Sugar‐Based Arylsulfonamide Carboxylates as Selective and Water‐Soluble Matrix Metalloproteinase‐12 Inhibitors. (30th June 2016)

• Record Type: Journal Article
• Authors: Nuti, Elisa; Cuffaro, Doretta; D'Andrea, Felicia; Rosalia, Lea; Tepshi, Livia; Fabbi, Marina; Carbotti, Grazia; Ferrini, Silvano; Santamaria, Salvatore; Camodeca, Caterina; Ciccone, Lidia; Orlandini, Elisabetta; Nencetti, Susanna; Stura, Enrico A.; Dive, Vincent; Rossello, Armando
• Is Part Of: ChemMedChem. Volume 11:Number 15(2016)
• Page Start: 1626
• Page End: 1637
• Publication Date: 2016-06-30
• Subjects: carbohydrates -- drug discovery -- glycoconjugates -- MMP-12 inhibitors -- metalloproteins; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600235
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Matrix metalloproteinase‐12 (MMP‐12) can be considered an attractive target to study selective inhibitors useful in the development of new therapies for lung and cardiovascular diseases. In this study, a new series of arylsulfonamide carboxylates, with increased hydrophilicity resulting from conjugation with a β‐ N ‐acetyl‐d ‐glucosamine moiety, were designed and synthesized as MMP‐12 selective inhibitors. Their inhibitory activity was evaluated on human MMPs by using the fluorimetric assay, and a crystallographic analysis was performed to characterize their binding mode. Among these glycoconjugates, a nanomolar MMP‐12 inhibitor with improved water solubility, compound3 [( R )‐2‐( N ‐(2‐(3‐(2‐acetamido‐2‐deoxy‐β‐d ‐glucopyranosyl)thioureido)ethyl)biphenyl‐4‐ylsulfonamido)‐3‐methylbutanoic acid], was identified. Abstract : Sugar power : Ten glycoconjugate arylsulfonamide carboxylates were designed and synthesized as matrix metalloproteinase‐12 (MMP‐12)‐selective inhibitors with improved hydrophilicity. They were tested on recombinant MMPs by fluorimetric assays, and X‐ray crystallographic studies helped rationalize the results. Introduction of β‐ N ‐acetyl‐d ‐glucosamine at the P2′ position was found to maintain nanomolar activity against MMP‐12 and to boost bioavailability.