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Sugar‐Based Arylsulfonamide Carboxylates as Selective and Water‐Soluble Matrix Metalloproteinase‐12 Inhibitors
Author(s) -
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
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600235
Subject(s) - chemistry , glycoconjugate , matrix metalloproteinase , moiety , matrix metalloproteinase inhibitor , solubility , biochemistry , combinatorial chemistry , metalloproteinase , stereochemistry , organic chemistry
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, compound 3 [( R )‐2‐( N ‐(2‐(3‐(2‐acetamido‐2‐deoxy‐β‐ d ‐glucopyranosyl)thioureido)ethyl)biphenyl‐4‐ylsulfonamido)‐3‐methylbutanoic acid], was identified.