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 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.
Department of Biological Science and Technology, Faculty of Engineering, The University of Tokushima, Japan.
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S
Kasai
H
H
Nagasawa
M
M
Yamashita
M
M
Masui
H
H
Kuwasaka
T
T
Oshodani
Y
Y
Uto
T
T
Inomata
S
S
Oka
S
S
Inayama
H
H
Hori
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D015195:Drug Design; D004563:Electrochemistry; D005260:Female; D000860:Hypoxia / Q000139:chemically induced; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008958:Models, Molecular; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000517:prevention & control; D009368:Neoplasm Transplantation; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
C115855:2-nitroimidazole acetamide; D000970:Antineoplastic Agents; C121164:KIN 806; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents