Novel leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry

Jiangying Cao; Chunhua Ma; Jie Zang; Shuai Gao; Qianwen Gao; Xiujie Kong; Yugang Yan; Xuewu Liang; Qin'ge Ding; Chunlong Zhao; Binghe Wang; Wenfang Xu; Yingjie Zhang

doi:10.1016/j.bmc.2018.04.041

Novel leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry

Bioorg Med Chem. 2018 Jul 23;26(12):3145-3157. doi: 10.1016/j.bmc.2018.04.041. Epub 2018 Apr 22.

Authors

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, PR China.
² School of Chemistry and Chemical Engineering, Henan Normal University, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions of Ministry of Education, Xinxiang 453007, China.
³ Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA.
⁴ Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, PR China. Electronic address: [email protected].

PMID: 29859750
DOI: 10.1016/j.bmc.2018.04.041

Abstract

The over-expression of aminopeptidase N on diverse malignant cells is associated with the tumor angiogenesis and metastasis. In this report, one new series of leucine ureido derivatives containing the triazole moiety was designed, synthesized and evaluated as APN inhibitors. Among them, compound 13v showed the best APN inhibition with an IC₅₀ value of 0.089 ± 0.007 μM, which was two orders of magnitude lower than that of bestatin (IC₅₀ = 9.4 ± 0.5 μM). Compound 13v also showed dose-dependent anti-angiogenesis activities. Even at the lower concentration (10 μM), compound 13v presented similar anti-angiogenesis activity compared with bestatin at 100 μM in both the human umbilical vein endothelial cells (HUVECs) capillary tube formation assay and the rat thoracic aorta rings test. Moreover, compared with bestatin, 13v exhibited comparable, if not better in vivo anti-metastasis activity in a mouse H22 pulmonary metastasis model.

Keywords: Aminopeptidase N; Anti-angiogenesis; Anti-metastasis; CD13; Triazole.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Binding Sites
CD13 Antigens / antagonists & inhibitors*
CD13 Antigens / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Click Chemistry
Disease Models, Animal
Human Umbilical Vein Endothelial Cells
Humans
Leucine / analogs & derivatives*
Leucine / pharmacology
Leucine / therapeutic use
Liver Neoplasms / pathology
Lung Neoplasms / drug therapy
Lung Neoplasms / secondary
Mice
Molecular Docking Simulation
Neovascularization, Physiologic / drug effects
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacology
Protease Inhibitors / therapeutic use
Protein Structure, Tertiary
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protease Inhibitors
CD13 Antigens
Leucine
ubenimex