Pyridine-ring alkylation of cytotoxic r-1,c-3,c-5-tris[(2-pyridylmethyl)amino]cyclohexane chelators: Structural and electronic properties of the Mn-II, Fe-II, Ni-II, Cu-II and Zn-II complexes

Academic Article


  • AbstractEffects of pyridyl‐ring alkylation on complexation of MnII, FeII, NiII, CuII and ZnII by chelators based on r‐1,c‐3,c‐5‐triaminocyclohexane (tach) have been studied. The chelators studied are N,N′,N′′‐tris[(x‐alkyl‐2‐pyridyl)methyl] derivatives of tach, where the ring substituents are 3‐Me, 4‐Me, 5‐Me, 6‐Me or 6‐MeO (“tach‐x‐Rpyr”). Dicationic complexes were synthesized for most combinations of the above five metals and five chelators, using ClO4, NO3, Cl, or CF3SO3 as counterions. Their bonding, structure, and aqueous lability were analyzed by UV/Vis/NIR spectroscopy, magnetic moment determination, HPLC, and single‐crystal X‐ray crystallography. The striking features are seen in the 6‐alkylated complexes, where steric repulsions between the 6‐substituents at the threefold axis of the pseudo‐octahedral coordination sphere result in a substantially weakened metal–ligand interaction. In the [M(tach‐6‐Rpyr)]2+ series of divalent Mn, Ni, Cu and Zn, effects of these repulsions include bond angle and length distortions, decrease of the coordination number to five, shifts of d‐d electronic transitions to lower energies, and spin‐free complexes of the bound metal ion. Aqueous lability studies by HPLC agree with the spectroscopic findings. The bonding properties of the other tach‐x‐Mepyr chelators (x = 3, 4, 5) closely resemble the unalkylated parent tachpyr in solution. Similarly in the X‐ray studies, [Zn(tach‐3‐Mepyr)]2+ resembles [Zn(tachpyr)]2+. The cytotoxicities of the chelators toward human breast cancer cells (MCF7) at a fixed chelator concentration of 16 µM show time‐dependent induction of cell death in the order tach‐3‐Mepyr >≈ tach‐4‐Mepyr > tach‐5‐Mepyr > tachpyr, whereas tach‐6‐Mepyr and tach‐6‐MeOpyr had no effect on the cells. The depressed cytotoxicities of the latter two are attributed to inability to bind FeII or ZnII strongly. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
  • Authors

  • Childers, ML
  • Su, F
  • Przyborowska, AM
  • Bishwokarma, B
  • Park, G
  • Brechbiel, MW
  • Torti, SV
  • Torti, FM
  • Broker, G
  • Alexander, JS
  • Rogers, RD
  • Ruhlandt-Senge, K
  • Planalp, Roy
  • Status

    Publication Date

  • October 7, 2005
  • Keywords

  • antitumor activity
  • copper
  • iron
  • ligand design
  • tripodal ligands
  • zinc
  • Digital Object Identifier (doi)

    Start Page

  • 3971
  • End Page

  • 3982
  • Volume

  • 2005
  • Issue

  • 19