Abstract
In an effort to improve the zinc-chelating portion of matrix metalloproteinase (MMP) inhibitors, we have developed a family of heterocyclic zinc-binding groups (ZBGs) as alternatives to the widely used hydroxamic acid moiety. Elaborating on findings from an earlier report, we performed in vitro inhibition assays with recombinant MMP-1, MMP-2, and in a cell culture assay using neonatal rat cardiac fibroblast cells. In both recombinant and cell culture assays, the new ZBGs were found to be effective inhibitors, typically 10–100-fold more potent than acetohydroxamic acid. The toxicity of these chelators was examined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt cytotoxicity assays, which demonstrate that most of these compounds are nontoxic at concentrations of almost 100 μM. To address the possible interaction of sulfur-containing ZBGs with biological reductants, the reactivity of these chelators with 5,5′-dithiobis(2-nitrobenzoic acid) was examined. Finally, thione ZBGs were shown to be effective inhibitors of cell invasion through an extracellular matrix membrane. The data presented herein suggest these heterocyclic ZBGs are potent, nontoxic, and biocompatible compounds that show promise for incorporation into a new family of MMP inhibitors.
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Acknowledgements
This work was supported by the University of California, San Diego, a Chris and Warren Hellman Faculty Scholar award (S.M.C.), an award from the American Heart Association (S.M.C.), a Pilot Project Grant from the Rebecca and John Moores U.C.S.D. Cancer Center, a Cottrell Scholar Award from the Research Corporation (S.M.C.), and N.I.H. grants HL-43617 (F.J.V.) and HL-07444 (R.G.). J.A.L. was supported in part by a GAANN fellowship (GM-602020-03), an ARCS award, and a U.C. TSR&TP Fellowship.
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Puerta, D.T., Griffin, M.O., Lewis, J.A. et al. Heterocyclic zinc-binding groups for use in next-generation matrix metalloproteinase inhibitors: potency, toxicity, and reactivity. J Biol Inorg Chem 11, 131–138 (2006). https://doi.org/10.1007/s00775-005-0053-x
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DOI: https://doi.org/10.1007/s00775-005-0053-x