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

Abstract

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 [M^IIL](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 Λ(δδδ) 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)]²⁺, 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.