含有查尔酮侧链的二氢青蒿素衍生物的设计、合成及其抑制白血病细胞增殖活性作用  

Design and synthesis of novel dihydroartemisinin derivatives containing a substituted chalcone with improved antiproliferative effects in leukemia cells

作　　者：杨学林[1] 刘丹[1] 姚广丰[1] 钟杭[1] 赵璇[1] 赵临襄[1] 

机构地区：[1]沈阳药科大学制药工程学院,辽宁沈阳110016

出　　处：《沈阳药科大学学报》2011年第8期607-615,620,共10页Journal of Shenyang Pharmaceutical University

基　　金：国家自然科学基金资助项目(81072533);辽宁省教育厅科学技术研究项目(LS2010159)

摘　　要：目的设计合成一系列含有查尔酮侧链的二氢青蒿素衍生物,提高二氢青蒿素对白血病细胞的生长抑制活性。方法将取代查尔酮及其类似物拼合到二氢青蒿素的C-10位,设计28个查尔酮取代二氢青蒿素衍生物。采用细胞计数法测定其对HL-60、P388和P388/Adr细胞的生长抑制作用。结果与结论合成了28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,其结构均经1H-NMR、MS和IR确证。所有目标化合物对HL-60、P388和P388/Adr细胞都有不同程度的生长抑制作用,初步构效关系分析结果:青蒿芳香醚类化合物的抗增殖活性好于青蒿脂肪醚类化合物,取代查尔酮侧链中的α,β-不饱和酮结构并不是影响抗增殖活性的必需基团,双键还原和全部还原产物活性相当。化合物5d对HL-60细胞的生长抑制作用最强,化合物7a、7 c和7 e对HL-60、P388和P388/Adr细胞均表现出显著的生长抑制活性,值得深入研究。Objective To design and synthesize a series of novel dihydroartemisinin derivatives containing a substituted chalcone with improved antiproliferative effects in leukemia cells.Methods Twenty-eight dihydroartemisinin derivatives containing a substituted chalcone linked by ether were synthesized and investigated for their antiproliferative activity in human leukemia HL-60 and mouse lymphoma P388 cells.Results and Conclusions Twenty-eight novel dihydroartemisinin derivatives were synthesized and their chemical structures were confirmed by the application of 1H-NMR,MS and IR.These DHA ethers are the β-isomers and have improved cell growth inhibitory effects in both cell lines.Dihydroartemisinin chalcones linked by aromatic ether are more effective than dihydroartemisinin chalcones linked by aliphatic ether,but α,β-unsaturated ketone was not an essential group to affect antiproliferative activities.Among these compounds,5d was the most effective against HL-60 cells growth（IG50=16 mmol·L-1）,and 7a,7c and 7e were equally active towards mouse lymphoma P388 and adriamycin resistant P388/Adr cell lines.

关 键 词：查尔酮 二氢青蒿素 合成 细胞生长抑制 构效关系 

分 类 号：R914[医药卫生—药物化学]