Structure-Activity relationship and Molecular Bonding Parameters from room-temperature multifrequency ESR spectra of antitumor copper(II) complexes

A rigorous unambiguous way to extract all the necessary magnetic parameters for copper complexes in the fluid phase, by a combination of multifrequency ESR spectroscopy and computer simulation, is presented. By this method, which has the obvious advantage of not changing the physical state of the system, homologue copper complexes with very different cytotoxic and pharmacological activities (CuKTS and CuKTSMJ were examined. Having extracted the spin Hamiltonian parameters and the rotational correlation time from the room-temperature ESR spectra of the two complexes at multiple frequencies, small differences were found in the isotropic nitrogen coupling constants. This was never appreciated before because of the aggregation occurring in the samples at low temperature. This difference was precisely determined through an accurate computer simulation and sensitivity analysis procedure, and discussed in terms of a difference in molecular bonding parameters between CuKTS and CuKTSM2, using a simple LCAO molecular orbital scheme. The planar geometry previously proposed by Campbell et al. on the basis of frozen solution ESR data was eventually confirmed for CuKTS with the predicted sp2 hybridization for the nitrogen atoms coordinating the copper ion. In the case of CuKTSMz the hybridization coefficient n and the mixing coefficient aN have higher values consistent with an sp3 hybridization and an "out of planarity" of the chelating ring around the metal ion. A speculation on the possible correlation between the difference in the chemical arrangement and the well-known difference in the pharmacological behavior is proposed in the framework of the structurefunction relationship