title: New amide derivatives of Probenecid as selective inhibitors of carbonic anhydrase IX and XII: biological evaluation and molecular modelling studies.
abstract: Novel amide derivatives of Probenecid were synthesized and discovered to act as potent and selective inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) transmembrane isoforms hCA IX and XII. The proposed chemical transformation of the carboxylic acid into an amide group led to a complete loss of hCA I and II inhibition (Kis >10,000nM) and enhanced the inhibitory activity against hCA IX and XII, with respect to the parent compound (incorporating a COOH function). These promising biological results have been corroborated by molecular modelling studies within the active sites of the four studied human carbonic anhydrases, which enabled us to rationalize both the isoform selectivity and high activity against the tumor-associated isoforms hCA IX/XII.
authors.affiliation: Department of Pharmacy, 'G. D'Annunzio' University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy. Electronic address: simone.carradori@unich.it.
authors.forename: Simone
authors.initials: S
authors.lastname: Carradori
authors.affiliation: Department of Pharmacy, 'G. D'Annunzio' University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Mollica
authors.affiliation: Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Ceruso
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Melissa
authors.initials: M
authors.lastname: D'Ascenzio
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Celeste
authors.initials: C
authors.lastname: De Monte
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Chimenti
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Rocchina
authors.initials: R
authors.lastname: Sabia
authors.affiliation: Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmacology, Vatan Caddesi, 34093 Fatih, Istanbul, Turkey.
authors.forename: Atilla
authors.initials: A
authors.lastname: Akdemir
authors.affiliation: 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 Dept., Section of Pharmaceutical and Nutraceutical Sciences, Via U. 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: D000951:Antigens, Neoplasm / Q000737:chemistry*; D024401:Carbonic Anhydrase I / Q000737:chemistry*; D024402:Carbonic Anhydrase II / Q000737:chemistry*; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D002256:Carbonic Anhydrases / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D057075:Enzyme Assays; D006801:Humans; D062105:Molecular Docking Simulation; D011339:Probenecid / Q000031:analogs & derivatives / Q000138:chemical synthesis*; D011485:Protein Binding; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII; D011339:Probenecid
keywords: Molecular modelling; Probenecid; Selective carbonic anhydrase IX inhibitors; Selective carbonic anhydrase XII inhibitors; Tertiary sulfonamides