title: Hypoxia-selective activation of 5-fluorodeoxyuridine prodrug possessing indolequinone structure: radiolytic reduction and cytotoxicity characteristics.
abstract: 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 x 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.
authors.affiliation: Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Katsura Campus, Kyoto 615-8510, Japan. tanabeka@scl.kyoto-u.ac.jp
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tanabe
authors.forename: Yuji
authors.initials: Y
authors.lastname: Makimura
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Tachi
authors.forename: Akemi
authors.initials: A
authors.lastname: Imagawa-Sato
authors.forename: Sei-ichi
authors.initials: S
authors.lastname: Nishimoto
mesh_terms: D015687:Cell Hypoxia / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D005467:Floxuridine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D045563:Indolequinones / Q000737:chemistry* / Q000494:pharmacology; D010782:Photolysis; D011355:Prodrugs / Q000494:pharmacology*
chemical_list: D016166:Free Radical Scavengers; D045563:Indolequinones; D011355:Prodrugs; D005467:Floxuridine