1,2,3-三氮唑酰胺类氨肽酶N抑制剂设计合成和活性筛选  

Design,synthesis and activity screening of 1,2,3-triazol derivatives containing amide moiety as aminopeptidase N inhibitors

作　　者：曹江营 张晨 吕宁 CAO Jiang-ying;ZHANG Chen;LV Ning(School of Pharmacology,Shandong University of Traditional Chinese Medicine,Jinan 250355,China)

机构地区：[1]山东中医药大学药学院,济南250355

出　　处：《中国新药杂志》2022年第19期1922-1928,共7页Chinese Journal of New Drugs

基　　金：山东省医药卫生科技发展计划项目(202013051070);药学院青年教师科研强基计划项目(2021-0013);国家级大学生创新创业训练计划项目(202110441006);山东中医药大学大学生研究训练计划(SRT)项目(2021032,2021050)。

摘　　要：目的:设计合成9个三氮唑酰胺类氨肽酶N抑制剂,并进行氨肽酶N抑制活性和抗细胞增殖活性筛选。方法:利用生物电子等排体中的翻转酰胺策略,设计了三氮唑酰胺类化合物3a~3i。以氨基酸甲酯盐酸盐4a~4i为原料,经过酰化、亲核取代、点击化学、水解、酸化等步骤,合成了目标化合物3a~3i,测定了3a~3i对氨肽酶N的抑制作用;用MTT法测定了3g和3i对肿瘤细胞和正常细胞的增殖抑制作用;使用Autodock 4预测了化合物3i与氨肽酶N的结合模式。结果和结论:合成的9个目标化合物结构经过^(1)H-NMR和MS谱确证,化合物3i具有最优的氨肽酶N抑制活性,其半数抑制浓度(IC_(50))为(2.88±0.19)μmol·L^(-1)。对接结果显示,3i的异羟肟酸基团结合锌离子,三氮唑苯基侧链和4-溴苯丙氨酸残基分别与S和S’疏水口袋结合。化合物3g和3i的抗肿瘤细胞增殖活性优于乌苯美司(bestatin);化合物3g和3i对正常细胞HEK293的IC>1000μmol·L^(-1),显示了化合物低的细胞毒性。化合物3g和3i具有进一步研究的价值,可以作为氨肽酶N抑制剂设计的先导化合物。Objective:To design and synthesize nine 1,2,3-triazole derivatives with amide moiety and to evaluate their inhibitory activities against aminopeptidase N and the proliferation of cells.Methods:Target compounds 3 a~3 i were designed based on the flipped amide strategy of bioisostere principle.Using amino acid methyl ester hydrochloride 4 a~4 i as original materials,compounds 3 a~3 i were synthesized via acylation,nucleophilic substitution,click chemistry,hydrolysis,and acidification.The APN inhibitory activities of all the compounds and the anti-proliferation activities of selected compounds against tumor cells and normal cells were evaluated by MTT.The mode of 3 i interacting with aminopeptidase N was predicated by Autodock 4.Results and Conclusion:The structures of all target compounds were confirmed by^(1)H-NMR and MS spectra.Compound 3 i,with ICvalue of(2.88±0.19)μmol·L^(-1),showed the best inhibitory activity against aminopeptidase N.The docking results showed that the hydroxamate acid moiety of compound 3 i interacted with the zinc ion.The 1,2,3-triazole phenyl side chain and 4-bromophenylalanine residue bound the hydrophobic pockets Sand S’,respectively.The anti-proliferative activities of compounds 3 g and 3 i against tumor cells were better than those of bestatin.Moreover,the ICvalues of compounds 3 g and 3 i against normal cell HEK293 were above 1000μmol·L^(-1),showing the low cytotoxicities.Compounds 3 g and 3 i hold the possibility to be used as lead compounds for optimization.

关 键 词：氨肽酶N 抑制剂 1 2 3-三氮唑衍生物 抗肿瘤 点击化学 

分 类 号：R914.5[医药卫生—药物化学]