Insights into the coordination chemistry of antineoplastic doxorubicin with 3d-transition metal ions Zn2+, Cu2+, and VO2+: a study using well-calibrated thermodynamic cycles and chemical interaction quantum chemistry models.

We present a computational strategy based on thermodynamic cycles to predict and describe the chemical equilibrium between the 3d-transition metal ions Zn2+, Cu2+, and VO2+ and the widely used antineoplastic drug doxorubicin. Our method involves benchmarking a theoretical protocol to compute gas-phase quantities using DLPNO Coupled-Cluster calculations as reference, followed by estimating solvation contributions to the reaction Gibbs free energies using both explicit partial (micro)solvation steps for charged solutes and neutral coordination complexes, as well as a continuum solvation procedure for all solutes involved in the complexation process. We rationalized the stability of these doxorubicin-metal complexes by inspecting quantities obtained from the topology of their electron densities, particularly the bond critical points and non-covalent interaction index. Our approach allowed us to identify representative species in solution phase, infer the most likely complexation process for each case, and identify key intramolecular interactions involved in the stability of these compounds. To the best of our knowledge, this is the first study reporting thermodynamic constants for the complexation of doxorubicin with transition metal ions. Unlike other methods, our procedure is computationally affordable for medium-sized systems and provides valuable insights even with limited experimental data. Furthermore, it can be extended to describe the complexation process between 3d-transition metal ions and other bioactive ligands.

Chemical Equilibrium of Zinc Acetate Complexes in Ethanol Solution. A Theoretical Description through Thermodynamic Cycles.

The Gibbs free energy of complexation between the Zn(II) species and acetate ligands, forming the [Zn(OAc)n]2-n complexes with n = 1, 2 in an ethanol solution, was assessed by two different theoretical protocols based on thermodynamic cycles. In both approaches, the solution phase Gibbs free energy of each reaction is computed by summing up contributions from gas phase thermochemistry calculations to solvation Gibbs free energies obtained in a hybrid fashion, i.e., each (neutral or electrically charged) solute was first solvated by explicit solvent molecules in order to capture relevant (micro) solute-solvent and/or solvent-solvent interactions and then, a continuum model calculation is performed in order to get the corresponding bulky solute-solvent contributions. For our first thermodynamic protocol, here denominated as variant 1, a set of x independent solvent molecules are used to screen each of the involved solutes, while the variant 2 strategy uses the fact that a set of solvent molecules may exist as aggregates (or molecular clusters) in the solvent macroscopic media, before the solvation process of solutes. Our selected quantum theoretical protocol was the M05-2X/6-31+G(d)/SMD level. We made a systematic exploration about the influence of several sources of errors, such as the solvent conformation, the number of solvent molecules used to screen each of the involved solutes, the coordination geometry of the metallic center before and after the complexation process, and the pertinence of using molecular geometries optimized in gas phase and in ethanol solution, for the computation of the Gibbs free energy variation regarding the two chemical reactions under study. We set an accuracy threshold equal or less than 4.0 kcal·mol-1, with respect to the corresponding experimental records. The robustness of our thermodynamic strategies was then tested by computing the gas phase free energy contributions to the (solution phase) reaction free energies here assessed, using different density functional approximations, namely the M05-2X, BH&HLYP, PBE0, ωb97X-D and M06-2X functionals in conjunction with the larger 6-311+G(d,p) basis set.