新型α-甲基查尔酮类衍生物的合成及体外抗宫颈癌活性研究  

Synthesis and anti-cervical cancer activities of novel α-methyl chalcone derivatives

作　　者：艾孜提艾力·艾海提 杨争[1] 木合布力·阿布力孜[1] 玉苏普瓦吉木·阿力木江 赛力克阿拉·阿里汗 AIZITIAILI Aihaiti;YANG Zheng;MOURBOUL Ablise;Y USUPUWAJIMU Alimujiang;SAILIKEALA Alihan(College of Pharmacy,Xinjiang Medical University,Urumqi830011,China)

机构地区：[1]新疆医科大学药学院,新疆乌鲁木齐830011

出　　处：《中国药物化学杂志》2022年第1期8-18,共11页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(81960625);新疆天然药物活性组分与释药技术重点实验室(XJDX1713)。

摘　　要：目的以查尔酮母核为先导化合物,设计合成α⁃甲基查尔酮类衍生物并进行体外抗宫颈癌活性研究。方法以2,4⁃二氯苯丙酮与取代苯甲醛为原料,经Claisen⁃Schmidt反应合成一系列新型α⁃甲基查尔酮类衍生物3a~3k,其结构经^(1)H⁃NMR、^(13)C⁃NMR及HR⁃ESI⁃MS谱确证。通过MTT法测定3a~3k对人宫颈癌细胞(SiHa和HeLa)及中国仓鼠正常卵巢细胞(CHO)的体外抗增殖活性;采用流式细胞仪技术检测3g对HeLa细胞的促凋亡作用及对细胞周期的影响;通过CADD法对3g与鼠双微粒体2(MDM2)和微管蛋白进行分子对接,测定化合物结合能量及结合位点。结果与结论3a~3k对人宫颈癌细胞株均表现出不同程度的抗增殖作用,其中3g对HeLa细胞的抑制活性最显著,IC_(50)值为16.51μmol·L^(-1);3g对HeLa细胞作用24h凋亡比例高达84.06%;主要阻滞HeLa细胞于S期;分子对接结果预测3g对MDM2蛋白及微管蛋白均具有较强的抑制作用。α⁃Methyl chalcone derivatives with the core structure of chalcone were designed and synthesized as the lead compound for in vitro anti⁃cervical cancer activity studies.The2,4⁃dichloropropiophenone and substituted benzaldehyde were used as raw materials,by Claisen⁃Schmidt reaction,to synthesize a series of novelα⁃methylchalcone derivatives 3a⁃3k.These compounds were characterized by ^(1)H⁃NMR,^(13)C⁃NMR and HR⁃ESI⁃MS.The in vitro antiproliferative activities of 3a⁃3k on human cervical cancer cells(SiHa and HeLa)and Chinese hamster normal ovarian cells(CHO)were tested by MTT method.The apoptosis⁃inducing effect and influence on the cell cycle of compound 3g on HeLa cells was detected by flow cytometry.By CADD method,Autodock Tools software was used to molecularly docking of compound 3g with murine double minute2(MDM2)and microtubulin to determine the binding energy and binding site of the compound.As a result,compounds 3a⁃3k have different levels of inhibitory effects on human cervical cancer cell lines.Among them,compound 3g has the most significant inhibitory activity on HeLa cells,with IC_(50)of16.51μmol·L^(-1).The percentage of apoptosis of compound 3g on HeLa cells for24h was reached 84.06%.Compound 3g mainly blocked HeLa cells in the S cycle.The results of molecular docking showed a good binding affinity,which was predicted to have a strong inhibitory effect on MDM2protein and microtubulin.

关 键 词：α⁃甲基查尔酮 Claisen⁃Schmidt反应 宫颈癌 抗细胞增殖 细胞凋亡 细胞周期 

分 类 号：R914[医药卫生—药物化学]