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.
- Molecular orbital
ASJC Scopus subject areas
- Drug Discovery
- Computer Science Applications
- Physical and Theoretical Chemistry