Cyclophosphamides as hypoxia-activated diffusible cytotoxins: a theoretical study.

Abstract

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 beta-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 beta-elimination will not compete under oxic conditions with the important re-oxidation required for the protection of oxic tissue.

• Authors: J H Wu, C A Reynolds
• Journal: Journal of computer-aided molecular design (J Comput Aided Mol Des) Vol. 14 Issue 4 Pg. 307-16 (May 2000) ISSN: 0920-654X [Print] Netherlands
• PMID: 10815768 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• Cyclophosphamide

Topics

• Animals
• Antineoplastic Agents, Alkylating (chemistry, metabolism, pharmacology)
• Computer Simulation
• Cyclophosphamide (analogs & derivatives, chemistry, pharmacology)
• Diffusion
• Drug Design
• Humans
• Hypoxia (metabolism)
• In Vitro Techniques
• Thermodynamics