title: 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.affiliation: Department of Biological Sciences, University of Essex, UK.
authors.forename: J H
authors.initials: JH
authors.lastname: Wu
authors.forename: C A
authors.initials: CA
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003198:Computer Simulation; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004058:Diffusion; D015195:Drug Design; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D066298:In Vitro Techniques; D013816:Thermodynamics
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide