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

The tetrahedral zinc and cobalt complexes [(TpPh,Me)ZnOH] (TpPh,Me = hydrotris(3,5-phenylmethylpyrazolyl)borate) and [(TpPh,Me)CoCl] were combined with 3-hydroxy-2H-pyran-2-one (3,2-pyrone), 3-hydroxy-4H-pyran-4-one (3,4-pyrone), and tropolone to form the corresponding [(TpPh,Me)M(L)] complexes (L = bidentate ligand, M = Zn2+, Co2+). 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 [(TpPh,Me)M(3,2-pyrone)] (M = Zn2+, Co2+) 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.

Graphical abstractModel complexes of zinc(II) and cobalt(II) have been used to predict the interaction of 3,2-pyrone, 3,4-pyrone, and tropolone with the active site metal ion of zinc metalloproteinases. The six new metal complexes have been structurally and spectroscopically characterized. The complexes with 3,2-pyrone represent the first reported metal complexes with this chelator. The results of these studies will be used to facilitate design of metalloproteinase inhibitors derived from these ligating groups.Figure optionsDownload full-size imageDownload as PowerPoint slide