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

Abstract

The elucidation of the mechanism by which the reduction of coordinatively saturated Pt prodrugs occurs, leading to the release of the two axial ligands, is of foremost importance, being the key step for the activation of these anticancer compounds, and addressing their synthetic strategies. A systematic DFT computational analysis of the reduction process by small biomolecules, which is supposed to occur by inner- or outer-sphere electron-transfer mechanisms, has been undertaken using the recently synthesised Asplatin Pt complex, c,c,t-[PtCl (NH ) (OH)(aspirin)], as model system and l-ascorbic acid as reducing agent. Further calculations have been carried out on Asplatin analogues that should be obtained replacing the OH ligand with Cl and Br . The most accredited inner-sphere mechanistic suggestions have been explored and a recently proposed computational methodology has been applied to estimate the corresponding standard redox potentials, which cannot be directly obtained from voltammetric experiments due to the irreversibility of the platinum(IV)-to-platinum(II) reduction process.

Theoretical Prediction of Dual-Potency Anti-Tumor Agents: Combination of Oxoplatin with Other FDA-Approved Oncology Drugs

“…With the aim of proposing molecules applicable to the treatment of cancer rather than conducting a gedankenexperiment, we adapted the computational strategy of Ponte et al [ 10 ] to screen the latest Food and Drug Administration (FDA)-approved oncology drug set (AOD9) published by the National Cancer Institute, part of the US National Institutes of Health (NIH). This set contains the most recent 147 approved anti-cancer drugs [ 11 ].…”

“…This is, however, not a trivial task because an efficient prodrug has to fulfil two prerequisites: (1) the Pt(IV)–ligand bond must be sufficiently stable so as not to dissociate prior to reaching the cancerous tissues; and (2) there must be an efficient activation pathway in the intracellular media of the malignant cells [ 12 ]. These two crucially important points have been assessed in a recent theoretical contribution by Ponte, Russo and Sicilia [ 10 ], who used density functional theory (DFT) calculations to simulate the mechanism for the reduction of asplatin. The reported theoretical outcomes allow us to understand the mechanism behind the reduction by mono-deprotonated ascorbic acid (AscH – ), which is the predominant state of ascorbic acid at physiological pH [ 15 ].…”

“…The constructed models correctly mimic the expected mechanism for a two-electron transference process, Pt(IV)→Pt(II). It has been shown that one of the hydrogen atoms in AscH – is transferred to the hydroxyl ligand opposite the bioactive ligand in the initial stage [ 10 ]. This proton transfer subsequently activates the release of a water molecule that is concomitant with the detachment of the bioactive ligand at the opposite trans position.…”

“…The asplatin geometry optimized by Ponte et al [ 10 ] was used as a template to build our model systems. We replaced the aspirin moiety present in asplatin (marked in orange in Figure 1 ) with the anti-cancer drug set shown in Figure 2 .…”

“… [a] Previous reported activation energy for aspirin in the anionic form of the asplatin is ΔG ‡ = 6.2 kcal mol −1 . See [ 10 ] for further details. …”