Carbonic Anhydrase Inhibitors: Bioreductive Nitro-Containing Sulfonamides with Selectivity for Targeting the Tumor Associated Isoforms IX and XII

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• 作者：Katia D’ ; Ambrosio ; Rosa-Maria Vitale ; Jean-Michel Dogné ; Bernard Masereel ; Alessio Innocenti ; Andrea Scozzafava ; Giuseppina De Simone ; Claudiu T. Supuran
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：June 12, 2008
• 年：2008
• 卷：51
• 期：11
• 页码：3230 - 3237
• 全文大小：1177K
• 年卷期：v.51,no.11(June 12, 2008)
• ISSN：1520-4804

文摘

2-Substituted-5-nitro-benzenesulfonamides incorporating a large variety of secondary/tertiary amines were explored as inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), with the aim of designing bioreductive inhibitors targeting the hypoxia overexpressed, tumor-associated isozymes. The compounds were ineffective inhibitors of the cytosolic isoform I, showed a better inhibition of the physiologically relevant CA II (K_Is of 8.8−4975 nM), and strongly inhibited the tumor-associated CA IX and XII (K_Is of 5.4−653 nM). Some of these compounds showed excellent selectivity ratios for the inhibition of the tumor-associated isozymes over the cytosolic ones (in the range of 10−1395). The X-ray crystal structure of the adduct of hCA II with the lead molecule 2-chloro-5-nitro-benzenesulfonamide as well as molecular modeling studies for interaction with hCA IX afforded a better understanding of factors governing the discrimination of the two isoforms for this type of bioreductive compound targeting specifically hypoxic tumors.