Identification of 3,4-Dihydroisoquinoline-2(1H)-sulfonamides as potent carbonic anhydrase inhibitors: synthesis, biological evaluation, and enzyme--ligand X-ray studies.

Abstract

Following previous studies we herein report the exploration of the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects and enzyme selectivity of a small class of 1-(cyclo)alkylisoquinolines containing a sulfonamide function considered a key feature for inhibiting CA. The results of enzymatic assays against human (h) CA isoforms, hCA I and hCA II (cytosolic, ubiquitous enzymes), hCA IX (transmembrane, tumor-associated), and hCA XIV (transmembrane), suggested that the presence of C-1 small substituents on isoquinoline scaffold controls both inhibitory potency and selectivity. Some derivatives showed potent hCA IX and hCA XIV inhibitory effects at nanomolar concentrations as well as low affinity for the ubiquitous hCA II. Moreover, we report the X-ray crystal structure of one of these derivatives in complex with dominant human isoform II, thus confirming the sulfonamide--zinc interactions. Finally, the results of docking experiments suggested the hypothetic interactions in the catalytic binding site for the most active and selective hCA IX and hCA XIV inhibitor.

• Authors: Rosaria Gitto, Stefano Agnello, Stefania Ferro, Laura De Luca, Daniela Vullo, Jiri Brynda, Pavel Mader, Claudiu T Supuran, Alba Chimirri
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 6 Pg. 2401-8 (Mar 25 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20170095 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Carbonic Anhydrase Inhibitors
• Isoquinolines
• Ligands
• Sulfonamides
• Carbonic Anhydrase I
• Carbonic Anhydrase II
• CA9 protein, human
• Carbonic Anhydrase IX
• Carbonic Anhydrases
• carbonic anhydrase XIV

Topics

• Antigens, Neoplasm (chemistry, metabolism)
• Binding, Competitive
• Carbonic Anhydrase I (antagonists & inhibitors, chemistry, metabolism)
• Carbonic Anhydrase II (antagonists & inhibitors, chemistry, metabolism)
• Carbonic Anhydrase IX
• Carbonic Anhydrase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Carbonic Anhydrases (chemistry, metabolism)
• Catalytic Domain
• Crystallography, X-Ray
• Dose-Response Relationship, Drug
• Humans
• Isoquinolines (chemistry)
• Ligands
• Models, Chemical
• Models, Molecular
• Molecular Structure
• Protein Binding
• Protein Structure, Tertiary
• Structure-Activity Relationship
• Sulfonamides (chemical synthesis, chemistry, pharmacology)