title: Multimeric xanthates as carbonic anhydrase inhibitors.
abstract: The field of multivalent inhibition of enzymes is growing exponentially from the first reported multivalent effect on a glycosidase enzyme. However, the investigations have generally remained restricted to carbohydrate-processing enzymes. Carbonic anhydrases are ubiquitous metallo-enzymes involved in many key biological processes, that catalyze the reversible hydration/dehydration of [Formula: see text]. This study reports the first synthesis of multimeric xanthates addressing the selectivity and potency of CA multivalent inhibition. Six multivalent compounds containing three, four, and six xanthate moieties were prepared and assayed against four relevant CA isoforms together with their monovalent analogues. Some of the multimers were stronger inhibitors than the monomeric species. For hCA I, the two best molecules 18 and 20 showed an improvement of the ligand affinity of 4.8 and 2.3 per xanthate units (valence-corrected values), respectively, which corresponds to a clear multivalent effect. Moreover, the biochemical assays demonstrated that the multimeric presentation of xanthates, also affected the selectivity of the relative inhibition among the four CAs assayed.
authors.affiliation: a Laboratoire de Chimie Bio-Organique, Département de Chimie, Académie Louvain , University of Namur (UNamur) , Namur , Belgium and.
authors.forename: Marta
authors.initials: M
authors.lastname: Abellán-Flos
authors.affiliation: b Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche , Università degli Studi di Firenze , Florence , Italy.
authors.forename: Muhammet
authors.initials: M
authors.lastname: Tanç
authors.affiliation: b Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche , Università degli Studi di Firenze , Florence , Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: a Laboratoire de Chimie Bio-Organique, Département de Chimie, Académie Louvain , University of Namur (UNamur) , Namur , Belgium and.
authors.forename: Stéphane P
authors.initials: SP
authors.lastname: Vincent
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D014970:Xanthines; D002256:Carbonic Anhydrases
keywords: Carbonic anhydrases; enzyme inhibitors; multivalent inhibitors; xanthates