4,6-双取代吡啶并[3,2-d]嘧啶类PIM/MNK双靶点抑制剂的设计、合成及抗肿瘤活性研究  

Design,synthesis and antitumor activity evaluation of 4,6-disubstituted pyrido[3,2-d]pyrimidine derivatives as PIM/MNK dual inhibitors

作　　者：邢坤 臧洁 李景欢 穆志颖 张澜馨 赵临襄[1] XING Kun;ZANG Jie;LI Jinghuan;MU Zhiying;ZHANG Lanxin;ZHAO Linxiang(School of Pharmaceutical Engineering,Shenyang Pharmaceutical University,Shenyang 110016,China)

机构地区：[1]沈阳药科大学制药工程学院,辽宁沈阳110016

出　　处：《中国药物化学杂志》2024年第4期259-269,共11页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(81773578)。

摘　　要：目的设计并合成一类4,6-双取代吡啶并嘧啶类PIM/MNK双靶点抑制剂,并对其进行抗肿瘤活性研究。方法以21o为先导化合物,通过计算机分子对接技术,设计一类4,6-双取代吡啶并嘧啶类化合物。以4,6-二氯吡啶并[3,2-d]嘧啶为原料,经亲核取代、Suzuki偶联反应等得到目标化合物10a~10n。此外,通过骨架跃迁策略,将酰胺键替换为刚性的异吲哚啉酮,进一步限定化合物构象,得到化合物11a~11g。采用MTT法测试目标化合物对人结直肠癌细胞HCT-116和人前列腺癌细胞PC-3的抗增殖活性。采用HTRF法测试目标化合物对PIM和MNK激酶的抑制活性。结果部分化合物表现出较强的PIM/MNK激酶抑制活性和抗肿瘤细胞增殖活性,其中化合物11f与先导化合物21o和阳性对照SGI-1776活性相当。结论本研究发现了基于4,6-双取代吡啶并[3,2-d]嘧啶结构的PIM/MNK双靶点抑制剂11f,其表现出较优的激酶抑制活性以及抗肿瘤细胞增殖活性,值得进一步研究。With compound 21o as the lead,a series of 4,6-disubstituted pyrido[3,2-d]pyrimidine derivatives with PIM/MNK dual inhibitory activity were designed through molecular docking technique.Using 4,6-dichloropyrido[3,2-d]pyrimidine as the starting material,the target compounds 10a-10n were obtained via nucleophilic substitution reaction,followed with Suzuki coupling reaction.Moreover,the scaffold hopping strategy was used to design the isoindolinone derivatives 11a-11g with more restricted conformation.The kinase inhibitory activity of target compounds was assayed by HTRF method,and the results indicated that some compounds displayed potent PIM and MNK dual inhibitory activity.The antiproliferation activity of target compounds against PC-3 and HCT-116 cell lines was measured using MTT assay.The result demonstrated that compound 11f displayed better antiproliferation activity than compound 21o and SGI-1776,which worthed further research.

关 键 词：MNK激酶 PIM激酶 吡啶并[3 2-d]嘧啶类化合物 抗肿瘤 

分 类 号：R914[医药卫生—药物化学]