title: Sugar-Based Arylsulfonamide Carboxylates as Selective and Water-Soluble Matrix Metalloproteinase-12 Inhibitors.
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, compound 3 [(R)-2-(N-(2-(3-(2-acetamido-2-deoxy-β-d-glucopyranosyl)thioureido)ethyl)biphenyl-4-ylsulfonamido)-3-methylbutanoic acid], was identified.
authors.affiliation: Department of Pharmacy, University of Pisa, via Bonanno 6, 56126, Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Nuti
authors.affiliation: Department of Pharmacy, University of Pisa, via Bonanno 6, 56126, Pisa, Italy.
authors.forename: Doretta
authors.initials: D
authors.lastname: Cuffaro
authors.affiliation: Department of Pharmacy, University of Pisa, via Bonanno 6, 56126, Pisa, Italy.
authors.forename: Felicia
authors.initials: F
authors.lastname: D'Andrea
authors.affiliation: Department of Pharmacy, University of Pisa, via Bonanno 6, 56126, Pisa, Italy.
authors.forename: Lea
authors.initials: L
authors.lastname: Rosalia
authors.affiliation: CEA-Saclay, Service d'Ingenierie Moleculaire des Proteines, CEA, iBiTec-S, 91191, Gif sur Yvette, France.
authors.forename: Livia
authors.initials: L
authors.lastname: Tepshi
authors.affiliation: Biotherapy Unit, IRCCS AOU San Martino-IST, Largo R. Benzi 10, 16132, Genoa, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Fabbi
authors.affiliation: Biotherapy Unit, IRCCS AOU San Martino-IST, Largo R. Benzi 10, 16132, Genoa, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Carbotti
authors.affiliation: Biotherapy Unit, IRCCS AOU San Martino-IST, Largo R. Benzi 10, 16132, Genoa, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, OX3 7FY, Oxford, UK.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Santamaria
authors.affiliation: Division of Immunology, Transplants and Infectious Diseases, San Raffaele Scientific Institute, Via Olgettina, 20132, Milan, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Camodeca
authors.affiliation: Department of Pharmacy, University of Pisa, via Bonanno 6, 56126, Pisa, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Ciccone
authors.affiliation: Department of Pharmacy, University of Pisa, via Bonanno 6, 56126, Pisa, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orlandini
authors.affiliation: Department of Pharmacy, University of Pisa, via Bonanno 6, 56126, Pisa, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Nencetti
authors.affiliation: CEA-Saclay, Service d'Ingenierie Moleculaire des Proteines, CEA, iBiTec-S, 91191, Gif sur Yvette, France.
authors.forename: Enrico A
authors.initials: EA
authors.lastname: Stura
authors.affiliation: CEA-Saclay, Service d'Ingenierie Moleculaire des Proteines, CEA, iBiTec-S, 91191, Gif sur Yvette, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
authors.affiliation: Department of Pharmacy, University of Pisa, via Bonanno 6, 56126, Pisa, Italy. armando.rossello@farm.unipi.it.
authors.forename: Armando
authors.identifier: 0000-0002-6795-8091
authors.initials: A
authors.lastname: Rossello
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D020134:Catalytic Domain; D005960:Glucosides / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D053508:Matrix Metalloproteinase 12 / Q000737:chemistry*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D012995:Solubility; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry; D013890:Thiourea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: C000622623:2-(N-(2-(3-(2-acetamido-2-deoxyglucopyranosyl)thioureido)ethyl)biphenyl-4-ylsulfonamido)-3-methylbutanoic acid; D005960:Glucosides; D061965:Matrix Metalloproteinase Inhibitors; D013449:Sulfonamides; D014230:Triazoles; D014867:Water; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12; D013890:Thiourea; D000117:Acetylglucosamine
keywords: MMP-12 inhibitors; carbohydrates; drug discovery; glycoconjugates; metalloproteins