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目的寻找具有较高APN酶抑制活性的新型化合物。方法以光学纯的L-谷氨酰胺为原料,经Boc保护、环合、取代、脱Boc保护、缩合、催化氢化、缩合、脱Boc保护成盐等反应合成目标化合物。并对目标化合物进行了初步的体外抑酶活性试验。结果合成了1个未见文献报道的N-取代-2,6-哌啶二酮类氨肽酶N(APN/CD13)抑制剂:(R)-2-氨基-N-((S)-1-(2-(2-(二甲胺基)乙氨基)-2-氧乙基)-2,6-二氧哌啶-3-基)-3-苯丙酰胺,其结构经核磁共振氢谱和电喷雾质谱确证。结论目标化合物对APN表现出一定的抑制活性,其IC50值为56.4μmol.L-1,但低于阳性对照药Bestatin(IC50值为3.6μmol.L-1)。通过进一步的结构修饰,有望找到活性更好的化合物。
Aim To find novel compounds with high APN enzyme inhibitory activity. Methods The optically pure L-glutamine was used as the starting material to synthesize the target compound by Boc protection, cyclization, substitution, deprotection, Boc protection, condensation, catalytic hydrogenation, condensation and deprotection into salt. The target compounds were tested for their inhibitory activity in vitro. Results A novel inhibitor of N-substituted-2, 6-piperidinedione aminopeptidase N (APN / CD13) was synthesized in the literature: (R) 1- (2- (2- (Dimethylamino) ethylamino) -2-oxoethyl) -2,6-dioxopiperidin-3-yl) -3-phenylpropionamide whose structure has been confirmed by nuclear magnetic resonance Hydrogen and electrospray mass spectrometry confirmed. Conclusion The target compounds showed some inhibitory activity against APN with IC50 value of 56.4μmol.L-1, but lower than that of the positive control drug Bestatin with IC50 value of 3.6μmol.L-1. Through further structural modification, it is expected to find a more active compound.