Design and Synthesis of Inhibitors of Dihydrofolate Reductase

Abstract

The biochemical role of dihydrofolate reductase (DHFR) (EC 1.5.1.3) is discussed, together with the role of tetrahydrofolate in intermediary cellular metabolism. The development of classical folate analogues and non-classical, small molecule inhibitors, and some of the problems associated with their use in cancer chemotherapy is reviewed. The novel lipophilic inhibitor of DHFR, methylbenzaprim, is the parent compound from which a series of analogues were synthesised. The preparative route to formation of these analogues involved the aromatic nucleophilic substitution of a series of substituted benzylamines onto m-nitropyrimethamine. The possibility of the preparation of an azido-substituted analogue of methylbenzaprim was also investigated...