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

Abstract
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.
AuthorsS Kasai, H Nagasawa, M Yamashita, M Masui, H Kuwasaka, T Oshodani, Y Uto, T Inomata, S Oka, S Inayama, H Hori
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 9 Issue 2 Pg. 453-64 (Feb 2001) ISSN: 0968-0896 [Print] England
PMID11249137 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • 2-nitroimidazole acetamide
  • Antineoplastic Agents
  • KIN 806
  • Nitroimidazoles
  • Radiation-Sensitizing Agents
Topics
  • Animals
  • Anoxia (chemically induced)
  • Antineoplastic Agents (administration & dosage, chemical synthesis, pharmacology)
  • Breast Neoplasms (pathology)
  • Cell Movement (drug effects)
  • Drug Design
  • Electrochemistry
  • Female
  • Leukocytes, Mononuclear (cytology, drug effects)
  • Lung Neoplasms (drug therapy, radiotherapy)
  • Macrophages (cytology, drug effects)
  • Mice
  • Mice, Inbred C3H
  • Models, Molecular
  • Neoplasm Metastasis (drug therapy, prevention & control)
  • Neoplasm Transplantation
  • Nitroimidazoles (chemical synthesis, pharmacology)
  • Radiation-Sensitizing Agents (administration & dosage, chemical synthesis, pharmacology)
  • Structure-Activity Relationship
  • Tumor Cells, Cultured (drug effects)

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