We designed, based on the molecular orbital (MO) calculation, synthesized, and evaluated the
biological activities of the new antimetastatic hypoxic cell 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 partition coefficient (P) of more than 0.021, showed satisfactory enhancement ratios (ER > 1.60) at doses of I 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 at a dose of 0.4 mg/g.
TX-1877 reduced markedly the mean number of metastatic lung nodules in comparison with
KIN-806. Moreover,
TX-1877 and
KIN-806 enhanced macrophage and helper T lymphocyte infiltration for 3 weeks after
drug treatment.
TX-1877 shows a high EA value and has the C2 of HOMO localizing on N-methylamide and the C2 of LUMO localizing on
2-nitroimidazole group. The MO data might be useful for designing a bifunctional hypoxic cell radiosensitizer.
TX-1877 and its analogues are potential antimetastatic hypoxic cell radiosensitizers, which would improve the efficiency of
radiotherapy and quality of life in
cancer treatment.