Rhenium Inhibitors of Cathepsin B (ReO(SYS)X (Where Y = S, py; X = Cl, Br, SPhOMe-p)): Synthesis and Mechanism of Inhibition

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• 作者：Renee Mosi ; Ian R. Baird ; Jennifer Cox ; Virginia Anastassov ; Beth Cameron ; Renato T. Skerlj ; Simon P. Fricker
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：August 24, 2006
• 年：2006
• 卷：49
• 期：17
• 页码：5262 - 5272
• 全文大小：265K
• 年卷期：v.49,no.17(August 24, 2006)
• ISSN：1520-4804

文摘

The synthesis of four new oxorhenium(V) complexes containing the "3 + 1" mixed-ligand donor set, ReO(SYS)X (where Y = S, py; X = Cl, Br), is described. All of the complexes tested exhibited selectivity forcathepsin B over K. Most notably, compound 6, ReO(SSS-2,2')Br (IC₅₀(cathepsin B) = 1.0 nM), was 260times more potent against cathepsin B. It was also discovered that complexes containing the same tridentate(SSS) ligand were more potent when the leaving group was bromide versus chloride (e.g., IC₅₀(cathepsinB): ReO(SSS-2,2')Cl (4), 8.8 nM; ReO(SSS-2,2')Br (6), 1.0 nM). Mechanistic studies with cathepsin Bshowed that both compounds 2 (ReO(SpyS)(SPhOMe-p)) and 4 were active-site-directed. Compound 2 wasdetermined to be a tight-binding, reversible inhibitor, while compound 4 was a time-dependent, slowlyreversible inhibitor. The results described in this paper show that the oxorhenium(V) "3 + 1" complexesare potent, selective inhibitors of cathepsin B and have potential for the treatment of cancer.