Synthesis of aza homologs of folic acid

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Abstract
Folic acid analogs containing an additional N 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 homolog of folic acid, 4 [N-[4-[[(2-amino-3,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]phenylcarbamoyl]-DL-glutamic acid] and the aspartic acid analog 14 [N-[4-[[(2-amino-3,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]phenylcarbamoyl]-DL-aspartic acid] showed no increase in life span over control animals. These compounds were more toxic in vivo than the corresponding methotrexate analog. Compound 4 supported the growth of Streptococcus faecium (ATCC 8043) and its tetrahydro derivative supported the growth of Pediococcus cerevisiae (ATCC 8081). Apparently, 4 can substitute for folate derivatives as cofactors for serine transhydroxymethylase, thymidylate synthetase and dihydrofolate reductase.