TY - JOUR
T1 - Sugar-Based Arylsulfonamide Carboxylates as Selective and Water-Soluble Matrix Metalloproteinase-12 Inhibitors
AU - Nuti, Elisa
AU - Cuffaro, Doretta
AU - D'Andrea, F.
AU - Rosalia, Lea
AU - Tepshi, Livia
AU - Fabbi, Marina
AU - Carbotti, Grazia
AU - Ferrini, Silvano
AU - Santamaria, Salvatore
AU - Camodeca, Caterina
AU - Ciccone, Lidia
AU - Orlandini, Elisabetta
AU - Nencetti, Susanna
AU - Stura, Enrico A.
AU - Dive, Vincent
AU - Rossello, Armando
PY - 2016/8/5
Y1 - 2016/8/5
N2 - 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.
AB - 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.
KW - carbohydrates
KW - drug discovery
KW - glycoconjugates
KW - metalloproteins
KW - MMP-12 inhibitors
UR - http://www.scopus.com/inward/record.url?scp=84981164201&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84981164201&partnerID=8YFLogxK
U2 - 10.1002/cmdc.201600235
DO - 10.1002/cmdc.201600235
M3 - Article
SP - 1626
EP - 1637
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
ER -