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

Dalton Trans. 2004 May 7:(9):1304-11. doi: 10.1039/b403476g. Epub 2004 Mar 31.

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(II)L](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)]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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cations, Divalent / chemistry
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chelating Agents / chemical synthesis*
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacology
  • Copper / chemistry*
  • Crystallography, X-Ray
  • Ethylenediamines / chemical synthesis*
  • Ethylenediamines / chemistry
  • Ethylenediamines / pharmacology
  • Humans
  • Mice
  • Mice, Inbred C3H
  • Models, Molecular
  • Molecular Structure
  • Nickel / chemistry*
  • Organometallic Compounds / chemical synthesis*
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / pharmacology
  • Zinc / chemistry*

Substances

  • Cations, Divalent
  • Chelating Agents
  • Ethylenediamines
  • Organometallic Compounds
  • Copper
  • Nickel
  • Zinc