Aminopeptidase N( APN/CD13 ) is an important zinc dependent metallo-exopeptidase, which isover expressed in tumor cells and plays a critical role in tumor invasion, metastasis and tumor angiogenesis.In order to find better aminopeptidase N inhibitors, One N-substituted-2,6-dioxopiperidin derivative (S)-2-amino-N-( (S) -1 -( 2-( 2-( dimethylamino ) ethylamino ) -2-oxoethyl ) -2,6-dioxopiperidin-3-yl ) -3-phenylpro-panamide(8) was synthesized.Boc-L-glutamine(2) was synthesized from optical pure L-glutamine by pro-tection with (Boc)2O and then cyclization in the presence of DCC and NHSu in THF.(S)-tert-buty1-2,6-dioxopiperidin-3-yicarbamate(3) ,which was synthesized by alkylation of compound 2 with benzyl bromoacetate, was then treated with TFA to give compound 4.Then compound 4 was coupled with Boc-L-Phe to give compound 5,which was then catalytically hydrogenated using 10％ Pd/C to afford compound 6.Coupling between compound 6 and N, N-dimethylpropan-l-amine in the presence of CDI gave compound 7.Compound 7 was finally treacted with HCl-EtOAc to give the target compound 8.The in vitro inhibitory activity of the target compound against APN was evaluated, and the IC50 value was 56.4 μmol· L -1 ( the IC50 value of the control Bestatin was 3.6 μmol· L- 1 ).The result showed that the target compound had some activity while it need further modification to find better APN inhibitors.%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、催化氧化、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Ⅳ-取代-2,6-哌啶二酮类氨肽酶N(APN/CD13)抑制剂:(R)-2-氨基-Ⅳ-((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56.4 μmol·L-1,但低于阳性对照药Bestatin(IC50值为3.6 μmol·L-1).通过进一步的结构修饰,有望找到活性更好的化合物.
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