摘要
本文设计合成了22个新型嘌呤类衍生物,其中化合物25显示出最高效的抗增殖活性,其对肿瘤细胞HepG2,A549和MCF-7的ICso值分别为15.4,13.7,7.9μM,与阳性对照Roscovitine相比表现出相当或更高效的活性。此外,化合物25对正常细胞BHK-21的毒性较低,ICso值为211μM。构效关系研究表明R,位置取代基的体积对活性影响很大,其中R位置为乙基时活性最优;R²位置为(R)-(-)-2-氨基-1-丁醇取代时比乙醇胺更利于活性;R,位置为合适取代的苄基时对活性有益,苄基上取代基位置对活性影响较大(3位>4位>2位)。进一步评价显示化合物25可有效诱导肿瘤细胞HepG2,A549和MCF-7调亡,调亡率分别为56.56%,38.20%,38.20%。综上,新型嘌呤衍生物25是一个高效低毒的抗肿瘤先导化合物,仍需进一步优化和开发。
In this work,22 new purine derivatives were designed and synthesized,in which compound 25 showed the strongest antiproliferative activity toward HepG2,A549 and MCF-7 cells with the ICso values of 15.4,13.7,7.9μM separately,comparable or more potent than the positive control Roscovitine.In addition,molecule 25 possessed low toxicity toward BHK-21 cells with the ICso value of 211μM.The structure-activity relationship studies(SARs)indicated that the volume of substituents at R,had significant influence in activity.Especially,the ethyl group at R,was preferred.Additionally,compounds bearing a(R)-(-)-2-amino-1-butanol group at R2 were more favorable than those with an ethanolamine group.Besides,suitable substituted benzyl groups at R,were beneficial for activity.The position of substituents on the benzyl was important for activity with a relative order of 3>4>2-position.The further evaluation displayed that compound 25 could effectively induce HepG2,A549 and MCF-7 cell apoptosis with the apoptosis rate of 56.56%,38.20%,38.20%,respectively.Taken together,our findings revealed that purine derivative 25 could be regarded as a promising anticancer lead for further optimization and development.
作者
侯学会
郭俊
何张旭
马志伟
耿广威
张荷丽
杨静
张京玉
HOU Xue-hui;GUO Jun;HE Zhang-xu;MA Zhi-wei;GENG Guang-wei;ZHANG He-li;YANG Jing;ZHANG Jing-yu(Faculty of Scienee,Henan University of Animal Husbandry and Eeonomy,Zhengøhou 450046,China;Schonl of pharmacy,Henan University of Chinese Medicine,Zhengzhou 450046,China;Bioinformatics center of AMMS,Beijing 100850,China)
出处
《化学研究与应用》
CAS
北大核心
2024年第4期803-815,共13页
Chemical Research and Application
基金
河南省自然科学基金项目(202300410264)资助
河南省科技攻关项目(232102111051)资助。
