Model complexes of cobalt-substituted matrix metalloproteinases: tools for inhibitor design.

Journal article

The tetrahedral cobalt(II) complex [(Tp(Ph,Me))CoCl] (Tp(Ph,Me) = hydrotris(3,5-phenylmethylpyrazolyl)borate) was combined with several hydroxypyridinone, hydroxypyridinethione, pyrone, and thiopyrone ligands to form the corresponding [(Tp(Ph,Me))Co(L)] complexes. X-ray crystal structures of these complexes were obtained to determine the mode of binding for each ligand L. The structures show that the [(Tp(Ph,Me))Co(L)] complexes are pentacoordinate complexes, with a general tendency toward square pyramidal geometry. The electronic, EPR, and paramagnetic NMR spectroscopy of the [(Tp(Ph,Me))Co(L)] complexes have been examined. The frozen-solution EPR spectra are indicative of pentacoordination in frozen solution, while the NMR indicates some dynamics in ligand binding. The findings presented here suggest that [(Tp(Ph,Me))Co(L)] complexes can be used as spectroscopic references for investigating the mode of inhibitor binding in metalloproteinases of medicinal interest. Potential limitations when using cobalt(II) model complexes are also discussed.

Authors: Jacobsen, F; Breece, R; Myers, W; Tierney, D; Cohen, S

• Publication status: Published
• Journal: Inorganic chemistry
• Volume: 45
• Issue: 18
• Pages: 7306-7315
• Publication date: 2006-09-01
• DOI: 10.1021/ic060901u
• EISSN: 1520-510X
• ISSN: 0020-1669
• Language: English
• Keywords: Models, Chemical; Ligands; Crystallography, X-Ray; Electron Spin Resonance Spectroscopy; Models, Molecular; Protease Inhibitors; Binding Sites; Molecular Conformation; Matrix Metalloproteinases; Stereoisomerism; Matrix Metalloproteinase Inhibitors; Cobalt; Structure-Activity Relationship; Organometallic Compounds; Magnetic Resonance Spectroscopy; Sensitivity and Specificity