title: Propargylic sulfones possessing a 2-nitroimidazole function: novel hypoxic-cell radiosensitizers with intracellular non-protein thiol depletion ability.
abstract: Propargylic sulfones (1a-c) containing a 2-nitroimidazole structure were synthesized, and their non-protein thiol (NPSH) depletion abilities were investigated. Propargylic sulfones 1a,c containing an electron withdrawing p-nitrophenyl group showed high reactivity toward capturing glutathione (GSH), a typical intracellular NPSH, in phosphate buffer. Among the three propargylic sulfones 1a-c, carboxylic acid derivative 1c showed the most potent radiosensitizing activity toward hypoxic EMT6/KU tumor cells. In view of these results and the partition coefficients between 1-octanol and water, we concluded that appropriate NPSH-depletion ability and lipophilicity are both important in achieving potent hypoxic-cell radiosensitization by propargylic sulfones possessing a 2-nitroimidazole function in biological systems.
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: Ryusuke
authors.initials: R
authors.lastname: Kojima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hatta
authors.forename: Sei-ichi
authors.initials: S
authors.lastname: Nishimoto
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D000860:Hypoxia / Q000378:metabolism*; D007510:Isatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D009593:Nitroimidazoles / Q000737:chemistry / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000378:metabolism*
chemical_list: D000480:Alkynes; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D013438:Sulfhydryl Compounds; C116442:propargylic sulfone; D007510:Isatin; D005978:Glutathione