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Bioorg Med Chem Lett. 2014 Apr 1;24(7):1776-9. doi: 10.1016/j.bmcl.2014.02.030. Epub 2014 Feb 21.

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.

Author information

1
Department of Life and Environment Sciences, University of Cagliari, via Ospedale 72, Cagliari I-09124, Italy. Electronic address: ccongiu@unica.it.
2
Department of Life and Environment Sciences, University of Cagliari, via Ospedale 72, Cagliari I-09124, Italy.
3
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.

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.

KEYWORDS:

Carbonic anhydrase; Isoforms I, II, IX, XII; Sulfanilamide; Sulfonamide; Tumor-associated enzymes

PMID:
24589511
DOI:
10.1016/j.bmcl.2014.02.030
[Indexed for MEDLINE]

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