期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 15, 页码 7185-7209出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b00757
关键词
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资金
- National Health and Medical Research Council [1063786]
- Monash University
- Sir James McNeil Foundation
- Cancer Therapeutics CRC, CTx
- National Health and Medical Research Council of Australia [1063786] Funding Source: NHMRC
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-MI 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-yOethyl)-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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