基于喹喔啉为母核的PI3K抑制剂的合成及抗肿瘤活性研究  

Synthesis and biological evaluation of phosphoinositide 3-kinase(PI3K) inhibitors based on a quinoxaline scaffold

作　　者：黄涛 赖惠芳 林荣坤 林锦 李柱来[2] 许秀枝[2] HUANG Tao;LAI Hui-fang;LIN Rong-kun;LIN Jin;LI Zhu-lai;XU Xiu-zhi(Fujian Provincial Children's Hospital(Fujian Provincial Maternity and Children's Hospital),Fuzhou 350001,China;Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research,College of Pharmacy,Fujian Medical University,Fuzhou 350122,China)

机构地区：[1]福建省儿童医院(福建省妇幼保健院),福建福州350001 [2]福建医科大学药学院,福建省药物靶点发现与结构功能研究重点实验室,福建福州350122

出　　处：《药学学报》2020年第1期96-105,共10页Acta Pharmaceutica Sinica

基　　金：福建省科技创新联合资金资助项目(2016Y9052);福建省高校杰出青年科研人才培育计划(2017B021);福建医科大学引进高层次创业创新人才计划(XRCGZX2017010);福建省自然科学基金项目(2018J01846);福建省自然科学基金青年创新项目(2019J05073)

摘　　要：以含有喹喔啉母核的PI3K抑制剂XL765和WR23为结构基础,通过生物电子等排,在喹喔啉母核上2位引入取代苯氧基片段,延长3位连接链改为磺酰肼,并在7位引入氟原子;去掉3位取代并在7位引入丙烯酰胺基。初步设计并合成了22个喹喔啉类衍生物,通过1H NMR、13C NMR、ESI-MS进行结构确证。以人非小细胞肺癌A549、人乳腺癌细胞MCF-7、人结肠癌细胞HCT-116和人肝癌细胞HepG2进行体外抗肿瘤活性筛选(MTT法)。结果表明, P6b、P6e、P6f对HCT116活性较好(IC50=3.24, 4.78和4.50μmol·L-1), P6d对MCF-7具有较强抑制作用(IC50=0.228 7μmol·L-1)。Based on the structure of inhibitors XL765 and WR23, the quinoxaline scaffold was selected as an attractive structure for drug design. In this protocol, the 2-position of quinoxaline was modified with a substituted phenoxy fragment. Meanwhile, the linking chain at the 3-position was changed to a sulfonyl hydrazine or was removed. A series of substituent groups were added at the 6-position of the quinoxaline scaffold. Twenty-two quinoline derivatives were designed and synthesized, and their structures were confirmed by1 H NMR,13 C NMR, and ESI-MS. All compounds were screened for anti-tumor activity in vitro in A549, MCF-7, HCT-116 and HepG2 cancer cells. The results showed that P6 b was effective, P6 e and P6 f had better activity against HCT116(IC50=3.24, 4.78 and 4.50 μmol·L-1), and P6 d had strong inhibitory effect on MCF-7(IC50= 0.228 7 μmol·L-1).

关 键 词：喹喔啉类衍生物 抗肿瘤 PI3K抑制剂 

分 类 号：R916[医药卫生—药学]