19 F NMR Allows the Investigation of the Fate of Platinum(IV) Prodrugs in Physiological Conditions

Angew Chem Int Ed Engl. 2022 Jan 21;61(4):e202114250. doi: 10.1002/anie.202114250. Epub 2021 Dec 16.

Abstract

PtIV prodrugs can overcome resistance and side effects of conventional PtII anticancer therapies. By 19 F-labeling of a PtIV prodrug (Pt-FBA, FBA=p-fluorobenzoate), the activation under physiological conditions could be investigated. Unlike single-electron reductants, multi-electron agents can efficiently promote the two electrons reduction of PtIV to PtII . The activation of Pt-FBA in cell lysate is highly dependent upon the type of cancer cells. When administered to E. coli, Pt-FBA is reduced intracellularly and free FBA can shuttle out of the cell. The reduction rate greatly increases by inducing metallothionein overexpression and is lowered by addition of ZnII ions. When injected into mice, Pt-FBA undergoes fast reduction in the bloodstream accompanied by metabolic degradation of FBA; nevertheless, unreduced Pt-FBA can accumulate to detectable levels in liver and kidneys. The 19 F NMR approach has the advantage of avoiding the interference of all background signals.

Keywords: antitumor agents; fluorine NMR; metabolism in vivo; platinum; prodrugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fluorides
  • Mice
  • Molecular Structure
  • Nuclear Magnetic Resonance, Biomolecular
  • Organoplatinum Compounds / administration & dosage
  • Organoplatinum Compounds / chemistry
  • Organoplatinum Compounds / metabolism*
  • Prodrugs / administration & dosage
  • Prodrugs / chemistry
  • Prodrugs / metabolism*

Substances

  • Organoplatinum Compounds
  • Prodrugs
  • Fluorides