新型吖啶二酮类GPR40激动剂的结构优化和抗2型糖尿病的活性研究  

Structural optimization and anti-type 2 diabetes activity of novel acridinedione GPR40 agonists

作　　者：巨世杰 魏朝 郭凯蕾 李琦 梁佳龙 马丽莎 张东旭 卫培峰[1] 刘雪英 JU Shi-jie;WEI Zhao;GUO Kai-lei;LI Qi;LIANG Jia-long;MA Li-sha;ZHANG Dongxu;WEI Pei-feng;LIU Xue-ying(Department of Pharmacy,Shaanxi University of Chinese Medicine,Xianyang Shaanxi 712046;Department of Medicinal Chemistry,School of Pharmacy,Air Force Medical University,Xi’an 710032;School of Life Sciences,Henan University,Kaifeng Henan 475004;No.946 Hospital of the People’s Liberation Army Ground Force,Yining Xingjiang 835000)

机构地区：[1]陕西中医药大学药学院,陕西咸阳712046 [2]空军军医大学药学系药物化学与药物分析教研室,西安710032 [3]河南大学生命科学学院,河南开封475004 [4]中国人民解放军陆军第九四六医院医疗保障中心,新疆伊宁835000

出　　处：《中南药学》2023年第4期917-923,共7页Central South Pharmacy

基　　金：陕西省手性药物工程技术研究中心(No.陕科计发[2011]251)。

摘　　要：目的以ADD-16为先导化合物进行结构优化,总结构效关系,设计合成新型吖啶二酮类抗2型糖尿病药物。方法采用生物电子等排体、同系物原则对ADD-16进行结构衍生化设计合成。利用糖刺激的胰岛素分泌实验(GSIS)评估目标化合物对MIN6细胞胰岛素分泌的影响。通过分子对接考察衍生物与GPR40的结合模式。结果共设计合成8个新型ADD-16衍生物,体外活性筛选发现化合物ADD-20的活性显著优于ADD-16,其刺激胰岛素分泌的能力更强。此外,在3μmol·L^(-1)时,ADD-18、ADD-20与ADD-24的活性显著优于ADD-16,在10μmol·L^(-1)时,ADD-20与ADD-21活性显著优于ADD-16,其他化合物在同等浓度下活性无显著差别。分子对接发现化合物ADD-20结合作用模式与TAK-875极其相似,ADD-20结构中的羧基与ARG-183和ARG-2258的关键氨基酸残基之间形成氢键相互作用。结论设计合成的新型ADD-16衍生物ADD-20具有更强的糖促胰岛素分泌能力,构效关系发现吖啶二酮3,6位氢由二甲基取代、苯甲酸上羧基在间位、1位苯环5位上有取代基且为给电子基时可提高化合物活性,为进一步研究奠定了基础。Objective To design and synthesize drugs with better anti-type 2 diabetes activity based on the ADD-16 acridinedione backbone.Methods Combination of bioelectronic isomers and homologue principles were used to synthesize ADD-16 acridinedione skeleton,synthesis by structural derivatization.The effect of the target compounds on insulin secretion in MIN6 cells was assessed with glucose-stimulated insulin secretion assay(GSIS).The binding mode of GPR40 to the derivatives was determined by molecular docking.Results Totally 8 new acridinedione derivatives were designed and synthesized,and in vitro activity screening revealed that ADD-20 was more active than ADD-16 and had a greater ability to stimulate insulin secretion.In addition,ADD-18,ADD-20 and ADD-24 activities were significantly better than ADD-16 at 3μmol·L^(-1),activities of ADD-20 and ADD-21 were significantly better than ADD-16 at 10μmol·L^(-1);other compounds showed essentially no obvious difference in activity at the same concentration.Molecular docking revealed that the binding mode of action of ADD-20 was very similar to that of TAK-875,with the carboxyl group in the ADD-20 structure forming a hydrogen bond interaction with the key amino acid residue of ARG-183 and ARG-2258.Conclusion Design and synthesis of a novel ADD-16 derivative,namely ADD-20,with enhanced glucagon secretory capacity are accomplished.The structure-effect relationship reveals that the activity of acridinedione is improved when hydrogen at 3,6 position is substituted by dimethyl,the carboxyl group on benzoic acid is in the interposition,and the substituent at the 5-position of the benzene ring at 1 position is an electron donor group,laying the foundation for further study.

关 键 词：吖啶二酮 抗2型糖尿病 结构优化 胰岛素分泌 分子对接 

分 类 号：R914[医药卫生—药物化学] R96[医药卫生—药学]