Examination of novel zinc-binding groups for use in matrix metalloproteinase inhibitors

The tetrahedral zinc complex [(Tp(Ph,Me))ZnOH] (Tp(Ph,Me) = hydrotris(3,5-phenylmethylpyrazolyl)borate) was combined with 1-hydroxy-2(1H)-pyridinone, 3-hydroxy-2(1H)-pyridinone, 3-hydroxy-1-methyl-2(1H)-pyridinone, 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone, 1-hydroxy-2(1H)-pyridinethione, and 3-hydroxy-2-methyl-4-pyrone to generate the complexes [(Tp(Ph,Me))Zn(ZBG)] (ZBG = zinc-binding group). These complexes were synthesized to explore the coordination geometry of potential novel zinc-binding groups for use in matrix metalloproteinase (MMP) inhibitors. The solid-state structures of all six metal complexes were determined by X-ray crystallography. These structures combined with IR and H-1 NMR data demonstrate that these ZBGs bind in a strong, bidentate fashion to the zinc(II) ion. Modeling studies indicate that these ZBGs can easily fit into the MMP active site. In an effort to develop more effective inhibitors of MMPs, this work has revealed molecular-level interactions for six potential new ZBGs.