Strategy for Imidazotetrazine Prodrugs with Anticancer Activity Independent of MGMT and MMR

  • ACS Med Chem Lett. 2012 Sep 18;3(12):965-8. doi: 10.1021/ml300132t.
Elrashied A E Garelnabi  1 ,  Dimitrios Pletsas  1 ,  Li Li  1 ,  Konstantinos Kiakos  2 ,  Nazira Karodia  1 ,  John A Hartley  2 ,  Roger M Phillips  1 ,  Richard T Wheelhouse  1
Affiliations
  • 1. School of Pharmacy, Institute of Cancer Therapeutics, and Chemical and Forensic Sciences, University of Bradford , Bradford BD7 1DP, U.K.
  • 2. UCL Cancer Institute , Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, U.K.
PMID: 24900418 DOI: 10.1021/ml300132t
Abstract

The imidazotetrazine ring is an acid-stable precursor and prodrug of highly reactive alkyl diazonium ions. We have shown that this reactivity can be managed productively in an aqueous system for the generation of aziridinium ions with 96% efficiency. The new compounds are potent DNA alkylators and have antitumor activity independent of the O6-methylguanine-DNA methyltransferase and DNA mismatch repair constraints that limit the use of Temozolomide.

Keywords
13C NMR; DNA; Imidazotetrazine; Temozolomide; aziridinium; cancer.