Cyclic Secondary Sulfonamides: Unusually Good Inhibitors of Cancer-Related Carbonic Anhydrase Enzymes

详细信息    查看全文

• 作者：Janina Moeker ; Thomas S. Peat ; Laurent F. Bornaghi ; Daniela Vullo ; Claudiu T. Supuran ; Sally-Ann Poulsen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 24, 2014
• 年：2014
• 卷：57
• 期：8
• 页码：3522-3531
• 全文大小：392K
• 年卷期：v.57,no.8(April 24, 2014)
• ISSN：1520-4804

文摘

Carbonic anhydrase IX (CA IX) is a target for hypoxic cancer therapies, and the discovery of CA IX selective ligands is imperative for the development of these agents. Primary sulfonamides are broad specificity inhibitors of CA enzymes, while secondary sulfonamides are generally poor CA inhibitors. However, saccharin, a cyclic secondary sulfonamide, has unusually good inhibition of CA IX (K_i = 103 nM). In this study, we demonstrate that the affinity and selectivity of saccharin for CA IX can be further modulated when linked to hydrophobic or hydrophilic substituents. The hydrophilic glycoconjugate derivative (12) showed improved inhibition of CA IX (K_i = 49.5 nM) and extremely poor inhibition of the predominant off-target CAs (K_i > 50鈥?00 nM) compared to saccharin. This >1000-fold selectivity for CA IX over off-target CAs is unprecedented for classical primary sulfonamide CA inhibitors. Our study highlights the potential of cyclic secondary sulfonamides to be exploited for the discovery of potent, cancer-selective CA inhibitors.