Design, synthesis, and biological activity of anti-angiogenic hypoxic cell radiosensitizer haloacetylcarbamoyl-2-nitroimidazoles.
We designed, synthesized, and evaluated haloacetylcarbamoyl-2-nitroimidazoles, including chloro (KIN-1800, TX-1835, and TX-1836) and bromo derivatives (TX-1844, TX-1845, and TX-1846), as potential hypoxic cell radiosensitizers with antiangiogenic activities. To establish biological function owing to the haloacetylcarbamoyl group in the side-chain, we compared their in vitro radiosensitizing activities with those of their parent 2-nitroimidazoles without haloacetylcarbamoyl groups: misonidazole (MISO), TX-1831, and TX-1832, respectively. Both tert-butoxy substituted derivatives. TX-1835 and TX-1845, were more potent radiosensitizers than TX-1831. The p-tert-butylphenoxy-substituted derivatives, TX-1836 and TX-1846, and the methoxysubstituted derivatives, KIN-1800 and TX-1844, were stronger radiosensitizers than TX-1832 and MISO. We examined the anti-angiogenic activities of these 2-nitroimidazole derivatives containing haloacetylcarbamoyl group by the rat lung endothelial (RLE) cell proliferation assay and chick embryo chorioallantoic membrane (chick CAM) angiogenesis assay and showed that haloacetylcarbamoyl-2-nitroimidazoles were more potent angiogenic inhibitors than the corresponding desacetylcarbamoyl-2-nitroimidazoles. The in vivo chick CAM angiogenesis assay showed that the strong bromoacetylcarbamoyl-2-nitroimidazole radiosensitizers, such as TX-1845 and TX-1846, were the strongest angiogenic inhibitors among them. We concluded that the bromoacetylcarbamoyl-2-nitroimidazole radiosensitizers, such as TX-1845 and TX-1846, are promising as anti-angiogenic hypoxic cell radiosensitizers.
Hori
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Department of Biological Science and Technology, Faculty of Engineering, University of Tokushima, Japan. hori@bio.tokushima-u.ac.jp
Jin
C Z
CZ
Kiyono
M
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Kasai
S
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Shimamura
M
M
Inayama
S
S
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects*; D002642:Chick Embryo; D015195:Drug Design; D010450:Endopeptidases / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008920:Misonidazole / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis*; D051381:Rats
D000970:Antineoplastic Agents; D002219:Carbamates; D007093:Imidazoles; D011838:Radiation-Sensitizing Agents; C107230:TX 1835; C107231:TX 1845; D008920:Misonidazole; D000255:Adenosine Triphosphate; D010450:Endopeptidases