Lipophilic Inhibitors of Dihydrofolate Reductase

Abstract

The evaluation of lipophilic inhibitors of dihydrofolate reductase (DHFR) as anticancer agents is a continuing effort because of the development of clinical resistance to methotrexate (MTX) and its limited spectrum of activity. The temperature-sensitive entry of MTX into cells is carrier-dependent and, in some tumors, MTX uptake is so slow that the cells are unresponsive to this drug. The very rapid temperature-insensitive passage of lipophilic DHFR inhibitors across cell membranes accounts for their activity against MTX-resistant cells and for their better entry into various tissues including brain. Among the many heterocyclic DHFR inhibitors which were synthesized as potential antibacterial and antiparasitic agents, some were too potent as inhibitors of mammalian DHFR and were tested as anticancer agents (1,2). Extensive studies of diaminopyrimidines, such as metoprine (DDMP), and diaminotriazines, such as triazinate (Bakers antifol), indicated some useful features but limited efficacy at tolated doses and unsuitable pharmacokinetics led to the search for other compounds (2). Subsequently, several diaminopyridopyrimidines and diaminoquinazolines were found to be as potent as MTX as inhibitors of DHFR and cell growth and, like MTX, their toxic effects can be prevented by calcium leucovorin (2–4).