title: Open saccharin-based secondary sulfonamides as potent and selective inhibitors of cancer-related carbonic anhydrase IX and XII isoforms.
abstract: A large number of novel secondary sulfonamides based on the open saccharin scaffold were synthesized and evaluated as selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). They were obtained by reductive ring opening of the newly synthesized N-alkylated saccharin derivatives and were shown to be inactive against the two cytosolic off-target hCA I and II (Kis > 10 µM). Interestingly, these compounds inhibited hCA IX in the low nanomolar range with Kis ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (Kis ranging between 4.3 and 432 nM). Since hCA IX and XII are the cancer-related isoforms recently validated as drug targets, these results represent an important goal in the development of new anticancer candidates. Finally, a computational approach has been performed to better correlate the biological data to the binding mode of these inhibitors.
authors: a School of Life Sciences , University of Dundee , Dundee , Scotland , UK.
authors: Melissa
authors: M
authors: D'Ascenzio
authors: b Dipartimento di Chimica e Tecnologie del Farmaco , Sapienza University of Rome , Rome , Italy.
authors: Paolo
authors: P
authors: Guglielmi
authors: c Department of Pharmacy , "G. D'Annunzio" University of Chieti-Pescara , Chieti , Italy.
authors: Simone
authors: S
authors: Carradori
authors: b Dipartimento di Chimica e Tecnologie del Farmaco , Sapienza University of Rome , Rome , Italy.
authors: Daniela
authors: D
authors: Secci
authors: c Department of Pharmacy , "G. D'Annunzio" University of Chieti-Pescara , Chieti , Italy.
authors: Rosalba
authors: R
authors: Florio
authors: c Department of Pharmacy , "G. D'Annunzio" University of Chieti-Pescara , Chieti , Italy.
authors: Adriano
authors: A
authors: Mollica
authors: d Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze , Sesto Fiorentino , Florence , Italy.
authors: Mariangela
authors: M
authors: Ceruso
authors: e Department of Pharmacology, Faculty of Pharmacy , Bezmialem Vakif University , Fatih , Istanbul , Turkey.
authors: Atilla
authors: A
authors: Akdemir
authors: f Magnetic Resonance Laboratory "Annalaura Segre", National Research Council , Institute of Chemical Methodologies , Monterotondo , Rome , Italy.
authors: Anatoly P
authors: AP
authors: Sobolev
authors: d Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze , Sesto Fiorentino , Florence , Italy.|g Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences , Università degli Studi di Firenze , Sesto Fiorentino , Florence , Italy.
authors: Claudiu T
authors: CT
authors: Supuran
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000201:enzymology*; D020033:Protein Isoforms / Q000187:drug effects*; D012439:Saccharin / Q000737:chemistry*; D013057:Spectrum Analysis / Q000379:methods; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D020033:Protein Isoforms; D013449:Sulfonamides; D002256:Carbonic Anhydrases; D012439:Saccharin
keywords: Cancer-related isoforms; saccharin; secondary sulphonamides; selective carbonic anhydrase inhibitors