Angiogenesis inhibitor TX-1898: syntheses of the enantiomers of sterically diverse haloacetylcarbamoyl-2-nitroimidazole hypoxic cell radiosensitizers.
(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.
Jin
Cheng-Zhe
CZ
Department of Biological Science and Technology, Faculty of Engineering, University of Tokushima, Tokushima 770-8506, Japan.
Nagasawa
Hideko
H
Shimamura
Mariko
M
Uto
Yoshihiro
Y
Inayama
Seiichi
S
Takeuchi
Yoshio
Y
Kirk
Kenneth L
KL
Hori
Hitoshi
H
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
D020533:Angiogenesis Inhibitors; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C496997:TX-1898