Cyclophosphamides as hypoxia-activated diffusible cytotoxins: A theoretical study

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Cyclophosphamides have been in clinical use as anti-cancer drugs for a long time and much research has been directed towards reducing their side effects. Here we have performed a theoretical investigation into the possibility of designing bioreductive analogues of cyclophosphamides. Our calculations have employed semiempirical molecular orbital AM1-SM2 and PM3-SM3 calculations, as implemented in MOPAC 93, which include a modified Born method for the treatment of solvation. We have investigated the effect of bioreductive activation on the β-elimination reaction that is central to the activation of cyclophosphamides. The approach was tested on two known bioreductive agents, including CB1954, and gave results in agreement with experiment. Non-local density functional calculations on CB1954 and its metabolites, including the radical anion, were in agreement with the semiempirical calculations. The calculations have identified a number of potentially novel bioreductive cyclophosphamides. In particular, our calculations identified compounds in which the initial one-electron reduction was not activating. Such compounds are likely to be more effective bioreductive agents, as the β-elimination will not compete under oxic conditions with the important re-oxidation required for the protection of oxic tissue.

Original languageEnglish
Pages (from-to)307-316
Number of pages10
JournalJournal of Computer-Aided Molecular Design
Issue number4
Publication statusPublished - 4 May 2000
Externally publishedYes


  • Bioreductive
  • Cyclophosphamides
  • Molecular orbital
  • Nitroimidazole
  • Tirapazamine

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry


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