title: Kinetic and X-ray crystallographic investigations on carbonic anhydrase isoforms I, II, IX and XII of a thioureido analog of SLC-0111.
abstract: SLC-0111 (4-(4-fluorophenylureido)-benzenesulfonamide) is the first carbonic anhydrase (CA, EC 4.2.1.1) IX inhibitor to reach phase I clinical trials as an antitumor/antimetastatic agent. Here we report a kinetic and X-ray crystallographic study of a congener of SLC-0111 which incorporates a thioureido instead of ureido linker between the two aromatic rings as inhibitor of four physiologically relevant CA isoforms. Similar to SLC-0111, the thioureido derivative was a weak hCA I and II inhibitor and a potent one against hCA IX and XII. X-ray crystallography of its adduct with hCA II and comparison of the structure with that of other five hCA II-sulfonamide adducts belonging to the SLC-0111 series, afforded us to understand the particular inhibition profile of the new sulfonamide. Similar to SLC-0111, the thioureido sulfonamide primarily interacted with the hydrophobic side of the hCA II active site, with the tail participating in van der Waals interactions with Phe131 and Pro202, in addition to the coordination of the deprotonated sulfonamide to the active site metal ion. On the contrary, the tail of other sulfonamides belonging to the SLC-0111 series (2-isopropyl-phenyl; 3-nitrophenyl) were orientated towards the hydrophilic half of the active site, which was correlated with orders of magnitude better inhibitory activity against hCA II, and a loss of selectivity for the inhibition of the tumor-associated CAs.
authors.affiliation: University of Florida College of Medicine, Department of Biochemistry and Molecular Biology, Gainesville, FL, USA.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Lomelino
authors.affiliation: University of Florida College of Medicine, Department of Biochemistry and Molecular Biology, Gainesville, FL, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Mahon
authors.affiliation: University of Florida College of Medicine, Department of Biochemistry and Molecular Biology, Gainesville, FL, USA. Electronic address: rmckenna@ufl.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
authors.affiliation: Dipartimento di Chimica Ugo Schiff, Università degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino (Firenze), Italy; Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.affiliation: Dipartimento di Chimica Ugo Schiff, Università degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino (Firenze), Italy; Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy. Electronic address: claudiu.supuran@unifi.it.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D054879:Halogenation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D020033:Protein Isoforms; D013449:Sulfonamides; D013890:Thiourea; D000096926:Benzenesulfonamides
keywords: Carbonic anhydrase; Sulfonamide; Thioureido; Ureido; X-ray crystallography