二氢青蒿素-查尔酮杂合物的设计、合成及其抗肿瘤活性研究  

Design,synthesis and antitumor activity of dihydroartemisinin-chalcone hybrids

作　　者：姚垚[1] 钟杭[1] 蔡婷[1] 包宇[1] 刘志强[1] 刘丹[1] 赵临襄[1] 

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,辽宁沈阳110016

出　　处：《中国药物化学杂志》2015年第5期339-347,共9页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(81072533)

摘　　要：目的设计合成二氢青蒿素-查尔酮杂合物,提高二氢青蒿素类化合物对白血病细胞的生长抑制活性。方法将取代查尔酮以醚键拼合到二氢青蒿素的C-10位,设计并合成了29个二氢青蒿素-查尔酮杂合物。采用细胞计数法测定目标化合物对人白血病HL-60细胞的生长抑制作用。结果得到了29个含有查尔酮侧链的二氢青蒿素衍生物,均为未见文献报道的新化合物,其结构经1H-NMR、MS和IR谱确证。所有目标化合物对人白血病HL-60细胞都有不同程度的生长抑制作用。结论所有目标化合物对HL-60细胞株的生长抑制活性均强于二氢青蒿素,GI50值均小于0.10μmol·L-1。连接链的改变、查尔酮A环和B环的调换以及取代基的改变对化合物活性的影响没有显著差异。Artemisinin is isolated from Traditional Chinese M edicine Artemisia annua L,which contains a1,2,4-trioxane moiety in its structure,it has become a potential lead compound in the development of antimalarial agent. In addition to its antimalarial activity,artemisinin had been reported to have cytotoxic effects against HL-60 tumor cells,which would be a suitable lead compound for antitumor drugs. To improve the efficacy of artemisinin against tumor cell growth,dihydroartemisinin（ DHA） was taken as the lead compound,structure modification was done,and twenty-nine dihydroartemisinin-chalcone hybrids linked by ether were synthesized. All the target compounds have never been reported in literatures,and their chemical structures were confirmed by1H-NM R,M S and IR. The antiproliferative effects of these artemisinin derivatives in human leukemia HL-60 cells were determined by direct cell counting,and all the target compounds had improved cell growth inhibitory effects（ GI50 0. 10 μmol·L^-1） in HL-60 cells compared to the mother compound DHA with GI50 value of 0. 73 μmol·L^-1. In all the compounds,2d showed the best activity against HL-60 cells growth（ GI50= 0. 021 μmol·L^-1）. However,there is no significantly difference in inhibitory effects when changing the linker between dihydroartemisinin and chalcone,exchanging ring A and ring B of chalcone or altering a substituent of chalcone.

关 键 词：二氢青蒿素 查尔酮 合成 抗肿瘤活性 

分 类 号：R284[医药卫生—中药学] R285[医药卫生—中医学]