Metallocene-Based Inhibitors of Cancer-Associated Carbonic Anhydrase Enzymes IX and XII

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• 作者：Adam J. Salmon ; Michael L. Williams ; Quoc K. Wu ; Julia Morizzi ; Daniel Gregg ; Susan A. Charman ; Daniela Vullo ; Claudiu T. Supuran ; Sally-Ann Poulsen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：55
• 期：11
• 页码：5506-5517
• 全文大小：433K
• 年卷期：v.55,no.11(June 14, 2012)
• ISSN：1520-4804

文摘

In this study, 20 metallocene-based compounds comprising extensive structural diversity were synthesized and evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. These compounds proved moderate to good CA inhibitors in vitro, with several compounds displaying selectivity for cancer-associated isozymes CA IX and CA XII compared to off-target CA I and CA II. Compound 6 was the most potent ferrocene-based inhibitor with K_is of 5.9 and 6.8 nM at CA IX and XII, respectively. A selection of key drug-like parameters comprising Log P, Log D, solubility, and in vitro metabolic stability and permeability were measured for two of the ferrocene-based compounds, regioisomers 1 and 5. Compounds 1 and 5 were found to have characteristics consistent with lipophilic compounds, however, our findings show that the lipophilicity of the ferrocene moiety is not well modeled by replacement with either a naphthyl or a phenyl moiety in software prediction tools.