Inhibition of membrane-associated carbonic anhydrase isozymes IX, XII and XIV with a library of glycoconjugate benzenesulfonamides.
A library of glycoconjugate benzenesulfonamides that contain diverse carbohydrate-triazole tails were investigated for their ability to inhibit the enzymatic activity of the three human transmembrane carbonic anhydrase (CA) isozymes hCA IX, hCA XII and hCA XIV. These isozymes have their CA domains located extracellularly, unlike the physiologically dominant hCA II, and are of immense current interest as druggable targets. Elevated expression of isozymes IX and XII is a marker for a broad spectrum of hypoxic tumors-this physiology may facilitate a novel approach to discriminate between healthy cells and cancerous cells. Many of these glycoconjugates were potent inhibitors (low nM), but importantly exhibited different isozyme selectivity profiles. The most potent hCA IX inhibitor was the glucuronic acid derivative 20 (K(i)=23nM). This compound was uniquely hCA IX selective cf. all other isozymes (16.4-, 16.8- and 4.6-fold selective against hCA II, XII, and XIV, respectively). At hCA XII there were many inhibitors with K(i)s<10nM that also demonstrated excellent selectivity (up to 344-fold) against other isozymes. Potent hCA XIV inhibitors were also identified, several with K(i)s approximately 10nM, however no hCA XIV-selective derivatives were evidenced from this library. The sugar tails of this study have shown promise as a valuable approach to both solubilize the aromatic sulfonamide CA recognition pharmacophore and to deliver potent inhibition and isozyme differentiation of the transmembrane CAs.
Wilkinson
Brendan L
BL
Griffith University, Eskitis Institute for Cell and Molecular Therapies, 170 Kessels Road, Nathan, Qld 4111, Australia.
Bornaghi
Laurent F
LF
Houston
Todd A
TA
Innocenti
Alessio
A
Vullo
Daniela
D
Supuran
Claudiu T
CT
Poulsen
Sally-Ann
SA
D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D003500:Cyclization; D006001:Glycoconjugates / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008566:Membranes / Q000201:enzymology; D010637:Phenolsulfonphthalein; D011994:Recombinant Proteins / Q000737:chemistry; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*
D002257:Carbonic Anhydrase Inhibitors; D006001:Glycoconjugates; D007527:Isoenzymes; D011994:Recombinant Proteins; D013449:Sulfonamides; D010637:Phenolsulfonphthalein