New synthesis of N-[4-[[(2-amino-4(3H)-oxopyrido[3,2-d]pyrimidin-6-yl)methyl]amino]benzoyl]-L-glutamic acid (8-deazafolic acid) and the preparation of some 5,6,7,8-tetrahydro derivatives.
Previously, 8-deazafolic acid (17) was shown to be a potent inhibitor of the folate-dependent bacteria, Streptococcus faecium (ATCC 8043) and Lactobacillus casei (ATCC 7469), and to have activity against lymphoid leukemia L1210 in mice. To examine the 5,6,7,8-tetrahydro derivatives, a new synthesis of 17 was developed from 8-deaza-2,4-dichloro-6-methylpteridine. Treatment of the latter with aqueous base gave the corresponding pteridin-4(3H)-one, which was aminated with ammonia to give 8-deaza-6-methylpterin (9). Bromination of 9 gave mainly 8-deaza-6-(tribromomethyl)pterin, which on reaction with p-aminobenzoyl-L-glutamic acid resulted in the formation of the 9-oxo derivative of 17. In contrast, bromination of the 2-acetyl derivative of 9 gave mainly the corresponding 6-(bromomethyl)pterin, which was converted to 17 in 23% yield (from 9). Hydrogenation of 17 at atmospheric pressure and room temperature was unsuccessful either in a basic medium or formic acid. In trifluoroacetic acid, overreduction occurred to give a mixture containing 8-deaza-5,6,7,8-tetrahydro-6-methylpterin and the 5,6,7,8-tetrahydro derivative of 17. The latter was characterized by conversion to the methenyl analogue 21, which was also prepared by hydrogenation of the 10-formyl derivative of 17. Treatment of 21 with hydroxide gave 8-deaza-10-formyl-5,6,7,8-tetrahydrofolic acid. Compound 21 showed cytotoxicity to cultured H.Ep.-2 cells and was tested as an inhibitor of bovine dihydrofolic reductase. Lineweaver-Burk analysis indicated inhibition competitive with dihydrofolate.
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005493:Folic Acid Antagonists; D051379:Mice; D013763:Tetrahydrofolates / Q000138:chemical synthesis* / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D013763:Tetrahydrofolates; C007224:8-deazafolic acid; C033299:5,6,7,8-tetrahydro-8-deazafolic acid; D005492:Folic Acid