title: Carbonic anhydrase inhibitors: aliphatic N-phosphorylated sulfamates--a novel zinc-anchoring group leading to nanomolar inhibitors.
abstract: 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.
authors.affiliation: 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.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bonnac
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Winum
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Montero
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Veronique
authors.initials: V
authors.lastname: Barragan
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: 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*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D013451:Sulfonic Acids; C005741:sulfamic acid; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D015032:Zinc