Flavin-Conjugated Pt(IV) Anticancer Agents

Abstract

In situ activation of Pt(IV) to Pt(II) species is a promising strategy to control the anticancer activity and overcome the 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 covalently bonded 2′,3′,4′,5′tetraacetylriboflavin moiety (TARF). 1 H and 195 Pt NMR spectroscopy shows that 1•TARF and 2•TARF can be effectively activated into toxic Pt(II) species, when incubated with nicotinamide adenine dinucleotide, sodium ascorbate, and glutathione 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 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 preincubated with nontoxic amounts of ascorbate, 2•TARF displays enhanced toxicity (between 1 and 2 orders of magnitude), suggesting that the generation of oxaliplatin can selectively be triggered by redox activation. Such an effect is not observed when 2 and TARF are coadministered under the same conditions, demonstrating that covalent binding of the flavin to the Pt complex is pivotal.

Highly photoactive Ir(iii)–Pt(iv) heterometallic conjugates for anticancer therapy

“…29 Thus, the reduced form of Ir may also transfer an electron to the Pt(IV) center to initiate the reduction in Ir(III)-Pt(IV) conjugates. Based on this and previously reported other PS-conjugated Pt(IV) complexes, 10,12,15 another photoactivation mechanism of IrPt was proposed. Ir is excited under irradiation and subsequently reduced by an electron donor.…”

“…Recent studies have shown that photosensitizers (PSs) can facilitate the reduction of Pt( iv ) complexes under irradiation. 8,9 This has led to the development of photoactivable Pt( iv ) prodrugs by conjugating various organic PSs, such as porphyrin, 10 coumarin, 11 rhodamine, 12 boron dipyrromethene, 13 AIE dyes, 14 flavin, 15 heptamethine cyanine, 16 and fluorescein 17 with Pt( iv ) moieties. These photoactivatable Pt( iv ) prodrugs exhibit promising anticancer properties.…”

Pt(iv) anticancer prodrugs bearing an oxaliplatin scaffold: what do we know about their bioactivity?

“…36) to evaluate its ability to activate the photoredox conversion to Pt( ii ). 133 Light irradiation (460 nm, 0.1 mW cm −2 ) significantly accelerated the conversion to oxaliplatin in the presence of biological reducing agents (NADH, ascorbate, GSH). Its cytotoxicities were reported to be comparable to that of oxaliplatin in MDA-MB-231 and slightly improved for MCF7 cells.…”

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. 23,28–32 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.…”