Antitumor Platinium(IV) Prodrugs: A Systematic Computational Exploration of Their Reduction Mechanism by l-Ascorbic Acid

Abstract

The reduction mechanism of Pt(IV) anticancer prodrugs, still today a matter of debate, assisted by one of the dominant reductants in human plasma, that is L-ascorbic acid in its monodeprotonated form, has been computationally examined in this work. In order to check what should be the influence on the reduction rate of the identity of the ligands in axial and equatorial position, both cisplatin and oxaliplatin derivatives have been studied, varying the ligands in axial position in connection with the role they should play as bridges, trans leaving species, and proton acceptors. OH, OAc, Cl, and Br ligands have been tested as bridging/ leaving ligands, whereas Cl and aspirin have been used as trans labile and less labile ligands, respectively. The most recent theoretical and experimental investigations have demonstrated that the generally adopted grouping of reduction mechanisms into inner-and outer-sphere does not properly take into account all the viable alternatives. Therefore, inner-sphere mechanisms, classified as ligand-bridged, ligand-bridged-H transfer and enolate β-carbon attack, have been explored for all the complexes under investigation. Concerning the outer-sphere mechanism, redox potentials have been calculated adopting a recently proposed procedure based on the separation between electrochemical and chemical events to evaluate their propensity to be reduced. Moreover, according to the hypothesis that the outer-sphere reduction mechanism involves the sequential addition of two electrons causing the formation of a Pt(III) intermediate, the possibility that singlet and triplet pathways can cross for the Pt(IV) cisplatin derivative having two chlorido ligands in axial position has been explored in detail. Results show that the mechanism indicated as base-assisted outer sphere can become competitive with respect to the inner one if two singlet−triplet spin inversions occur. Results presented here are helpful in addressing synthetic strategies as they show that Pt(IV) prodrugs propensity to be reduced can be properly tuned and give indications on how this aim can be accomplished.

Iodido equatorial ligands influence on the mechanism of action of Pt(IV) and Pt(II) anti‐cancer complexes: A DFT computational study

“…With respect to the iodide complex, a barrier higher by about 2 kcal mol −1 for mechanisms B) and the same height of 24.3 kcal mol −1 for mechanism C) , have calculated. This result is in line with the conclusion formerly drawn 26 about the influence of the identity of the equatorial ligands on the reduction mechanisms when AscH − is the reducing agent. On the contrary, the presence of chlorides in equatorial position instead of iodides introduces significant changes when the alternative B′) mechanism is examined (see Figure S2 of the SI).…”

“…Therefore, mechanism C) is calculated to be less kinetically favored, according to what previously reported, 26 and the barrier of the second step of the process, leading to the formation of DHA through the elimination of a water molecule formed by the transferred OH − with the abstraction of a proton from the geminal hydroxide, should be even higher.…”

“…In the former case a direct contact, involving new bond formation, is established with the reducing agent, in the latter the electrons are transferred without any direct interaction. However, theoretical investigations carried out recently by some of us 26 have allowed to further classify the reduction mechanisms of Pt(IV) prodrugs, when AscH − is the reducing agent as A) ligand bridged , B) ligand‐bridged H‐transfer and C) enolate β‐carbon attack . In both A) and B) mechanisms one of the axial ligands is able to form a bridge between the Pt(IV) center and the reductant mediating the flow of the electrons.…”

“…Furthermore, L-Cysteine (Cys), as a model of sulfur-containing bioreductants, has been used as reducing agent involved in the inner-sphere mechanism.Therefore, all the three A), B) and C) mechanisms have been explored as a function of the identity of both the reducing agent and the involved ligand. Concerning the outer-sphere mechanism, the calculation of the standard redox potential of the examined complex has been performed adopting the decomposition scheme proposed by Baik and coworkers29 and already tested26,30,31 assuming that reduction can take place through a two steps electron transfer encompassing formation of a metastable six-coordinate Pt(III) inter-mediate. The comparison between the outcomes of the inner-and outer-sphere mechanism computational exploration can allow to deduce what is the preferred mode of reduction.…”

Investigations of the Kinetics and Mechanism of Reduction of a Carboplatin Pt(IV) Prodrug by the Major Small-Molecule Reductants in Human Plasma

“…However, the major small-molecule reductants ascorbic acid, Cys, and GSH are commonly used for estimation of the activation processes of various Pt(IV) prodrugs [12,14,15,16,19,20]. Kinetic and mechanistic studies to elucidate the detailed reduction processes by these small-molecule reductants are still of current interest [23,32,33,34]. We have analyzed in detail the redox kinetics of one of the carboplatin Pt(IV) prodrugs, cis,trans -[Pt(cbdca)(NH 3 ) 2 Cl 2 ] (cbdca = cyclobutane-1,1-dicarboxylate) [17,18], by these major small-molecule reductants in human plasma by stopped-flow spectrophotometry and identified the most reactive protolytic species at the physiological pH of 7.4.…”