DESIGN, SYNTHESIS, AND BIOLOGICAL-ACTIVITY OF ANTI-ANGIOGENIC HYPOXICCELL RADIOSENSITIZER HALOACETYLCARBAMOYL-2-NITROIMIDAZOLES

We designed, synthesized, and evaluated haloacetylcarbamoyl-2-nitroimi dazoles, including chloro (KIN-1800, TX-1835, and TX-1836) and bromo d erivatives (TX-1844, TX-1845, and TX-1846), as potential hypoxic cell radiosensitizers with antiangiogenic activities. To establish biologic al function owing to the haloacetylcarbamoyl group in the side-chain, we compared their in vitro radiosensitizing activities with those of t heir parent 2-nitroimidazoles without haloacetylcarbamoyl groups: miso nidazole (MISO), TX-1831, and TX-1832, respectively. Both tert-butoxy substituted derivatives, TX-1835 and TX-1845, were more potent radiose nsitizers than TX-1831. The p-tert-butylphenoxy-substituted derivative s, TX-1836 and TX-1846, and the methoxy-substituted derivatives, KIN-1 800 and TX-1844, were stronger radiosensitizers than TX-1832 and MISO. We examined the antiangiogenic activities of these 2-nitroimidazole d erivatives containing haloacetylcarbamoyl group by the rat lung endoth elial (RLE) cell proliferation assay and chick embryo chorioallantoic membrane (chick CAM) angiogenesis assay and showed that haloacetylcarb amoyl-2-nitroimidazoles were more potent angiogenic inhibitors than th e corresponding desacetylcarbamoyl-2-nitroimidazoles. The in vivo chic k CAM angiogenesis assay showed that the strong bromoacetylcarbamoyl-2 -nitroimidazole radiosensitizers, such as TX-1845 and TX-1846, were th e strongest angiogenic inhibitors among them. We concluded that the br omoacetylcarbamoyl-2-nitroimidazole radiosensitizers, such as TX-1845 and TX-1846, are promising as anti-angiogenic hypoxic cell radiosensit izers. (C) 1997 Elsevier Science Ltd.