Carbonic anhydrase inhibitors: inhibition of isozymes I, II, and IX with triazole-linked O-glycosides of benzene sulfonamides.
We report the synthesis of a series of benzene sulfonamides containing triazole-O-glycoside tails for evaluation as carbonic anhydrase (CA) inhibitors. These glycoconjugates were synthesized by the 1,3-dipolar cycloaddition reaction of 4-azidobenzenesulfonamide with O-propynyl glycosides. Compounds were assessed for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA I and II and the tumor-associated isozyme hCA IX (h = human). Against hCA I these compounds were either micromolar or low-nanomolar inhibitors, while against hCA II and IX inhibition in the range of 6.8-53 and 9.7-107 nM, respectively, was observed. The most potent inhibitor against hCA IX was the galactose derivative 8 (Ki = 9.7 nM); this is so far the most potent glycoconjugate inhibitor reported for the tumor-associated hCA IX. These carbohydrate-tethered sulfonamides may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly.
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
Vullo
Daniela
D
Supuran
Claudiu T
CT
Poulsen
Sally-Ann
SA
D024401:Carbonic Anhydrase I / Q000737:chemistry*; D024402:Carbonic Anhydrase II / Q000737:chemistry*; D024403:Carbonic Anhydrase III / Q000737:chemistry*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005697:Galactosides / Q000138:chemical synthesis* / Q000737:chemistry; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry; D000096926:Benzenesulfonamides
D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D024403:Carbonic Anhydrase III; D002257:Carbonic Anhydrase Inhibitors; D005697:Galactosides; D006027:Glycosides; D007527:Isoenzymes; D013449:Sulfonamides; D014230:Triazoles; C519519:4-(4-((2',3',4',6'-tetra-O-acetylgalactopyranosyl)oxymethyl)-1H-1,2,3-triazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides