Phenanthriplatin is a cationic monofunctional anticancer agent derived from cisplatin, with a phenanthridine ligand instead of a chlorido one, that has shown significantly enhanced cytotoxic activity compared to its parent complex. Moreover, phenanthriplatin has been derivatized to its prodrug using carboxylate ligands in the axial positions to decrease side effects and improve the therapeutic index. Here are reported the results of a computational investigation of the key step of the mechanism of action of Pt(IV) prodrugs, that is activation by reduction leading to the release of the active Pt(II) species. Results of both inner-sphere reduction mechanism exploration and quantum–mechanical calculation of the reduction potentials are reported. Only one of the two enantiomeric forms of Phenanthriplatin, originating from the asymmetry of the phenanthridine ligand, has been taken into consideration. For such isomer the influence that several possible arrangements of reacting Pt(IV) prodrugs and the monodeprotonated ascorbic acid reducing agent as well as site of attack can have on the rate of the reduction reaction has been studied. It is worth underscoring that the presence of the sterically hindered phenanthridine ligand does not influence the course of the reaction except that for the possibility that π-π interactions are established between the ligand and the ascorbate.

Theoretical exploration of the reduction reaction of monofunctional phenanthriplatin Pt(IV) prodrugs

Dabbish E.;Imbardelli D.;Russo Nino;Sicilia Emilia
2019

Abstract

Phenanthriplatin is a cationic monofunctional anticancer agent derived from cisplatin, with a phenanthridine ligand instead of a chlorido one, that has shown significantly enhanced cytotoxic activity compared to its parent complex. Moreover, phenanthriplatin has been derivatized to its prodrug using carboxylate ligands in the axial positions to decrease side effects and improve the therapeutic index. Here are reported the results of a computational investigation of the key step of the mechanism of action of Pt(IV) prodrugs, that is activation by reduction leading to the release of the active Pt(II) species. Results of both inner-sphere reduction mechanism exploration and quantum–mechanical calculation of the reduction potentials are reported. Only one of the two enantiomeric forms of Phenanthriplatin, originating from the asymmetry of the phenanthridine ligand, has been taken into consideration. For such isomer the influence that several possible arrangements of reacting Pt(IV) prodrugs and the monodeprotonated ascorbic acid reducing agent as well as site of attack can have on the rate of the reduction reaction has been studied. It is worth underscoring that the presence of the sterically hindered phenanthridine ligand does not influence the course of the reaction except that for the possibility that π-π interactions are established between the ligand and the ascorbate.
Ascorbic acid reductant; DFT; Phenanthriplatin (IV) prodrugs; Reduction reaction
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11770/298888
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