New antimetastatic hypoxic cell radiosensitizers: Design, synthesis, and biological activities of 2-nitroimidazole-acetamide, TX-1877, and its analogues

We designed, based on the molecular orbital (MO) calculation, synthesized, and evaluated the biological activities of the new antimetastatic hypoxic c ell radiosensitizer, 2-nitroimidazole-acetamide, TX-1877. and its analogues . Each analogue has an electron-affinic imidazole group, an acetamide group and a certain hydrophilic group to control its biological effect, toxicity , and pharmacokinetics. In in vitro radiosensitization assay, most TX-1877 analogues, which have an electron affinity (EA) of more than 0.9 eV and par tition coefficient (P) of more than 0.021, showed satisfactory enhancement ratios (ER > 1.60) at doses of 1 mM. On the other hand, imidazole analogues , such as TX-1908 (EA = 0.67 eV), TX-1910 (EA = -0.34 eV) and TX-1931 (EA = -0.37 eV), which have low electron affinities, had an ER of 1.31 or less. TX-1877 and KIN-806 effectively inhibited tumor regrowth when administered with irradiation in vivo at a dose of 0.4 mg/g. Tumor lung metastasis: was inhibited by treatment with either TX-1877 or KIN-806 without irradiation a t a dose of 0.4 mg/g. TX-1877 reduced markedly the mean number of metastati c lung nodules in comparison with KIN-806. Moreover, TX-1877 and KIN-806 en hanced macrophage and helper T lymphocyte infiltration for 3 weeks after dr ug treatment. TX-1877 shows a high EA value and has the C-2 of HOMO localiz ing on N-methylamide and the C-2 of LUMO localizing on 2-nitroimidazole gro up. The MO data might be useful fbr designing 3 bifunctional hypoxic cell r adiosensitizer. TX-1877 and its analogues are potential antimetastatic hypo xic cell radiosensitizers. which would improve the efficiency of radiothera py and quality of life in cancer treatment. (C) 2001 Elsevier Science Ltd. All rights reserved.