IMIDAZOLE AND TETRAZOLE AS LIGANDS FOR CALCIUM AND MAGNESIUM. Drake S. Eggleston, R. Curtis Haltiwanger, Dana Sherman, Lisa Garber, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia PA 19406 USA
With an eye toward the potential utility of such heterocycles as components of molecules with pharmacological action we have prepared and characterized structurally a number of Mg(II) and Ca(II) complexes with neutral imidazoles or ionized tetrazole in the primary coordination sphere. A desire to understand the roles of the group IIa metal ions Mg(II) and Ca(II) in biological processes and biomolecular structure stabilization has prompted many previous investigations into the nature and extent of their coordination environment(s). Magnesium always exhibits octahedral coordination while Ca(II) can easily expand its coordination sphere1. Based on observations from biological systems it is also generally accepted that oxygen containing ligands present a preferred coordination milieu for both ions, consistent with hard-soft acid-base theory. In a majority of Mg(II) binding sites one or more protein carboxylate ligand(s) are found coordinated, with oxygen(s) from backbone carbonyl or alcohol groups also heavily represented. Histidine nitrogen has been reported once as a Mg(II) ligand2, but apparently no such examples with Ca(II) are known. Small molecule crystal structure data provides a corroborating view of preferred ligands; ie. there is only a single example of magnesium3 or calcium4 structures with an imidazole (a model for histidine residues in proteins) ligand. Further database examination suggests, however, sufficient general potential for imino-type (sp2) nitrogen coordination to both metals with energetically favorable interactions. To examine the possibilities further, complexes containing neutral imidazole, N-methyl imidazole, 2-methyl imidazole, imidazole acetic acid or ionized tetrazole ligands for Mg(II) and Ca(II) have been isolated and studied.
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3. Sarna, R., Ramirez, F., Narayanan, P., McKeever, B., Marecek, J. F. J. Am. Chem. Soc. 101: 5015-5019 (1979).
4. Cole, L. B., Holt, E. M. J. Chem. Soc. Perkin Trans. I 151-154 (1986).