药学学报, 2020, 55(1): 96-105
引用本文:
黄涛, 赖惠芳, 林荣坤, 林锦, 李柱来, 许秀枝. 基于喹喔啉为母核的PI3K抑制剂的合成及抗肿瘤活性研究[J]. 药学学报, 2020, 55(1): 96-105.
HUANG Tao, LAI Hui-fang, LIN Rong-kun, LIN Jin, LI Zhu-lai, XU Xiu-zhi. Synthesis and biological evaluation of phosphoinositide 3-kinase (PI3K) inhibitors based on a quinoxaline scaffold[J]. Acta Pharmaceutica Sinica, 2020, 55(1): 96-105.

基于喹喔啉为母核的PI3K抑制剂的合成及抗肿瘤活性研究
黄涛1,2, 赖惠芳2, 林荣坤2, 林锦2, 李柱来2, 许秀枝2
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
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,P6bP6eP6f对HCT116活性较好(IC50=3.24,4.78和4.50 μmol·L-1),P6d对MCF-7具有较强抑制作用(IC50=0.228 7 μmol·L-1)。
关键词:    喹喔啉类衍生物      抗肿瘤      PI3K抑制剂     
Synthesis and biological evaluation of phosphoinositide 3-kinase (PI3K) inhibitors based on a quinoxaline scaffold
HUANG Tao1,2, LAI Hui-fang2, LIN Rong-kun2, LIN Jin2, LI Zhu-lai2, XU Xiu-zhi2
1. Fujian Provincial Children's Hospital(Fujian Provincial Maternity and Children's Hospital), Fuzhou 350001, China;
2. Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, College of Pharmacy, Fujian Medical University, Fuzhou 350122, China
Abstract:
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 by 1H NMR, 13C 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 P6b was effective, P6e and P6f had better activity against HCT116 (IC50=3.24, 4.78 and 4.50 μmol·L-1), and P6d had strong inhibitory effect on MCF-7 (IC50=0.228 7 μmol·L-1).
Key words:    quinoxaline derivative    anti-tumour    PI3K inhibitor   
收稿日期: 2019-08-26
DOI: 10.16438/j.0513-4870.2019-0679
基金项目: 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).
通讯作者: 许秀枝,Tel:86-591-22862016,E-mail:xiuzhi_xu@126.com;李柱来,E-mail:lizhulai@126.com
Email: xiuzhi_xu@126.com;lizhulai@126.com
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