title: Structural study of the location of the phenyl tail of benzene sulfonamides and the effect on human carbonic anhydrase inhibition.
abstract: The crystal structure of 4-phenylacetamidomethyl-benzenesulfonamide (4ITP) bound to human carbonic anhydrase (hCA, EC 4.2.1.1) II is reported. 4ITP is a medium potency hCA I and II inhibitor (KIs of 54-75nM), a strong mitochondrial CA VA/VB inhibitor (KIs of 8.3-8.6nM) and a weak transmembrane CA inhibitor (KIs of 136-212nM against hCA IX and XII). This elongated compound binds in an extended conformation to hCA II, with its tail lying towards the hydrophobic half of the active site whereas the sulfonamide moiety coordinates the zinc ion. The present structure was compared to that of structurally related aromatic sulfonamides, such as 4-phenylacetamido-benzene-sulfonamide (3OYS), 4-(2-mercaptophenylacetamido)-benzene-sulfonamide (2HD6) and 4-(3-nitrophenyl)-ureido-benzenesulfonamide (3N2P). Homology models of the hCA I, VA, VB, IX and XII structures were build which afforded an understanding of the amino acids involved in the binding of these compounds to these isoforms. The main conclusion of the study is that the orientation of the tail moiety and the presence of flexible linkers as well polar groups in it, strongly influence the potency and the selectivity of the sulfonamides for the inhibition of cytosolic, mitochondrial or transmembrane CA isoforms.
authors.affiliation: Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy; Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34116 Beyazit, Istanbul, Turkey.
authors.forename: Ozlen
authors.initials: O
authors.lastname: Güzel-Akdemir
authors.forename: Shyamasri
authors.initials: S
authors.lastname: Biswas
authors.forename: Katherine
authors.initials: K
authors.lastname: Lastra
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D024401:Carbonic Anhydrase I / Q000737:chemistry / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008928:Mitochondria / Q000201:enzymology; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D000096926:Benzenesulfonamides
chemical_list: D000951:Antigens, Neoplasm; D024401:Carbonic Anhydrase I; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C089226:CA9 protein, human; C477378:carbonic anhydrase XII
keywords: Carbonic anhydrase; Inhibitor; Phenylacetamido; Sulfonamide; Tail; X-ray crystallography