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.
Kasai
S
S
Department of Biological Science and Technology, Faculty of Engineering, The University of Tokushima, Japan.
Nagasawa
H
H
Yamashita
M
M
Masui
M
M
Kuwasaka
H
H
Oshodani
T
T
Uto
Y
Y
Inomata
T
T
Oka
S
S
Inayama
S
S
Hori
H
H
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