Cyclic secondary sulfonamides: unusually good inhibitors of cancer-related carbonic anhydrase enzymes.

Abstract

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 (Ki = 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 (Ki = 49.5 nM) and extremely poor inhibition of the predominant off-target CAs (Ki > 50000 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.

• Authors: Janina Moeker, Thomas S Peat, Laurent F Bornaghi, Daniela Vullo, Claudiu T Supuran, Sally-Ann Poulsen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 8 Pg. 3522-31 (Apr 24 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 24689792 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Carbonic Anhydrase Inhibitors
• Sulfonamides
• CA9 protein, human
• Carbonic Anhydrase IX
• Carbonic Anhydrases
• Saccharin

Topics

• Antigens, Neoplasm (chemistry, drug effects)
• Carbonic Anhydrase IX
• Carbonic Anhydrase Inhibitors (chemical synthesis, pharmacology)
• Carbonic Anhydrases (chemistry, drug effects)
• Drug Discovery
• Humans
• Neoplasms (enzymology)
• Saccharin (pharmacology)
• Sulfonamides (chemical synthesis, pharmacology)