title: A thiazole-containing tripodal ligand: synthesis, characterization, and interactions with metal ions and matrix metalloproteinases.
abstract: 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 (Zn(2+), 1; Mn(2+), 2; Co(2+), 3) and the alkaline earth metal ions (Ca(2+), 4; Mg(2+), 5). Single-crystal X-ray structures of 1, 2, and 5 revealed six-coordinate chelate complexes with formula [M(Tatren)](ClO(4))(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, P2(1)/c space group. Crystals of 4 are triclinic, P space group. The Ca(2+) 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 K(i) = 3.5 +/- 0.6 microM. Molecular mechanics-based docking calculations suggest that one leg of Tatren coordinates to the catalytic Zn(2+) 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 Zn(2+) 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 (K(i) = 30 +/- 10 microM). Hence, this study shows that tripodal chelating ligands of this class and their Ca(2+) complexes have potential as active-site inhibitors for MMPs.
authors.affiliation: Department of Chemistry, North Dakota State University, Fargo, North Dakota 58105-5516, USA.
authors.forename: Hongshan
authors.initials: H
authors.lastname: He
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Linder
authors.forename: Kenton R
authors.initials: KR
authors.lastname: Rodgers
authors.forename: Indrani
authors.initials: I
authors.lastname: Chakraborty
authors.forename: Atta M
authors.initials: AM
authors.lastname: Arif
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D002384:Catalysis; D003035:Cobalt / Q000378:metabolism; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008345:Manganese / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D013844:Thiazoles; D003035:Cobalt; D008345:Manganese; D053509:Matrix Metalloproteinase 13; D015032:Zinc