New beginnings for matrix metalloproteinase inhibitors: identification of high-affinity zinc-binding groups

Journal of the American Chemical Society
David T PuertaSeth M Cohen

Abstract

In an effort to identify promising non-hydroxamate inhibitors of matrix metalloproteinases (MMPs), several new zinc-binding groups (ZBGs) based on pyrone, pyrothione, hydroxypyridinone, and hydroxypyridinethione chelators have been examined. Structural studies with tris(pyrazolyl)borate model complexes show that these ligands bind to the MMP active site zinc(II) ion in a bidentate fashion, similar to that found with hydroxamate-based inhibitors. Fluorescence- and colorimetric-based enzyme assays have been used to determine the IC50 values for these ZBGs against MMP-3; mixed O,S-donor ligands were found to be remarkably potent, with IC50 values as much as 700-fold lower than that found for acetohydroxamic acid. Inhibitory activity was found to parallel metal binding affinity as determined in titrations with model complexes. These results demonstrate that MPIs based on new ZBGs are feasible and may indeed improve the overall performance of inhibitors designed against these important medicinal targets.

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Citations

Aug 4, 2007·Journal of the American Chemical Society·Janelle Lauer-FieldsGregg B Fields
Dec 30, 2010·Journal of Medicinal Chemistry·Jennifer A JacobsenSeth M Cohen
Oct 25, 2011·Journal of Medicinal Chemistry·Sérgio M MarquesM Amélia Santos
Apr 4, 2013·Journal of Medicinal Chemistry·Vishal PatilAdegboyega K Oyelere
Jan 28, 2009·Journal of Medicinal Chemistry·Arpita AgrawalSeth M Cohen
Dec 17, 2005·The Journal of Organic Chemistry·M Burak OnaranChristopher T Seto
May 8, 2010·Chemical Communications : Chem Comm·Jody L Major Jourden, Seth M Cohen
Apr 26, 2012·Chemical Communications : Chem Comm·David P Martin, Seth M Cohen
Mar 14, 2012·Dalton Transactions : an International Journal of Inorganic Chemistry·Alisa TanakitSeth M Cohen
Mar 2, 2005·Lipids in Health and Disease·Timothy ClairMary L Stracke
Oct 19, 2014·Cancer Metastasis Reviews·Marilena TauroConor C Lynch
Dec 13, 2012·Expert Opinion on Drug Discovery·Prashant R MurumkarMange Ram Yadav
Dec 17, 2004·Journal of Cellular and Molecular Medicine·I SvabMaria-Luiza Flonta
Nov 29, 2007·Proteins·Birte SeebeckMatthias Rarey
May 26, 2011·Chemical Biology & Drug Design·Jacob D DurrantJ Andrew McCammon
Jan 27, 2011·Chemical Biology & Drug Design·Sarah L WilliamsJ Andrew McCammon
Nov 3, 2009·Journal of Molecular Recognition : JMR·Jacob D DurrantJ Andrew McCammon
Aug 29, 2009·Biochimica Et Biophysica Acta·Jennifer A JacobsenSeth M Cohen
Jan 12, 2012·Journal of Enzyme Inhibition and Medicinal Chemistry·Sara R SchlesingerSung-Kun Kim
Jun 19, 2014·Journal of Enzyme Inhibition and Medicinal Chemistry·Ilze MutulePeteris Trapencieris
Mar 1, 2005·Chemistry & Biology·Christian K EngelK Ulrich Wendt
Apr 21, 2009·Biochimica Et Biophysica Acta·Cynthia TallantF Xavier Gomis-Rüth
Jul 29, 2008·Molecular Aspects of Medicine·Athanasios Yiotakis, Vincent Dive
Apr 9, 2017·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Benjamin L DickSeth M Cohen
Mar 16, 2006·British Journal of Cancer·C M Overall, O Kleifeld
Feb 27, 2007·Bioorganic Chemistry·Sherida L JohnsonMaurizio Pellecchia
Nov 22, 2007·Bioorganic & Medicinal Chemistry Letters·Ryuji HayashiGregory R Cook
Mar 1, 2005·Chemistry & Biology·Zelda R Wasserman
Aug 15, 2014·Journal of Medicinal Chemistry·David P MartinSeth M Cohen
Mar 2, 2018·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Alexey P OrlovDmitry A Kuznetsov
Feb 7, 2012·Chembiochem : a European Journal of Chemical Biology·Carole DuboisMarius Réglier
Dec 14, 2006·ChemMedChem·Faith E JacobsenSeth M Cohen
Jan 9, 2008·ChemMedChem·Arpita AgrawalSeth M Cohen
Jan 9, 2010·ChemMedChem·Arpita AgrawalSeth M Cohen
Jul 19, 2005·Dalton Transactions : an International Journal of Inorganic Chemistry·Jana A LewisSeth M Cohen
Jan 5, 2006·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·David T PuertaSeth M Cohen
Dec 24, 2005·Chemical Communications : Chem Comm·Daniel BraytonPatrick J Farmer
Feb 6, 2019·Chemistry : a European Journal·Thomas FischerRainer Riedl
Sep 1, 2015·The Journal of Pharmacology and Experimental Therapeutics·Elisabeth MacColl, Raouf A Khalil
Jul 31, 2008·Chembiochem : a European Journal of Chemical Biology·Faith E JacobsenSeth M Cohen

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