药学学报, 2015, 50(7): 868-874
引用本文:
左志忠, 钟杭, 蔡婷, 包宇, 刘志强, 刘丹, 赵临襄. 青蒿素-氮杂环化合物的设计、合成及其抗肿瘤活性研究[J]. 药学学报, 2015, 50(7): 868-874.
ZUO Zhi-zhong, ZHONG Hang, CAI Ting, BAO Yu, LIU Zhi-qiang, LIU Dan, ZHAO Lin-xiang. Design, synthesis and antiproliferative activities of artemisinin derivatives substituted by N-heterocycles[J]. Acta Pharmaceutica Sinica, 2015, 50(7): 868-874.

青蒿素-氮杂环化合物的设计、合成及其抗肿瘤活性研究
左志忠, 钟杭, 蔡婷, 包宇, 刘志强, 刘丹, 赵临襄
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, 辽宁 沈阳 110016
摘要:
近年来, 青蒿素类化合物抗肿瘤活性受到越来越多的关注, 对人急性早幼粒白血病细胞HL-60、小鼠白血病细胞P388、人乳腺癌细胞MCF-7等肿瘤细胞都表现出较好的抑制作用。本文设计并合成16个新型10-O-氮杂环取代二氢青蒿素类化合物, 采用细胞计数法和MTT法测试所合成化合物对人急性早幼粒白血病细胞HL-60、人乳腺癌细胞MCF-7及耐多柔比星细胞MCF-7/Adr的生长抑制活性。药理实验结果表明: 在敏感细胞HL-60和MCF-7中, 所有目标化合物的生长抑制活性比先导物二氢青蒿素都有所提升, 但弱于阳性对照药多柔比星; 在耐药细胞MCF-7/Adr中, 所有目标化合物表现出强于在敏感细胞MCF-7的生长抑制作用, 其GI50值显著低于二氢青蒿素和多柔比星; 化合物GF02GH04ZH04在3个细胞株中均表现出强烈的生长抑制活性, 值得深入研究。
关键词:    青蒿素      氮杂环化合物      抗肿瘤     
Design, synthesis and antiproliferative activities of artemisinin derivatives substituted by N-heterocycles
ZUO Zhi-zhong, ZHONG Hang, CAI Ting, BAO Yu, LIU Zhi-qiang, LIU Dan, ZHAO Lin-xiang
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
Abstract:
Increasing attention has been focused on the antitumor activity of artemisinin derivatives in recent years, for artemisinin had been reported to have cytotoxic effects against HL-60, P388 and MCF-7 tumor cells. We report here the synthesis and evaluation for antitumor activity of a series of artemisinin-ether derivatives bearing tetrahydropyrrole, morpholine, piperidine, substituted piperidines and azoles with various linkers. Sixteen 10-O-substituted dihydroartemisinin derivatives were designed and synthesized, all of which have never been reported in literatures and whose antiproliferative effects on human breast cancer MCF-7, MCF-7/Adr and HL-60 cells were determined by MTT assay or direct cell counting. Each of these artemisinin derivatives possessed better effects than dihydroartemisinin evidently against HL-60 and MCF-7 cells growth, while less potent than doxorubicin. All target compounds exhibited significantly improved potency compared to DHA and doxorubicin on the doxorubicin-resistant MCF-7/Adr cells, so did they in their sensitive counterparts MCF-7 cells. Among them, compounds GF02, GH04 and ZH04 showed strong activity against these three cell lines growth. Further research is undergoing.
Key words:    artemisinin    nitrogen-containing heterocyclic compound    antitumor   
收稿日期: 2015-03-02
基金项目: 国家自然科学基金资助项目 (81072533).
通讯作者: 赵临襄
Email: zhaolinxiang@syphu.edu.cn
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