Electron-Mediated Aminyl and Iminyl Radicals from C5 Azido-Modified Pyrimidine Nucleosides Augment Radiation Damage to Cancer Cells

  • Org Lett. 2018 Dec 7;20(23):7400-7404. doi: 10.1021/acs.orglett.8b03035.
Zhiwei Wen  1 ,  Jufang Peng  1 ,  Paloma R Tuttle  1 ,  Yaou Ren  1 ,  Carol Garcia  1 ,  Dipra Debnath  2 ,  Sunny Rishi  2 ,  Cameron Hanson  2 ,  Samuel Ward  2 ,  Anil Kumar  2 ,  Yanfeng Liu  3 ,  Weixi Zhao  3 ,  Peter M Glazer  3 ,  Yuan Liu  1 ,  Michael D Sevilla  2 ,  Amitava Adhikary  2 ,  Stanislaw F Wnuk  1
Affiliations
  • 1. Department of Chemistry and Biochemistry , Florida International University , Miami , Florida 33199 , United States.
  • 2. Department of Chemistry , Oakland University , Rochester , Michigan 48309 , United States.
  • 3. Department of Therapeutic Radiology , Yale University School of Medicine , New Haven , Connecticut 06520 , United States.
PMID: 30457873 DOI: 10.1021/acs.orglett.8b03035
Abstract

Two classes of azido-modified pyrimidine nucleosides were synthesized as potential radiosensitizers; one class is 5-azidomethyl-2'-deoxyuridine (AmdU) and cytidine (AmdC), while the second class is 5-(1-azidovinyl)-2'-deoxyuridine (AvdU) and cytidine (AvdC). The addition of radiation-produced electrons to C5-azido nucleosides leads to the formation of π-aminyl radicals followed by facile conversion to σ-iminyl radicals either via a bimolecular reaction involving intermediate α-azidoalkyl radicals in AmdU/AmdC or by tautomerization in AvdU/AvdC. AmdU demonstrates effective radiosensitization in EMT6 tumor cells.

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