Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: Part II.

Antifolates that inhibit the key enzymes thymidylate synthase (TS) and dihydrofolate reductase (DHFR) have found clinical utility as antitumor and antiopportunistic agents. Methotrexate {MTX, (1)} and 5-fluorouracil (5-FU) were among the first clinically useful DHFR and TS inhibitors, respectively. The development of resistance to 5-FU, its occasional unpredictable activity and toxicity resulted in the search of novel antifolates. Pemetrexed (4) and raltitrexed (5) are newer antifolates that specifically inhibit TS, and are clinically useful as antitumor agents. A major mechanism of tumor resistance to clinically useful antifolates is based on their need for polyglutamylation via the enzyme folylpoly-gamma-glutamate synthetase (FPGS). Recently, classical antifolates that do not need to be polyglutamylated have also been developed and include plevitrexed (6) and GW1843 (7). Nolatrexed (8), trimethoprim {TMP, (11)} and piritrexim {PTX, (12)} are nonclassical antifolates for antitumor and parasitic chemotherapy that passively diffuse into cells and hence do not have to depend on FPGS or the reduced folate carrier (RFC). Structural requirements for inhibition with antifolates have been studied extensively and novel agents that exploit key interactions in the active site of TS, DHFR, FPGS, and RFC have been proposed. This two-part review discusses the design, synthesis and structural requirements for TS and DHFR inhibition and their relevance to antitumor and parasitic chemotherapy, since 1996. Monocyclic and 6-5 fused bicyclic antifolates were discussed in Part I. The 6-6 bicyclic and tricyclic antifolates will be discussed here in Part II.