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Flavin-Conjugated Pt(IV) Anticancer Agents. | LitMetric

AI Article Synopsis

  • The study focuses on a new strategy to enhance the effectiveness of platinum-based anticancer drugs by converting inactive Pt(IV) compounds into active Pt(II) species within the tumor environment.
  • Two new asymmetric Pt(IV) derivatives designed with a flavin moiety were developed, which can be activated through specific biochemical interactions in both dark and light conditions.
  • The results showed that one of the derivatives significantly increased toxicity to breast cancer cells when ascorbate was present, highlighting the importance of the covalent flavin binding in the activation process.

Article 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 ( and , respectively) bearing a covalently bonded 2',3',4',5'-tetraacetylriboflavin moiety (). H and Pt NMR spectroscopy shows that and 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 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, 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 and are coadministered under the same conditions, demonstrating that covalent binding of the flavin to the Pt complex is pivotal.

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Source
http://dx.doi.org/10.1021/acs.inorgchem.3c00193DOI Listing

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