化学
异羟肟酸
基质金属蛋白酶抑制剂
酶
生物化学
氨肽酶
体外
细胞毒性
恶性疟原虫
立体化学
药理学
氨基酸
生物
亮氨酸
免疫学
疟疾
作者
Jisook Lee,Nguyen X. Vinh,N. Drinkwater,Wei Yang,Komagal Kannan Sivaraman,Luke S. Schembri,Michelle Gazdik,Peter M. Grin,Georgina S. Butler,Christopher M. Overall,Susan A. Charman,Sheena McGowan,Peter J. Scammells
标识
DOI:10.1021/acs.jmedchem.9b00757
摘要
Aminopeptidase N (APN/CD13) is a zinc-dependent M1 aminopeptidase that contributes to cancer progression by promoting angiogenesis, metastasis, and tumor invasion. We have previously identified hydroxamic acid-containing analogues that are potent inhibitors of the APN homologue from the malarial parasite Plasmodium falciparum M1 aminopeptidase (PfA-M1). Herein, we describe the rationale that underpins the repurposing of PfA-M1 inhibitors as novel APN inhibitors. A series of novel hydroxamic acid analogues were developed using a structure-based design approach and evaluated their inhibition activities against APN. N-(2-(Hydroxyamino)-2-oxo-1-(3′,4′,5′-trifluoro-[1,1′-biphenyl]-4-yl)ethyl)-4-(methylsulfonamido)benzamide (6ad) proved to be an extremely potent inhibitor of APN activity in vitro, selective against other zinc-dependent enzymes such as matrix metalloproteases, and possessed limited cytotoxicity against Ad293 cells and favorable physicochemical and metabolic stability properties. The combined results indicate that compound 6ad may be a useful lead for the development of anticancer agents.
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