The poor prognosis associated with brain neoplasms is a significant health problem in the United States. Current chemotherapeutic approaches have been limited by the inability to achieve therapeutic concentrations in the brain. Cyclophosphamide is unique among widely used chemotherapeutic agents in that it and its chemotherapeutically active metabolites have been shown to have an extremely low neurotoxicity profile. If therapeutic levels of cyclophosphamide could be achieved in the brain, cyclophosphamide could become a clinically effective chemotherapeutic agent for a variety of brain neoplasms. Ordinarily, cyclophosphamide does not penetrate the blood-brain barrier in significant amounts. Acylation of the hydroxyl group of 4-hydroxycyclophosphamide would be our approach to develop lipophilic analogs of cyclophosphamide for enhanced brain uptake. However, these acylated compounds may undergo elimination to form iminocyclophosphamide which in the presence of water, would produce 4-hydroxycyclophosphamide. We, therefore, propose to synthesize esters of novel 5-substituted 4-hydroxycyclophosphamide. The proposed C-5 mono and difluoro analogs would be stable to the elimination-addition reaction. The stability of the fluoro analogs would be compared to that of the non-fluorinated derivatives. In Phase I, outlined in this proposal, the above analogs will be synthesized and radiolabeled. Hydrolytic stability would be determined by NMR techniques. Brain uptake would be determined in adult male rats using radiolabeled derivatives. Subsequently, in Phase II both in vitro and in vivo efficacy studies would be done along with large scale synthesis of the promising agents.
