Synthesis and biological evaluation of 8-deazahomofolic acid and its tetrahydro derivative.
The syntheses of 8-deazahomofolic acid and its tetrahydro derivative, potential inhibitors of thymidylate synthase (TS) and other folate related enzymes, are described. Wittig condensation of 2-acetamido-6-formyl-4-pyrimidinol with the triphenylphosphine ylide 3 derived from N-acetyl-4-(p-carbethoxyanilino)-1-chloro-2-butanone, hydrogenation of the enone intermediate 5, introduction of a 5-amino group via diazonium coupling, and reductive ring closure yielded ethyl N11-acetyl-8-deazahomopteroate (8). Alkaline hydrolysis gave 8-deazahomopteroic acid, which was blocked as the 11-trifluoroacetyl derivative, coupled with diethyl L-glutamate, and the blocking groups saponified to afford 8-deazahomofolic acid (12). Hydrogenation of the glutamate diester intermediate and subsequent saponification yielded the tetrahydro-8-deazahomofolate (14). Growth inhibition of Streptococcus faecium, Lactobacillus casei, and L1210 cells in culture by the target compounds was modest. They were also weak inhibitors of thymidylate synthase, dihydrofolate reductase, glycinamide-ribonucleotide transformylase, and aminoimidazolecarboxamide ribonucleotide transformylase. In contrast, 8-deazafolate showed moderate inhibition of aminoimidazolecarboxamide ribonucleotide transformylase, suggesting that inhibition of this enzyme may be related to its cytotoxic action. Tetrahydro-8-deazahomofolate showed low substrate activity with thymidylate synthase.
D000217:Acyltransferases / Q000037:antagonists & inhibitors; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D005493:Folic Acid Antagonists; D019877:Hydroxymethyl and Formyl Transferases; D007202:Indicators and Reagents; D007780:Lacticaseibacillus casei / Q000187:drug effects; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008826:Microbial Sensitivity Tests; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D051026:Phosphoribosylglycinamide Formyltransferase; D013291:Streptococcus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013763:Tetrahydrofolates / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
D000900:Anti-Bacterial Agents; D005493:Folic Acid Antagonists; D007202:Indicators and Reagents; D013763:Tetrahydrofolates; C054516:8-deazahomofolic acid; C054517:5,6,7,8-tetrahydro-8-deazahomofolic acid; D005492:Folic Acid; D013940:Thymidylate Synthase; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D000217:Acyltransferases