Synthesis of 2,4-diamino-5-substituted-furo[2,3-d]pyrimidines as potential substrates for the RFC and as classical antifolate analogs Free

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Folate coenzymes are required in more than twenty interrelated enzymatic reactions in cellular metabolism. Antimetabolites that interfere with this complex pathway are known as antifolates and are clinically useful as antimicrobial, antifungal, antiprotozoal, and antitumor agents. Reduced folate carrier (RFC) is the major membrane transporter for the uptake of folates and classical antifolates, and often impaired transport is a mechanism of antitumor resistance. To study the importance of the carboxylic acids, Gangjee et al. recently reported a series of classical 2,4-diamino-5-substituted-furo[2,3-d]pyrimidines with either a α- or γ-carboxylic acid in the glutamate moiety. The structure-activity relationship indicated that the α-carboxylic acid is more important than the γ-carboxylic acid of these compounds both for dihydrofolate reductase (DHFR) inhibitory activity and RFC binding affinity. To further investigate the structural requirements of antifolates with respect to their affinities for the RFC, a series of analogs without carboxylic acids in the glutamate moiety were synthesized. The synthesis, RFC substrate activities and DHFR inhibitory activities of these analogs will be presented.