Understanding Intrinsically Irreversible, Non-Nernstian, Two-Electron Redox Processes: A Combined Experimental and Computational Study of the Electrochemical Activation of Platinum(IV) Antitumor Prodrugs

Abstract

Six-coordinate Pt(IV)-complexes are prominent prodrug candidates for the treatment of various cancers where, upon two-electron reduction and loss of two axial ligands, they form more familiar, pharmacologically active four-coordinate Pt(II) drugs. A series of electrochemical experiments coupled with extensive density functional calculations has been employed to elucidate the mechanism for the two-electron reduction of Pt(IV)(NH3)2Cl2L2 to Pt(II)(NH3)2Cl2 (L = CH3COO(-), 1; L = CHCl2COO(-), 2; L = Cl(-), 3). A reliable estimate for the normal reduction potential E(o) is derived for the electrochemically irreversible Pt(IV) reduction and is compared directly to the quantum chemically calculated reduction potentials. The process of electron transfer and Pt-L bond cleavage is found to occur in a stepwise fashion, suggesting that a metastable six-coordinate Pt(III) intermediate is formed upon addition of a single electron, and the loss of both axial ligands is associated with the second electron transfer. The quantum chemically calculated reduction potentials are in excellent agreement with experimentally determined values that are notably more positive than peak potentials reported previously for 1-3.

Mechanism of the palladium-catalyzed hydrothiolation of alkynes to thioethers: a DFT study

“…However, for C 1 and C 2 atoms, the NBO charges are 3b (0.02, −0.50), 5b (−0.38, −0.19) and 7b (−0.03, −0.44), respectively. Meanwhile, the orbitals responsible for HOMO-1 in intermediates 3b, 5b and 7b are shown in Figure 7 [58][59][60]. The calculated results are also in good agreement with the experimental observations of Frech et al [47].…”

Insights from Computations on the Mechanism of Reduction by Ascorbic Acid of PtIV Prodrugs with Asplatin and Its Chlorido and Bromido Analogues as Model Systems

“…Nevertheless, the relative cathodic peak potentials of structurally related complexes are generally correlated to the relative facility with which the metal centre is reduced and are utilised to estimate reduction rates in solution . Baik and co‐workers have demonstrated, with a series of electrochemical experiments, that the two‐electron reduction process of Pt IV produgs to their Pt II analogues can be decomposed into electron transfers and Pt‐ligand bond cleavage. DFT calculations have been employed to elucidate the mechanism and the calculated reduction potentials have been found to be in excellent agreement with experimentally determined values that are notably more positive than peak potentials previously reported in the literature.…”

“…[6b] Baik and co-workers [13] have demonstrated, with a series of electrochemical experiments, that the two-electron reductionp rocess of Pt IV produgs to their Pt II analoguesc an be decomposed into electron transfers and Pt-ligand bond cleavage. DFT calculations have been employed to elucidate the mechanism and the calculated reduction potentials have been found to be in excellent agreement with experimentally determined values that are notably more positive than peak potentials previously reportedi nt he literature.…”

“…In addition, the same reduction mechanisms have been explored for Asplatin analogues that should be obtained by substituting the OH − group with either Cl − or Br − to assess the assumption that better bridging ligands (OH − <Cl − <Br − ) should favour bridge formation, lowering the energy barrier and increasing the reduction rate. Finally, by following an approach recently proposed in the literature, the reduction potentials for all the examined complexes have been quantum‐mechanically calculated by using DFT.…”

Prediction of the reduction potential in transition‐metal containing complexes: How expensive? For what accuracy?

“…Density functional theory (DFT) has proven to be a reliable, convenient, and advantageous tool for computing reduction potentials . Although many studies have utilized DFT, the absolute deviations between the experimental data and computed values are still quite large for some transition metal‐containing complexes (including both inorganic and organometallic complexes) compared with simple organic molecules.…”