Design, synthesis, and biological activity of anti-angiogenic hypoxic cell radiosensitizer haloacetylcarbamoyl-2-nitroimidazoles

• Published in: Bioorganic & medicinal chemistry 1997-03, Vol.5 (3), p.591-599
• Main Authors: Hori, Hitoshi, Jin, Cheng-Zhe, Kiyono, Masatoshi, Kasai, Soko, Shimamura, Mariko, Inayama, Seiichi
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - biosynthesis; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Carbamates - chemical synthesis; Carbamates - pharmacology; Cell Hypoxia - drug effects; Chick Embryo; Drug Design; Endopeptidases - metabolism; Imidazoles - chemical synthesis; Imidazoles - pharmacology; Misonidazole - chemistry; Misonidazole - pharmacology; Models, Chemical; Neovascularization, Physiologic - drug effects; Radiation-Sensitizing Agents - chemical synthesis; Rats
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(96)00274-X

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 anti-angiogenic 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 methoxy-substituted 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.