Faculty Collaboration Database

Heterocyclic zinc-binding groups for use in next-generation matrix metalloproteinase inhibitors: potency, toxicity, and reactivity. J Biol Inorg Chem 2006 Mar;11(2):131-8

Date

01/05/2006

Pubmed ID

16391944

DOI

10.1007/s00775-005-0053-x

Scopus ID

2-s2.0-32444434063 (requires institutional sign-in at Scopus site)   75 Citations

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 microM. 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.

Author List

Puerta DT, Griffin MO, Lewis JA, Romero-Perez D, Garcia R, Villarreal FJ, Cohen SM

Author

Michael O. Griffin MD, PhD Associate Professor in the Radiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cells, Cultured
Chelating Agents
Fibroblasts
Humans
Matrix Metalloproteinase 1
Matrix Metalloproteinase 2
Matrix Metalloproteinase Inhibitors
Molecular Structure
Myocardium
Rats
Rats, Sprague-Dawley
Recombinant Proteins
Sulfhydryl Compounds
Zinc