A Thiazole-containing Tripodal Ligand: Synthesis, Characterization, and Interactions with Metal Ions and Matrix Metalloproteinases

A new tripodal ligand, tris[2-(((2-thiazolyl)methylidene)amino)ethyl]amine (Tatren), has been synthesized and characterized by NMR, IR, and UV−visible absorbance spectroscopy and elemental analysis. Tatren forms stable complexes with transition metal ions (Zn2+, 1; Mn2+, 2; Co2+, 3) and the alkaline earth metal ions (Ca2+, 4; Mg2+, 5). Single-crystal X-ray structures of 1, 2, and 5 revealed six-coordinate chelate complexes with formula [M(Tatren)](ClO4)2 in which the metal centers are coordinated by three thiazolyl N atoms and three acyclic imine N atoms. Crystals of 1, 2, and 5 are monoclinic, P21/c space group. Crystals of 4 are triclinic, P1̄ space group. The Ca2+ complex is eight-coordinate with all N atoms of Tatren and one water molecule coordinated to the metal ion. Spectrophotometric titrations show that formation constants for the chelates of metal ions are ≫1 in methanol. Free Tatren inhibits the catalytic domain of matrix metalloproteinase-13 (MMP-13, collagenase-3) with Ki = 3.5 ± 0.6 μM. Molecular mechanics-based docking calculations suggest that one leg of Tatren coordinates to the catalytic Zn2+ in MMPs-2, -9, and -13 with significant hydrogen bonding to backbone amide groups. High-level DFT calculations suggest that, in the absence of nonbonded interactions between Tatren and the enzyme, the most stable first coordination sphere of the catalytic Zn2+ is achieved with three imidazolyl groups from His residues and two imine N atoms from one leg of Tatren. While complexes (1−3) do not inhibit MMP-13 to a significant extent, 4 does (Ki = 30 ± 10 μM). Hence, this study shows that tripodal chelating ligands of this class and their Ca2+ complexes have potential as active-site inhibitors for MMPs.