-2-ylthio ） acetate was synthesized by reacting pyridine-2-thiol with methyl bromoacetate, then was oxidized with potassium peroxymonosulfate to yield active methylene intermediate methyl 2-（ pyridin-2-ylthio ）acetate （3）. The intermediate 3 reacted with different substituted cinnamaldehyde through Michael addition reaction with （S） -2-（ diphenyl （ （triethylsilyl） oxy） methyl）pyrrolidine as catalyst, then reacted with different substituted benzylamine through amination and cyclization reaction to provide target compounds. MTT method was used to evaluate the cytotoxicity of compounds on Karpass299 cells. In summary, thirty-nine chiral compounds were synthesized, and their antitumor activities on Karpass299 cells were explored. Among them, compound 6q exhibited good inhibitory activity（99% at 10 μmol·L^-1） on Karpass299 cells,demonstrating that it was a good new anti-lymphoma lead compound.

关 键 词：六元内酰胺 手性化合物 Karpass299细胞 淋巴癌 

分 类 号：R914[医药卫生—药物化学]