Sugar-Based Arylsulfonamide Carboxylates as Selective and Water-Soluble Matrix Metalloproteinase-12 Inhibitors

Elisa Nuti; Doretta Cuffaro; F. D'Andrea; Lea Rosalia; Livia Tepshi; Marina Fabbi; Grazia Carbotti; Silvano Ferrini; Salvatore Santamaria; Caterina Camodeca; Lidia Ciccone; Elisabetta Orlandini; Susanna Nencetti; Enrico A. Stura; Vincent Dive; Armando Rossello

doi:10.1002/cmdc.201600235

Sugar-Based Arylsulfonamide Carboxylates as Selective and Water-Soluble Matrix Metalloproteinase-12 Inhibitors

Elisa Nuti, Doretta Cuffaro, F. D'Andrea, Lea Rosalia, Livia Tepshi, Marina Fabbi, Grazia Carbotti, Silvano Ferrini, Salvatore Santamaria, Caterina Camodeca, Lidia Ciccone, Elisabetta Orlandini, Susanna Nencetti, Enrico A. Stura, Vincent Dive, Armando Rossello

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1626-1637
Number of pages	12
Journal	ChemMedChem
DOIs	https://doi.org/10.1002/cmdc.201600235
Publication status	Published - Aug 5 2016

Keywords

carbohydrates
drug discovery
glycoconjugates
metalloproteins
MMP-12 inhibitors

ASJC Scopus subject areas

Pharmacology, Toxicology and Pharmaceutics(all)
Organic Chemistry
Molecular Medicine

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10.1002/cmdc.201600235

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Nuti, E., Cuffaro, D., D'Andrea, F., Rosalia, L., Tepshi, L., Fabbi, M., Carbotti, G., Ferrini, S., Santamaria, S., Camodeca, C., Ciccone, L., Orlandini, E., Nencetti, S., Stura, E. A., Dive, V., & Rossello, A. (2016). Sugar-Based Arylsulfonamide Carboxylates as Selective and Water-Soluble Matrix Metalloproteinase-12 Inhibitors. ChemMedChem, 1626-1637. https://doi.org/10.1002/cmdc.201600235

Nuti, E, Cuffaro, D, D'Andrea, F, Rosalia, L, Tepshi, L, Fabbi, M, Carbotti, G, Ferrini, S, Santamaria, S, Camodeca, C, Ciccone, L, Orlandini, E, Nencetti, S, Stura, EA, Dive, V & Rossello, A 2016, 'Sugar-Based Arylsulfonamide Carboxylates as Selective and Water-Soluble Matrix Metalloproteinase-12 Inhibitors', ChemMedChem, pp. 1626-1637. https://doi.org/10.1002/cmdc.201600235

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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.",

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AU - Rosalia, Lea

AU - Tepshi, Livia

AU - Fabbi, Marina

AU - Carbotti, Grazia

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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

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Sugar-Based Arylsulfonamide Carboxylates as Selective and Water-Soluble Matrix Metalloproteinase-12 Inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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