title: Synthesis and carbonic anhydrase I, II, IX and XII inhibition studies of 4-N,N-disubstituted sulfanilamides incorporating 4,4,4-trifluoro-3-oxo-but-1-enyl, phenacylthiourea and imidazol-2(3H)-one/thione moieties.
abstract: A series of sulfonamides incorporating the sulfanilamide (SA) scaffold were prepared. Reaction of the 4-amino moiety of SA with benzyl chlorides or substituted bromoacetophenones afforded the 4-mono-alkylated derivatives which were then reacted with 1,1,1-trifluoro-4-isobutoxybut-3-en-2-one leading to a series of 4-N,N-disubstituted SAs. The key intermediates were also reacted with ethoxycarbonyl isothiocyanate leading to thioureas or were cyclized in the presence of potassium cyanate/isothiocyanate to the corresponding imidazol-2(3H)-one/thiones. The new compounds were tested as inhibitors of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic CA I and II, and the transmembrane, tumor-associated CA IX and XII. These sulfonamides were ineffective CA I and II inhibitors but were nanomolar CA IX and XII inhibitors, making them of interest as clinical candidates for antitumor/antimetastasis applications.
authors.affiliation: Department of Life and Environment Sciences, University of Cagliari, via Ospedale 72, Cagliari I-09124, Italy. Electronic address: ccongiu@unica.it.
authors.forename: Cenzo
authors.initials: C
authors.lastname: Congiu
authors.affiliation: Department of Life and Environment Sciences, University of Cagliari, via Ospedale 72, Cagliari I-09124, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Onnis
authors.affiliation: Department of Life and Environment Sciences, University of Cagliari, via Ospedale 72, Cagliari I-09124, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Balboni
authors.affiliation: Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy; Università degli Studi di Firenze, Polo Scientifico, Dipartimento NEIROFABA, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy. Electronic address: claudiu.supuran@unifi.it.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D002074:Butanones / Q000737:chemistry*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013424:Sulfanilamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013871:Thiones / Q000737:chemistry*; D013890:Thiourea / Q000737:chemistry*
chemical_list: D002074:Butanones; D002257:Carbonic Anhydrase Inhibitors; D007093:Imidazoles; D013424:Sulfanilamides; D013871:Thiones; D002256:Carbonic Anhydrases; D013890:Thiourea
keywords: Carbonic anhydrase; Isoforms I, II, IX, XII; Sulfanilamide; Sulfonamide; Tumor-associated enzymes