Carbonic anhydrase inhibitors: aliphatic N-phosphorylated sulfamates--a novel zinc-anchoring group leading to nanomolar inhibitors.
A small library of phosphorylated sulfamates (N-(O-alkylsulfamoyl)-phosphoramidic acids) incorporating long aliphatic chains (C8-C16) has been synthesized and investigated for their interaction with two physiologically relevant carbonic anhydrase (CA) isozymes. These compounds behaved as very potent inhibitors of both isozymes, with inhibition constants in the range of 8.2-16.1nM against isozyme hCA I, and 5.3-11.9nM against isozyme hCA II. Activity was optimal for the n-octyl derivative (similarly with that of the corresponding unsubstituted sulfamates) and gradually decreased for the longer chain derivatives. Some of these compounds are much more effective CA inhibitors as compared to the clinically used derivatives acetazolamide, sulfanilamide or topiramate, which are used as standards for the enzymatic determinations. The phosphorylated sulfamate moiety represents a novel zinc-binding group for the design of effective CA inhibitors.
Bonnac
Laurent
L
Université Montpellier II, Laboratoire de Chimie Biomoléculaire, UMR 5032, UMII, Mayoly-Spindler, CNRS, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France.
Innocenti
Alessio
A
Winum
Jean-Yves
JY
Casini
Angela
A
Montero
Jean-Louis
JL
Scozzafava
Andrea
A
Barragan
Veronique
V
Supuran
Claudiu T
CT
D001665:Binding Sites; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D010766:Phosphorylation; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015032:Zinc / Q000737:chemistry*
D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D013451:Sulfonic Acids; C005741:sulfamic acid; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D015032:Zinc