Nickel(II), copper(II) and zinc(II) binding properties and cytotoxicity of tripodal, hexadentate tris(ethylenediamine) - analogue chelators

Three tripodal hexamine chelators based on cis,cis-1,3,5-triaminocyclohexane (tach) have been synthesized and their aqueous coordination chemistry with Ni(II), Cu(II) and Zn(II) is reported. The chelators have a 2-aminoethyl pendant arm attached to each nitrogen of tach, specifically 'tachen' (N, N', N"-tris(2-aminoethyl)cyclohexane-cis, cis-1, 3,5 triamine), and two with S,S,S-chiral pendant arms, 'tachpn' (N, N', N"-tris(2-aminopropyl)cyclohexane-cis, cis-1,3,5\-triamine) and 'tachbn'(N, N', N"- tris(2-amino-3-phenylpropyl)cyclohexane-cis, cis-1,3,5-triamine. These chelators complex Ni(II), Cu(II) and Zn(II) in aqueous or aqueous/methanolic medium. The crystalline products [(ML)-L-II](X)(2) are isolated, where M = Ni(II), Cu(II) or Zn(II), L = tachen, tachpn or tachbn, and X = ClO4-. Crystallographic study of selected tachpn and tachbn complexes shows the chelate arms are constrained in a Lambda(deltadeltadelta) configuration about M(II), which is attributed to their chirality Solution UV-vis spectroscopy of the Ni(II) and Cu(II) complexes indicates six-coordination and little effect of the pendant arm substitution on ligand-field strength. The single exception is [Cu(tachbn)]21, whose spectrum is consistent with five-coordination in solution. The cytotoxicities of tachen, tachpn and tachbn toward cultured cancer cells is in the order tachen < tachpn < tachbn < tachpyr, where tachpyr is the aminopyridyl chelator N,N', N"-tris(2-pyridylmethyl)cyclohexane- cis, cis-1,3,5-triamine. The cytotoxicity difference is attributed to an order of increasing lipophilicity, tachen < tachpn < tachbn.