Novel L-arginine derivatives as aminopeptidase N inhibitors: design, chemistry, and pharmacological evaluation
- 187 Downloads
Considering the important roles played in tumor, aminopeptidase N has been an appealing target for anti-tumor drug development. Here, a serial of novel aminopeptidase N inhibitors with L-arginine scaffold were designed, synthesized and evaluated for aminopeptidase N inhibitory activities. The preliminary anti-enzyme activity assay demonstrated that compounds 5e, 5h, 11e, 11g, and 11h showed comparable activities with the positive control bestatin, an approved aminopeptidase N inhibitor. In vitro anti-proliferation assay, compound 5f showed excellent activities against four kinds of tumor cells which overexpress aminopeptidase N. In vivo anti-metastasis assay, compounds 5f and 11g exhibited better activities than bestatin. So 5f and 11g should be lead compounds as novel aminopeptidase N inhibitors for further development.
KeywordsL-arginine derivatives Aminopeptidase N Synthesis Anti-enzyme activity Anti-proliferation activity Anti-metastasis activity
This work was supported by National Nature Science Foundation of China (Grant No. 21502142) and Tianjin Research Program of Application Foundation and Advanced Technology (No.15JCQNJC14100) and Program for Changjiang Scholars and Innovative Research Team in University (IRT_14R41). The authors thank South-central University for Nationalities for supporting of CADD softwares.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- Aoyagi T, Yoshida S, Nakamura Y, Shigihara Y, Hamada M, Takeuchi T (1990) Probestin, a new inhibitor of amino- peptidase M, produced by Streptomyces azureus MH663-2F6. I. Taxonomy, production, isolation, physico-chemical properties and biological activities. J Antibiot 43:143–148CrossRefPubMedGoogle Scholar
- Fujii H, Nakajima M, Saiki I, Yoneda J, Azuma I, Tsuruo T (1995) Human melanoma invasion and metastasis enhancement by high expression of aminopeptidase N/CD13. Clin Exp Metastsis 13:337–344Google Scholar
- Ito K, Nakajima Y, Onohara Y, Takeo M, Nakashima K, Matsubara F, Ito T, Yoshimoto T (2006) Crystal structure of aminopeptidase N (proteobacteria alanyl aminopeptidase) from Escherichia coli and conformational change of methionine 260 involved in substrate recognition. J Biol Chem 281:33664–33676CrossRefPubMedGoogle Scholar
- Reinhold D, Bank U, Täer M, Ansorge S, Wrenger S, Thielitz A, Lendeckel U, Faust J, Neubert K, Brocke S (2008) DPIV/CD26, APN/CD13 and related enzymes as regulators of T cell immunity: implications for experimental encephalomyelitis and multiple sclerosisD. Front Biosci 13:2356–2363CrossRefPubMedGoogle Scholar
- Shimazawa R, Takayama H, Fujimoto Y, Komoda M, Dodo K, Yamasaki R, Shirai R, Koiso Y, Miyata K, Kato F, Kato M, Miyachi H, Hashimoto Y (1999) Novel small molecule nonpeptide aminopeptidase n inhibitors with a cyclic imide skeleton. J Enzym Inhib Med Chem 14:259–275Google Scholar