Design and Synthesis of 2-Nitroimidazoles with Variable Alkylating and Acylating Functionality

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  • Winters Thomas
    Departments of Chemistry and Cancer Research, Pfizer Global Research and Development
  • Sercel Anthony
    Departments of Chemistry and Cancer Research, Pfizer Global Research and Development
  • Suto Carla
    Departments of Chemistry and Cancer Research, Pfizer Global Research and Development
  • Elliott William
    Departments of Chemistry and Cancer Research, Pfizer Global Research and Development
  • Leopold Wilbur
    Departments of Chemistry and Cancer Research, Pfizer Global Research and Development
  • Leopold Judith
    Departments of Chemistry and Cancer Research, Pfizer Global Research and Development
  • Showalter Hollis
    Departments of Chemistry and Cancer Research, Pfizer Global Research and Development

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The synthesis of a small series of 2-nitroimidazoles in which the β-amino alcohol side chain was amidated with a range of alkylating/acylating functionality is described. Synthetic methodologies were developed that generally provided for selective N-acyl versus N,O-bisacyl products. In vitro, target analogs showed minimal radiosensitization activity, with only a few exhibiting a sensitizer enhancement ratio (SER) >2.0 and C1.6 values comparable to reference agents RB-6145 and RSU-1069. In an assay to determine potential to alkylate biomolecules, representative analogs showed <1% of the alkylating activity of RSU-1069. In vivo, one analog showed an enhancement ratio of 1.6 relative to vehicle control when tested in B6C3F1 mice with an implanted KHT sarcoma. The data reinforce prior findings that there is a correlation between alkylation potential and in vivo activity.

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