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

• Published in: Chemical & pharmaceutical bulletin Vol. 62; no. 3; pp. 301 - 303
• Main Authors: Winters, Thomas, Sercel, Anthony, Suto, Carla, Elliott, William, Leopold, Wilbur, Leopold, Judith, Showalter, Hollis
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 2014; Pharmaceutical Soc Japan; Japan Science and Technology Agency
• Subjects: 2-nitroimidazole; Acylation - drug effects; Alkylating Agents - chemical synthesis; Alkylating Agents - pharmacology; alkylation potential; Animals; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Drug Design; Drug Screening Assays, Antitumor; Life Sciences & Biomedicine; Mice; Misonidazole - analogs & derivatives; Misonidazole - pharmacology; Nitroimidazoles - chemical synthesis; Nitroimidazoles - chemistry; Nitroimidazoles - pharmacology; Pharmacology & Pharmacy; Physical Sciences; radiation sensitizer; Radiation-Sensitizing Agents - chemical synthesis; Radiation-Sensitizing Agents - pharmacology; Science & Technology; soft drug; Structure-Activity Relationship; ANALOGS; radiation sensitizer; soft drug; CONSTRUCTION; 2-nitroimidazole; RSU-1069; RADIOSENSITIZER; alkylation potential
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c13-00903

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.