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Bioorg Med Chem. 2013 Apr 15;21(8):2314-2318. doi: 10.1016/j.bmc.2013.02.022. Epub 2013 Feb 21.

Structural effect of phenyl ring compared to thiadiazole based adamantyl-sulfonamides on carbonic anhydrase inhibition.

Author information

1
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, PB 100245, Gainesville, FL 32610, USA.
2
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
3
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, PB 100245, Gainesville, FL 32610, USA. Electronic address: rmckenna@ufl.edu.
4
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy; Università degli Studi di Firenze, NEUROFARBA Department, Section of Pharmaceutical Chemistry, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.

Abstract

We investigated the inhibitory activity of sulfonamides incorporating adamantyl moieties against the physiologically relevant human (h) CA (EC 4.2.1.1) isoforms hCA I, II III (cytosolic), IX and XII (transmembrane, tumor-associated). The presence of a benzenesulfonamide instead of an 1,3,4-thiadiazole-sulfonamide fragment in the molecule of CA inhibitors (CAIs) drastically affects both inhibition efficacy and binding within the enzyme active site, as rationalized by means of X-ray crystallography of the adduct of hCA II with 4-(1-adamantylcarboxamidomethyl)benzenesulfonamide. Comparing the present X-ray structure with that of the corresponding 1,3,4-thiadiazole-sulfonamide compound possessing the 1-adamantylcarboxamide moiety, important differences of binding emerged, which explain the highly different inhibition profile of the two compounds against the investigated CA isoforms, most of which (CA I, II, IX and XII) are important drug targets.

PMID:
23490152
DOI:
10.1016/j.bmc.2013.02.022
[Indexed for MEDLINE]

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