N-取代-2,6-哌啶二酮类氨肽酶N(APN/CD13)抑制剂的合成及生物活性  

Design,synthesis and bioactivity evalution of N-substituted-2,6-dioxopiperidin derivatives as aminopeptidase N(APN/CD13) inhibitors

作　　者：袁玉梅[1] 张晓攀[1] 李乾斌[1] 徐文方[1] 

机构地区：[1]山东大学药学院药物化学研究所,山东济南250012

出　　处：《中国药物化学杂志》2011年第1期53-56,共4页Chinese Journal of Medicinal Chemistry

基　　金：国家高技术研究发展计划项目(863项目;2007AA02Z314);国家自然科学基金重大专项研究课题(90713041)

摘　　要：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。Aminopeptidase N（APN/CD13） is an important zinc dependent metallo-exopeptidase,which is over 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-phenylpropanamide（8） was synthesized.Boc-L-glutamine（2） was synthesized from optical pure L-glutamine by protection with（Boc）2O and then cyclization in the presence of DCC and NHSu in THF.（S）-tert-butyl-2,6-dioxopiperidin-3-ylcarbamate（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-1-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.

关 键 词：哌啶二酮衍生物 氨肽酶N抑制剂 设计 合成 

分 类 号：R914[医药卫生—药物化学]