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, FeII, NiII, CuII and Zn II complexes

Abstract

Effects of pyridyl-ring alkylation on complexation of MnII, FeII, NiII, CuII and ZnII by chelators based on r-1,c-3,c-5-tri-aminocyclohexane (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 ClO 4-, NO3-, Cl-, or CF 3SO3- 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, 2005.