Thiosemicarbazide-Substituted Coumarins as Selective Inhibitors of the Tumor Associated Human Carbonic Anhydrases IX and XII
Arzu Gumus,
Murat Bozdag,
Atilla Akdemir,
Andrea Angeli,
Silvia Selleri,
Fabrizio Carta,
Claudiu T. Supuran
Affiliations
Arzu Gumus
Department of Chemistry, Faculty of Science and Art, Balikesir University, 10145 Balikesir, Turkey
Murat Bozdag
NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
Atilla Akdemir
Computer-Aided Drug Discovery Laboratory, Department of Pharmacology, Faculty of Pharmacy, Bezmialem Vakif University, 34093 Istanbul, Turkey
Andrea Angeli
NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
Silvia Selleri
NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
Fabrizio Carta
NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
Claudiu T. Supuran
NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
A novel series of thiosemicarbazide-substituted coumarins was synthesized and the inhibitory effects against four physiologically relevant carbonic anhydrase isoforms I, II, IX and XII showed selective activities on the tumor-associated IX and XII isozymes. Molecular modeling studies on selected compounds 14a and 22a were performed. The binding modes of such compounds were determined assuming their enzymatically active structures (i.e., cinnamic acid) in the thermodynamically favored, and not previously explored, E geometry. Molecular modelling suggests multiple interactions within the enzymatic cavity and may explain the high potency and selectivity reported for the hCAs IX and XII.
