摘要
目的设计合成1-取代四氢异喹唑啉类p21活化激酶4(PAK4)抑制剂,并对其酶抑制活性进行评价。方法以4-甲氧基苯甲醛和3,4-二甲氧基苯乙酸为起始原料,经过Perkin缩合反应、酯化、环合、水解、酰胺化、环合还原、缩合反应得到13个1-菲基-2-酰基-6,7-二甲氧基-2(1H)-1,2,3,4-四氢异喹啉类化合物(A类);以3,4-二甲氧基苯乙胺和取代的萘甲酸为起始原料,经过酰胺化、环合还原、酰化、脱保护、取代、二次脱保护反应得到9个1-萘基-2-酰基-6,7-二甲氧基-2(1H)-1,2,3,4-四氢异喹啉类化合物(B类)。采用均相时间分辨荧光技术测试目标化合物对PAK4的体外酶抑制活性。结果与结论合成了22个1-取代四氢异喹啉类衍生物,目标化合物的结构经ESI-MS和1H-NMR谱确证。初步体外酶活性测试结果表明,A类化合物的PAK4抑制活性与先导化合物1-[6,7-二甲氧基-1-(3,6,7-三甲氧基-9菲基)-2(1H)-3,4-二氢异喹啉]乙酮相当,其中3个化合物对PAK4的抑制活性显著优于先导化合物,具有进一步研究的价值;B类化合物的活性弱于先导化合物。
The 1-substituted tetrahydroisoquinoline PAK4 inhibitors were designed and synthesized,and their inhibitory activities were evaluated.Started from 4-methoxybenzaldehyde and 3,4-dimethoxyphenylacetic acid,thirteen 1-pheny-2-acyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives(series A)were obtained via Perkin condensation,esterification,cyclization,hydrolysis,amidation,cyclization-reduction and condensation reactions.Started from 2-(3,4-dimethoxyphenyl)ethan-1-amine and substituted naphthoic acid,nine 1-naphthyl-2-acyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives(series B)were obtained via amidation,cyclization-reduction,acylation,deprotection,substitution and another deprotection reactions.The structures of the target compounds were confirmed by ESI-MS and 1H-NMR.The enzyme inhibitory activities in vitro of the target compounds were tested by HTRF technology.The results showed that the activity of the series A was equivalent with lead compound 1-(6,7-dimethoxy-1-(3,6,7-trimethoxyphenanthren-9-yl)-3,4-dihydroiso-quinolin-2(1H)-yl)ethan-1-one,and three of them(A5,A6,A8)were better than lead compound,with further research value.However,the activity of series B was weaker than lead compound ■.
作者
赵伟东
宋帅
吴天啸
郝晨洲
郭靖
殷文博
赵冬梅
ZHAO Wei-dong;SONG Shuai;WU Tian-xiao;HAO Chen-zhou;GUO Jing;YIN Wen-bo;ZHAO Dong-mei(Key Laboratory of Structure-Based Drug Design&Discovery(Shenyang Pharmaceutical University),Ministry of Education,Shenyang 110016,China)
出处
《中国药物化学杂志》
CAS
CSCD
北大核心
2020年第10期589-598,605,共11页
Chinese Journal of Medicinal Chemistry
