Structural and Spectroscopic Study of Reactions between Chelating Zinc-Binding Groups and Mimics of the Matrix Metalloproteinase and Disintegrin Metalloprotease Catalytic Sites: The Coordination Chemistry of Metalloprotease Inhibition

To understand the coordination chemistry of zinc-binding groups (ZBGs) with catalytic zinc centers in matrix
metalloproteinases (MMPs) and disintegrin metalloproteases (ADAMs), we have undertaken a model compound
study centered around tris(3,5-methylphenypyrazolyl)hydroboratozinc(II) hydroxide and aqua complexes ([TpPh,MeZnOH] and [TpPh,MeZn(OH2)]+, respectively, wherein (TpPh,Me)- = hydrotris(3,5-methylphenylpyrazolyl)borate) and
the products of their reactions with a class of chelating Schiff's base ligands. The results show that the protic
ligands, HL (HL = N-propyl-1-(5-methyl-2-imidazolyl)methanimine (5-Me-4-ImHPr), N-propyl-1-(4-imidazolyl)methanimine (4-ImHPr), and N-propyl-1-(2-imidazolyl)methanimine (2-ImHPr)), react with [TpPh,MeZnOH] and give
products with the general formula [TpPh,MeZnL], whereas reactions with neutral aprotic ligands, L‘ (L‘ = N-propyl-1-(1-methyl-2-imidazolyl)methanimine (1-Me-2-ImPr) and N-propyl-1-(2-thiazolyl)methanimine (2-TaPr)), yield the
corresponding [TpPh,MeZnL]+ complexes. Although the phenol group of N-propyl-1-(2-hydroxyphenyl)methanimine
(2-HOPhPr) is protic, this ligand forms a cationic four-coordinate complex containing an intraligand hydrogen bond.
The solid-state structures of these complexes were determined by single-crystal X-ray diffraction, and the results
showed that the protic ligands form five-membered chelates of the Zn2+ ion. All ligands displace the aqua ligand
in [TpPh,MeZn(OH2)]+ to yield complexes having 1H NMR spectra consistent with the formation of five membered
chelates. The 1H resonance frequencies of the chelating ligands typically shift upfield upon coordination to the zinc
center, due to ring current effects from the pendant phenyl groups of the (TpPh,Me)- ligand. Thus, the 1H NMR
spectra provide a convenient and sensitive means of tracking the solution reactions by titration. The resulting
series of spectra showed that the stabilities of the chelates in solution depend on the propensity of the ligands to
deprotonate upon chelation of the zinc center. The behaviors of these bidentate ZBGs provide insight into the
structural and electronic factors that contribute to the stabilities of inhibited MMPs and ADAMs and suggest that
the proton acidity of the coordinated ZBG may be a crucial criterion for inhibitor design.