Synergistic Effects in Pt^II–Porphyrinoid Dyes as Candidates for a Dual‐Action Anticancer Therapy: A Theoretical Exploration

Abstract

The combination of a photosensitizer (PS) with a cisplatin-like unit represents a challenging strategy to increase the effectiveness of photodynamic therapy and to afford a dual-action anticancer treatment. Recently, new tetra-Pt -porphyrin conjugates have been proposed as promising multitarget agents. To reveal the effect of the Pt center on the chemical and physical properties of the PS and to explore the effect of the PS on the activation mechanism of Pt ligand before reaching its biological target, we carried out a first-principle investigation on these tetra-Pt -porphyrin conjugates. To propose a further advance in this novel field and to gain useful insights for the design of new, more efficient Pt -PS conjugates, we introduced structural modifications into the porphyrin dye, which involved the synthesis of the tetra-Pt -chlorin and tetra-Pt -bacteriochlorin derivatives. Results showed that the designed dyes better met the criteria to be successful in a dual-action therapy, as they displayed improved optical properties and reduced the hydrolysis rate of the Pt moiety, the latter being a desirable feature to avoid many side reactions of the conjugate during their transport to the biological target.

Os(II) Oligothienyl Complexes as a Hypoxia-Active Photosensitizer Class for Photodynamic Therapy

“…To simulate the effects of the solvent environment, the integral equation formalism polarizable continuum model (IEFPCM) , was adopted, setting a dielectric constant ε = 80. Absorption spectra were also modeled in water on the ground-state equilibrium structures, using the same basis set as for the optimizations by employing the M06 XC-functional, the performance of which has been widely tested and previously verified ,− in modeling the photophysical properties of metallic complexes. This protocol allows a direct comparison with results previously obtained for analogous Ru­(II) and Os­(II) compounds.…”

Synthesis, Characterization, Thermal Analysis, DFT, and Cytotoxicity of Palladium Complexes with Nitrogen-Donor Ligands

“…The exploration of the chlorideaqua substitution reactions is, therefore, essential to provide useful insights on the kinetics of the process. DFT studies have proven to be accurate in providing both mechanistic details as well as potential energy surfaces for Pt(II) and even Pd(II) compounds [32][33][34][35][36][37][38][39][40][41].…”

“…The use of implicit solvent and explicit water molecules allow for the proper solvation of the leaving chloride, better accounting for the hydrogen-bonding network during the substitution process. Such a model was previously adopted for the study of similar reactions [36][37][38][39][40][41]. The total free energy in solution, including all non-electrostatic terms (solute-solvent dispersion interaction energy, solute-solvent repulsion interaction energy, and solute cavitation energy), were obtained through single-point calculations with the larger basis set 6-31++G(2df,2pd), and were used to draw the relative free energy profiles of the hydrolysis mechanism.…”

“…The total free energy in solution, including all non-electrostatic terms (solute-solvent dispersion interaction energy, solute-solvent repulsion interaction energy, and solute cavitation energy), were obtained through single-point calculations with the larger basis set 6-31++G(2df,2pd), and were used to draw the relative free energy profiles of the hydrolysis mechanism. The used protocol allows a direct comparison with results previously obtained for analogous Pt(II) compounds [36][37][38][39][40][41].…”

Hypoxia-Selective Dissociation Mechanism of a Nitroimidazole Nucleoside in a DNA Environment

“…Several solutions to this problem have been proposed in the last years by the scientific community; a few examples include the use of nanoparticles, dual approaches that combine Pt anticancer drugs with other agents, − and other strategies. , Kuang et al have proposed a PS based on a modified nucleoside ( 1 ), in which a nitroimidazole group is appended to the methyl group of thymine (see Figure ). The modified nucleoside 1 was embedded into several DNA oligonucleotides, showing a preferential capacity to produce DNA cross-links in absence of oxygen.…”