Flavin-conjugated Pt(IV) anticancer agents

Abstract

In situ activation of Pt(IV) to Pt(II) species is a promising strategy to control anticancer activity and overcome off-target toxicity linked to classic platinum chemotherapeutic agents. Herein, we present the design and synthesis of two new asymmetric Pt(IV) derivatives of cisplatin and oxaliplatin (1·TARF and 2·TARF, respectively) bearing a 2',3',4',5'-tetraacetylriboflavin moiety (TARF) covalently bonded. 1H and 195Pt NMR spectroscopy shows that 1·TARF and 2·TARF can be effectively activated into toxic Pt(II) species, when incubated with NADH, sodium ascorbate, and glutathione (GSH) in the dark and under light irradiation. Density functional theory studies of the dark Pt(IV)-to-Pt(II) conversion of 2·TARF indicate that the process involves first a hydride transfer from the donor to the flavin moiety of the complex, followed by electron transfer to the Pt(IV) center. When administered to MDA-MB-231 breast cancer cells pre-incubated with non-toxic amounts of ascorbate, 2·TARF displays enhanced toxicity (between one and two orders of magnitude), suggesting that generation of oxaliplatin can selectively be triggered by redox activation. Such an effect is not observed when 2 and TARF are co-administered under the same conditions, demonstrating that covalent binding of the flavin to the Pt complex is pivotal.

The current status in computational exploration of Pt(iv) prodrug activation by reduction

“…27 Carboxylato ligands have been further exploited to enhance the pharmacological properties of Pt IV prodrugs and add bioactive ligands to the axial positions to exert multi-action effects. 23,[28][29][30][31][32] The nature of the axial and, although to a much lesser extent, equatorial ligands is, therefore, of key importance in determining the properties of Pt IV prodrugs and, in particular, their propensity to undergo two-electron reduction that provokes the breaking of the bonds between platinum and the axial ligands. 33 The rate of the reduction/activation step has to be appropriately tuned to avoid occurring too rapidly before the prodrug reaches the tumor, or too slowly if the prodrug resists the reductive nature of the reducing agents.…”