title: Exploring carbonic anhydrase inhibition with multimeric coumarins displayed on a fullerene scaffold.
abstract: Carbonic anhydrases (CAs) are ubiquitous Zn metallo-enzymes that catalyze the reversible hydration/dehydration of CO2/HCO3(-). CAs are involved in many key biological processes, therefore their inhibition has become an attractive research field. Distinct families of CA inhibitors (CAIs) have been reported, most of them interacting with the Zn(II) at the active site. Some compounds such as the coumarins are hydrolyzed before binding the entrance of the active site cavity, and thus behave as "suicide" inhibitors. This study reports the first synthesis of multimeric suicide inhibitors, designed to address the selectivity and the potency of CA multivalent inhibition. Twelve coumarin units have been grafted to a central fullerene scaffold thanks to a CuAAC reaction and the final dodecamers were assayed against 4 relevant CAs. The multimers were always stronger inhibitors than the monomeric species but no strong "multivalent effect" was found. However, our study showed that the multimeric presentation of the coumarin around the C60, indeed affected the selectivity of the relative inhibition among the 4 CAs assayed.
authors.affiliation: University of Namur (UNamur), Académie Louvain, Département de Chimie, Laboratoire de Chimie Bio-Organique, rue de Bruxelles 61, B-5000 Namur, Belgium. stephane.vincent@unamur.be.
authors.forename: Marta
authors.initials: M
authors.lastname: Abellán-Flos
authors.forename: Muhammet
authors.initials: M
authors.lastname: Tanç
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Stéphane P
authors.initials: SP
authors.lastname: Vincent
mesh_terms: D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry*; D003374:Coumarins / Q000737:chemistry*; D037741:Fullerenes / Q000737:chemistry*; D006801:Humans
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D003374:Coumarins; D037741:Fullerenes; C030123:coumarin