含有吡唑或二氢吡唑结构片段的青蒿苯基醚类化合物的设计、合成及抗肿瘤活性研究  

Design,synthesis and antiproliferative activity in cancer cells of novel dihydropyrazolyl and pyrazolyl artemisinin-phenyl ethers

作　　者：魏云飞 黄敏[1] 李爱花 赵丰 钟杭[1] 刘丹[1] 赵临襄[1] WEI Yun-fei;HUANG Min;LI Ai-hua;ZHAO Feng;ZHONG Hang;LIU Dan;ZHAO Lin-xiang(Key Laboratory of Structure-Based Drug Design and Discovery,Ministry of Education,Shenyang Pharmaceutical University,Shenyang 110016,China)

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室

出　　处：《中国中药杂志》2018年第17期3582-3588,共7页China Journal of Chinese Materia Medica

基　　金：国家“重大新药创制”科技重大专项(2017ZX09101002-002-007)

摘　　要：青蒿素分离自菊科植物黄花蒿,其衍生物二氢青蒿素对多种疟疾有效,抗疟疾作用已经得到广泛认可。通过近年来的研究表明,二氢青蒿素在抗肿瘤方面也有显著效果,其通过抑制肿瘤细胞增殖、促进细胞凋亡以及对肿瘤细胞的细胞毒作用来抑制肿瘤细胞的生长。该文以二氢青蒿素为先导化合物,通过杂合原理,设计了一系列含吡唑或二氢吡唑结构片段的青蒿苯基醚衍生物,以期望提高该类化合物的抗肿瘤作用。合成了14个未见文献报道的化合物,结构均经LC-MS和1H-NMR确证。以二氢青蒿素为阳性对照,采用MTT法考察了14个目标化合物对人乳腺癌细胞MCF-7及耐药细胞MCF/Adr的生长抑制活性,并测定了目标化合物对人前列腺癌细胞PC-3及雌激素非依赖型乳腺癌细胞MDA-MB-231的生长抑制作用。活性结果表明目标化合物的生长抑制活性均优于母体,对4种肿瘤细胞的抗增殖作用较母体化合物提高了几十到几百倍不等,尤其对耐药细胞MCF/Adr表现出强效的抑瘤作用,化合物5e和6f对MCF-7/Adr细胞活性突出,GI50为20 nmol·L-1左右,值得深入研究。To explore potent anticancer agent based on artemisinin scaffold,a series of 10-O-phenyl ethers derivatives containing dihydropyrazolyl or pyrazolyl moiety have been designed and synthesized. Their structures were determined by LC-MS and1 H-NMR date.Inhibitory effects of the target compounds in human breast cancer MCF-7,MCF/Adr,MDA-MB-231 cells and prostate cell line PC-3 were determined by MTT assay. Those derivatives displayed good antiproliferative activity against the tested cancer cells. Particularly,target compounds exhibited significant cytotoxicity against drug-resistance cells MCF/Adr,which was worthy for further investigation.

关 键 词：青蒿素 天然产物改造 肿瘤治疗 生长抑制 

分 类 号：R284[医药卫生—中药学] R285[医药卫生—中医学]