Synthesis of aza homologues of folic acid.
Folic acid analogues containing an additional nitrogen atom between the phenyl ring and the carbonyl group of the side chain were synthesized. None of the compounds showed significant inhibitory activity against human lymphoblastic leukemia cells (CCRF-CEM) in culture or against Lactobacillus casei (ATCC 7469) growth. Against L1210 leukemia in mice, the aza homologue of folic acid, 4, and the aspartic acid analogue, 14, showed no increase in life span over control animals. These compounds were more toxic in vivo than the corresponding methotrexate analogues. Compound 4 supported the growth of Streptococcus faecium (ATCC 8043), and its tetrahydro derivative supported the growth of Pediococcus cerevisiae (ATCC 8081). These results strongly suggest that 4 can substitute for folate derivatives as cofactors for serine transhydroxymethylase, thymidylate synthetase, and dihydrofolate reductase.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D007780:Lacticaseibacillus casei / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D007939:Leukemia L1210 / Q000188:drug therapy; D007945:Leukemia, Lymphoid / Q000188:drug therapy; D008297:Male; D051379:Mice; D010376:Pediococcus / Q000187:drug effects / Q000254:growth & development; D013291:Streptococcus / Q000187:drug effects / Q000254:growth & development; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D005492:Folic Acid; D013940:Thymidylate Synthase