title: Angiogenesis inhibitor TX-1898: syntheses of the enantiomers of sterically diverse haloacetylcarbamoyl-2-nitroimidazole hypoxic cell radiosensitizers.
abstract: (R)- and (S)-Epichlorohydrins were used to prepare the enantiomers of sterically diverse haloacetylcarbamoyl-2-nitroimidazoles that function as hypoxic cell radiosensitizers. The synthetic design allowed for introduction of a side chain of varying bulk that permitted an examination of the steric effects on enantio-discrimination in biological assay systems. The single stereocenter also connected the two pharmacophores--a 2-nitroimidazole moiety critical to hypoxic cell radiosensitization, and a haloacetylcarbamoyl group to function as an anti-angiogenesis pharmacophore. In the chick embryo chorioallantoic membrane (CAM) assay, the R-enantiomers possessing the bulky p-tert-butylphenyl group showed higher anti-angiogenic activity than the corresponding S-enantiomers, while there were no differences in the activity between the enantiomers containing the less bulky methyl and tert-butyl groups. Among the compounds we report, R-p-tert-butylphenyl-bromoacetylcarbamoyl-2-nitroimidazole, TX-1898, was found to be the most promising candidate for further development of as anti-angiogenic hypoxic cell radiosensitizer.
authors.affiliation: Department of Biological Science and Technology, Faculty of Engineering, University of Tokushima, Tokushima 770-8506, Japan.
authors.forename: Cheng-Zhe
authors.initials: CZ
authors.lastname: Jin
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Mariko
authors.initials: M
authors.lastname: Shimamura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uto
authors.forename: Seiichi
authors.initials: S
authors.lastname: Inayama
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Kirk
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hori
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002642:Chick Embryo; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D020533:Angiogenesis Inhibitors; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C496997:TX-1898