title: Kinetic characterization of 4,4'-biphenylsulfonamides as selective non-zinc binding MMP inhibitors.
abstract: We describe the characterisation of a series of 4,4'-biphenylsulfonamides as selective inhibitors of matrix metalloproteases MMP-2 and -13, two enzymes involved in cell invasion and angiogenesis. Double-inhibitor studies in the presence of acetohydroxamic acid show that these molecules do not bind the catalytic zinc. Moreover, two of the characterised inhibitors (11 and 19) act as non-competitive inhibitors, whereas the para-methyl ester derivative 13 behaves as a competitive inhibitor. This finding suggests that this class of molecules binds to a catalytic subsite, possibly the S1'-pocket. Moreover, since these compounds also act as inhibitors of carbonic anhydrases (CAs), another family of enzymes involved in cell invasion, they could be potentially useful as CA/MMP dual target inhibitors with increased efficacy as anticancer agents.
authors.affiliation: a Dipartimento di Farmacia , Università di Pisa , Pisa , Italy .
authors.forename: Salvatore
authors.initials: S
authors.lastname: Santamaria
authors.affiliation: a Dipartimento di Farmacia , Università di Pisa , Pisa , Italy .
authors.forename: Elisa
authors.initials: E
authors.lastname: Nuti
authors.affiliation: b Dipartimento di Biologia, Unità di Biochimica , Università di Pisa , Pisa , Italy .|c Istituto di Biofisica del CNR, Area della Ricerca di Pisa , Pisa , Italy .
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cercignani
authors.affiliation: d Dipartimento di Chimica e Tecnologie del Farmaco , Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma , Roma , Italy , and.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: La Regina
authors.affiliation: d Dipartimento di Chimica e Tecnologie del Farmaco , Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma , Roma , Italy , and.
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
authors.affiliation: e Laboratorio di Chimica Bioinorganica, Polo Scientifico, Università degli Studi di Firenze , Florence , Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: a Dipartimento di Farmacia , Università di Pisa , Pisa , Italy .
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
mesh_terms: D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D061965:Matrix Metalloproteinase Inhibitors; D013449:Sulfonamides; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2
keywords: Carbonic anhydrase; matrix metalloproteases; non-competitive inhibitors; non-zinc binding inhibitors