Computational Exploration of the Mechanism of Action of a Sorafenib-Containing Ruthenium Complex as an Anticancer Agent for Photoactivated Chemotherapy

Abstract

Ruthenium(II) polypyridyl complexes are being tested as potential anticancer agents in different therapies, which include conventional chemotherapy and light-activated approaches. A mechanistic study on a recently synthesized dual-action Ru(II) complex [Ru(bpy)₂(sora)Cl]⁺ is described here. It is characterized by two mono-dentate leaving ligands, namely, chloride and sorafenib ligands, which make it possible to form a di-aquo complex able to bind DNA. At the same time, while the released sorafenib can induce ferroptosis, the complex is also able to act as a photosensitizer according to type II photodynamic therapy processes, thus generating one of the most harmful cytotoxic species, ¹O₂. In order to clarify the mechanism of action of the drug, computational strategies based on density functional theory are exploited. The photophysical properties of the complex, which include the absorption spectrum, the kinetics of ISC, and the character of all the excited states potentially involved in ¹O₂ generation, as well as the pathway providing the di-aquo complex, are fully explored. Interestingly, the outcomes show that light is needed to form the mono-aquo complex, after releasing both chloride and sorafenib ligands, while the second solvent molecule enters the coordination sphere of the metal once the system has come back to the ground-state potential energy surface. In order to simulate the interaction with canonical DNA, the di-aquo complex interaction with a guanine nucleobase as a model has also been studied. The whole study aims to elucidate the intricate details of the photodissociation process, which could help with designing tailored metal complexes as potential anticancer agents.

Keywords: ISC; PACT; PDT; photosensitizer; ruthenium complexes; sorafenib.

Scheme 1

Schematic mechanism of action of the Ru-Sora complex, where ISC stands for intersystem crossing and EnT for energy transfer.

Figure 1

Optimized structures of the (a) synthesized Ru-Sora complex and the models (b) RuS and (c) Ru. Selected bond lengths and valence angles are reported in Å and degrees, respectively.

Figure 2

(a) Absorption spectra of the synthesized complex Ru-Sora [21] and the models RuS and Ru. (b) NTOs of the lowest-lying singlet state (λ_max).

Figure 3

(a) Absorption spectra of RuS complex in which the main vertical electronic transitions (those with an oscillator strength (a.u.) greater than 0.01), together with the main character of the two bands, are reported; (b) percentage of metal-centered (MC), ligand-centered (LC), metal-to-ligand (MLCT), ligand-to-metal (LMCT) and ligand-to-ligand (LLCT) charge transfers character for each vertical transition; (c) oscillator strength (a.u.) for the first thirty electronic transitions.

Figure 4

Computed spin density isosurfaces (accomplished with an isovalue of 1 × 10⁻³ a.u., envy and purple colors stand for positive and negative parts) of the intercepted TDA–PBE0 triplet states. The spin density of the metal center and adiabatic energy gap ΔE with respect to the GS are also provided.

Figure 5

Jablonski-like diagram representing the mechanism of action of the RuS complex. The kinetic constant of the most probable ISC process starting from the lowest-lying singlet state (S₁) is reported above the dashed red arrow in s⁻¹.

Figure 6

Calculated B3LYP-D3 free energy profile describing the activation mechanisms of Ru complex. Energies are in kcal mol⁻¹ and relative to separated reactants, which are Ru complex and two water molecules.

Scheme 2

Proposed activation mechanism of Ru-Sora complex.

Figure 7

Reaction mechanism found for the substitution reaction of a water molecule with the guanine purine base. Relative Gibbs free energies (kcal mol⁻¹) are reported in bold. The optimized structure of the intercepted transition states is reported above the arrows. For the sake of clarity in the sketched minima structures, the species around the metal complex, either guanine or water, are omitted.