Carbonic anhydrase inhibitors: glycosylsulfanilamides act as subnanomolar inhibitors of the human secreted isoform VI.
A series of sulfonamides incorporating sugar moieties and the sulfanilamide scaffold have been investigated for their interaction with the secretory isoform of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), CA VI. This isoform is secreted in saliva, tears, and milk of mammals - where it plays important physiological roles - even if little is understood at this moment regarding its inhibition, due to the lack of potent and/or selective inhibitors. Here we report a series of low nanomolar and subnanomolar CA VI inhibitors, belonging to the glycosylamine-sulfanilamide class. The glucose, ribose, arabinose, xylose, and fucose derivatives showed excellent CA VI inhibitory activity, with K(i)s in the range of 0.56-5.1 nm, whereas the least active derivatives, incorporating gallactose, mannose, and rhamnose scaffolds showed inhibition constants in the range of 10.1-34.1 nm. Many of these sulfonamides were also selective inhibitors for their interaction with CA VI over the physiologically dominant and ubiquitous isoform CA II, with selectivity ratios of 4.11-35.93 for inhibiting the secreted over the cytosolic isozyme. Because of their high water solubility and high affinity for CA VI over CA II, these compounds are useful tools for better understanding the secreted CA isoform CA VI.
Winum
Jean-Yves
JY
Institut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS-UM1-UM2 Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France. jean-yves.winum@univmontp2.fr
Montero
Jean-Louis
JL
Vullo
Daniela
D
Supuran
Claudiu T
CT
D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000378:metabolism*; D006801:Humans; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013424:Sulfanilamides / Q000737:chemistry* / Q000494:pharmacology
D002257:Carbonic Anhydrase Inhibitors; D020033:Protein Isoforms; D011994:Recombinant Proteins; D013424:Sulfanilamides; D002256:Carbonic Anhydrases; C477051:carbonic anhydrase VI