Sulfonamide linked neoglycoconjugates--a new class of inhibitors for cancer-associated carbonic anhydrases.
The contribution of membrane-bound carbonic anhydrases (CAs) to hypoxic tumor growth and progression in cancer implicates cancer-associated CAs as a promising drug target for oncology. In this paper, we present a new class of sulfonamide-linked neoglycoconjugate that was designed to selectively target and inhibit the extracellular domains of the cancer-relevant CA isozymes. We describe the application of novel, yet straightforward, chemistry toward the synthesis of inhibitors that comprise both S-glycosyl sulfenamides and S-glycosyl sulfonamides. We also present the CA inhibition profile of our new neoglycoconjugates, more specifically a library of 30 compounds (3-32) that were designed to optimize both SAR (structure-activity relationship) and SPR (structure-property relationship) characteristics. We show that our approach produces neutral, water-soluble, and potent inhibitors (K(i)s in the low nanomolar range) that target cancer-associated CAs.
Lopez
Marie
M
Eskitis Institute for Cell and Molecular Therapies, Griffith University, 170 Kessels Road, Nathan, Queensland 4111, Australia.
Bornaghi
Laurent F
LF
Innocenti
Alessio
A
Vullo
Daniela
D
Charman
Susan A
SA
Supuran
Claudiu T
CT
Poulsen
Sally-Ann
SA
D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D002463:Cell Membrane Permeability; D006001:Glycoconjugates / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*
D002257:Carbonic Anhydrase Inhibitors; D006001:Glycoconjugates; D007527:Isoenzymes; D013449:Sulfonamides; D002256:Carbonic Anhydrases