1-[2-(金刚烷-1-基)-1H-吲哚-5-基]-3-取代硫脲衍生物作为CDK9抑制剂的设计合成及抗胃癌活性研究  

Design,Synthesis and Anti-Gastric Cancer Activity of 1-(2-adamantan-1-yl-1H-indole-5-yl)-3-Substituted Thiourea Derivatives as CDK9 Inhibitors

作　　者：于明月 刘俊华[1] 张浩凡 朱德胜 黄建刚 胡鸿雨[1] YU Mingyue;LIU Junhua;ZHANG Haofan;ZHU Desheng;HUANG Jiangang;HU Hongyu(Xingzhi College,Zhejiang Normal University,Lanxi,321100,China;College of Chemistry and Bioengineering,Yichun University,Yichun 336000,China;School of Pharmaceutical Sciences,Xiamen University,Xiamen 361102,China;Jinhua Municipal Central Hospital,Jinhua 321000,China)

机构地区：[1]浙江师范大学行知学院,浙江兰溪321100 [2]宜春学院化学与生物工程学院,江西宜春336000 [3]厦门大学药学院,福建厦门361102 [4]金华中心医院,浙江金华321000

出　　处：《中国药学杂志》2024年第21期2003-2010,共8页Chinese Pharmaceutical Journal

基　　金：浙江省公益基金项目资助(LGF22H300015);金华市重点研发项目资助(2021-3-150,2023-3-082)。

摘　　要：目的设计合成新型的细胞周期蛋白依赖性激酶9(CDK9)抑制剂1-[2-(金刚烷-1-基)-^(1)H-吲哚-5-基]-3-取代硫脲衍生物,并对其抗胃癌的活性进行研究。方法金刚烷甲酰氯为起始原料,通过6步反应合成了一系列目标化合物7a~7m,并通过^(1)H-NMR、^(13)C-NMR和HRMS对所有目标化合物进行了结构鉴定。用噻唑蓝(MTT)法检测了合成化合物对于胃癌细胞生长的抑制作用,用二磷酸腺苷-人乙二醛酶(ADP-Glo)激酶测定法检测了合成化合物对CDK9激酶活性影响,并用免疫印迹法检测活性化合物对于下游信号的调控作用。结果表明目标化合物对于胃癌细胞的生长具有一定的抑制活性,其中化合物7l活性最优,其对胃癌细胞系(SGC-7901)的IC_(50)值为(2.26±0.04)μmol·L^(-1),且7l对正常胃黏膜上皮细胞(GES-1)的毒性较小(IC_(50)>100μmol·L^(-1))。在体外酶活性实验中,7l在1μmol·L^(-1)作用下,CDK9激酶活性为(21.67±1.47)%,且在胃癌细胞中7l呈浓度依赖性地抑制CDK9下游蛋白p-ser2的表达。最后,通过分子对接可知7l能稳定地结合在CDK9的活性位点并具有很高的结合亲和力。结论设计合成的目标化合物是潜在的CDK9抑制剂,具有较好的抗胃癌的活性,有进一步研究的意义。OBJECTIVE To design and synthesize novel CDK9 inhibitors 1-(2-adamantan-1-yl-^(1)H-indole-5-yl)-3-substituted thiourea derivatives and study their anti-gastric cancer activities.METHODS A series of target compounds 7a-7m were synthesized from adamantan formyl chloride by 6-step reactions.The structures of the target compounds were identified by^(1)H-NMR,^(13)C-NMR,and HRMS.MTT assay was used to detect the inhibitory effect of synthetic compounds on the growth of gastric cancer cells,ADP-Glo kinase assay was used to detect the effect of synthetic compounds on CDK9 kinase activity and Western blot assay was used to detect the regulatory effect of hit compound on downstream signaling pathways.RESULTS The target compounds had certain inhibitory activity on the growth of gastric cancer cells,among which compound 7l had the best activity on the gastric cancer cell line(SGC-7901)with IC_(50)value of(2.26±0.04)μmol·L^(-1),and 7l had little toxicity on normal gastric epithelial cells(IC_(50)>100μmol·L^(-1)).In addition,7l showed specific inhibitory effect on CDK9 kinase activity in vitro.Upon 1μmol·L^(-1)7l treatment,CDK9 kinase activity was only(21.67±1.47)%,and in gastric cancer cells 7l inhibited CDK9 downstream protein p-ser2 expression in a concentration-dependent manner.Finally,molecular docking study showed that 7l could stably bind to the active site of CDK9 and had a high binding affinity.CONCLUSION This series of compounds have good anti-gastric cancer activity and are worth of further study.

关 键 词：金刚烷衍生物 吲哚 细胞周期依赖性蛋白激酶9 胃癌 

分 类 号：R914[医药卫生—药物化学]