A novel class of carbonic anhydrase inhibitors: glycoconjugate benzene sulfonamides prepared by "click-tailing".
Aryl and heteroaryl sulfonamides (ArSO(2)NH(2)) are therapeutically used to inhibit the catalytic activity of carbonic anhydrases (CAs). Using a "click-tail" approach a novel class of glycoconjugate benzene sulfonamides have been synthesized that contain diverse carbohydrate-triazole tails. These compounds were assessed for their ability to inhibit three human CA isozymes in vitro: cytosolic hCA I and hCA II and transmembrane, tumor-associated hCA IX. This isozyme has a minimal expression in normal tissue but is overexpressed in hypoxic tumors and its inhibition is a current approach toward new cancer therapies. The qualitative structure-activity for all derivatives demonstrated that the stereochemical diversity present within the carbohydrate tails effectively interrogated the CA active site topology, to generate several inhibitors that were potent and selective toward hCA IX, an important outcome in the quest for potential cancer therapy applications based on CA inhibition.
Wilkinson
Brendan L
BL
Eskitis Institute for Cell and Molecular Therapies, Griffith University, 170 Kessels Road, Nathan, Queensland 4111, Australia.
Bornaghi
Laurent F
LF
Houston
Todd A
TA
Innocenti
Alessio
A
Supuran
Claudiu T
CT
Poulsen
Sally-Ann
SA
D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D002240:Carbohydrate Sequence; D002245:Carbon Dioxide / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006031:Glycosylation; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008969:Molecular Sequence Data; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*
D001555:Benzene Derivatives; D002257:Carbonic Anhydrase Inhibitors; D007202:Indicators and Reagents; D007527:Isoenzymes; D013449:Sulfonamides; D002245:Carbon Dioxide