Hypoxia-selective activation of 5-fluorodeoxyuridine prodrug possessing indolequinone structure: radiolytic reduction and cytotoxicity characteristics

We synthesized a 5-fluorodeoxyuridine (5-FdUrd) derivative possessing an indolequinone structure (IQ-FdUrd) to characterize the radiolytic reduction in aqueous solution and the radiation-activated cytotoxicity against EMT6/KU cells under hypoxic conditions. IQ-FdUrd released antitumor agent 5-FdUrd upon hypoxic, but not aerobic, irradiation with the G value of 0.38 × 10−7 mol J−1. Laser flash photolysis of IQ-FdUrd in Ar-purged aqueous solution with dimethylaniline as an electron donor gave rise to a transient absorption spectrum characteristic of semiquinone radical anion, which decayed via second order kinetics. It is most likely that bimolecular disproportionation of intermediate semiquinone radicals occurs to release 5-FdUrd. IQ-FdUrd showed enhanced cytotoxicity against EMT6/KU cells in a radiation dose-dependent manner upon hypoxic irradiation. IQ-FdUrd is potentially a prototype compound for new class of radiation-activated antitumor prodrugs that are useful for radiation treatment of hypoxic tumors.

Graphical abstractWe designed and synthesized a 5-fluorodeoxyuridine (5-FdUrd) prodrug possessing an indolequinone structure that releases antitumor agent 5-FdUrd via hypoxia-selective activation by ionizing radiation.Figure optionsDownload full-size imageDownload as PowerPoint slide