Characterization and evaluation of pyrone and tropolone chelators for use in metalloprotein inhibitors

Abstract

The tetrahedral zinc and cobalt complexes [(Tp Ph,Me)ZnOH] (Tp Ph,Me = hydrotris(3,5-phenylmethylpyrazolyl)borate) and [(Tp Ph,Me)CoCl] were combined with 3-hydroxy-2 H-pyran-2-one (3,2-pyrone), 3-hydroxy-4 H-pyran-4-one (3,4-pyrone), and tropolone to form the corresponding [(Tp Ph,Me)M( L)] complexes ( L = bidentate ligand, M = Zn 2+, Co 2+). X-ray crystal structures of these complexes were obtained to determine the mode of binding for each chelator and the coordination geometry of each complex. The complexes [(Tp Ph,Me)M(3,2-pyrone)] (M = Zn 2+, Co 2+) are the first structurally characterized metal complexes with this chelator. These complexes with the various chelators show that the cobalt(II) complexes are generally isostructural with their zinc(II) counterparts. In addition to structural characterization, inhibition data for each ligand against two different zinc(II) metalloproteins, matrix metalloproteinase-3 (MMP-3) and anthrax lethal factor (LF), were obtained. Examination of these chelators in the MMP-3 active site demonstrates the possible mode of inhibition.