Model complexes of cobalt-substituted matrix metalloproteinases: tools for inhibitor design.
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.
Jacobsen
Faith E
FE
Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, CA 92093-0358, USA.
Breece
Robert M
RM
Myers
William K
WK
Tierney
David L
DL
Cohen
Seth M
SM
D001665:Binding Sites; D003035:Cobalt / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D009942:Organometallic Compounds; D011480:Protease Inhibitors; D003035:Cobalt; D020782:Matrix Metalloproteinases