Stereochemistry of catabolism of the DNA base thymine and of the anti-cancer drug 5-fluorouracil

Abstract

(2S)-3-Amino-2-methylpropanoic acid (6) and (2RS,3S)-[3-²H₁]-3-amino-2-methylpropanoic acid (14) have been synthesized and used to provide an assay which shows that the catabolism of the DNA base thymine (1; R = Me) proceeds by overall anti addition of hydrogen to the pyrimidine at the si face at C-5 and the si face at C-6. X-Ray structure analysis of a derivative of the product of reaction of N,N-dibenzyl-L-serine methyl ester (15; R = Me) with (diethylamino)sulphur trifluoride followed by deprotection has shown it to be (2R)-3-amino-2-fluoropropanoic acid (19; R = H). This was identical with the product of catabolism of the anti-cancer drug 5-fluorouracil (1; R = F). Esters of (2R,3S)-[3-²H₁]- and (2R,3R)-[2,3-²H₂]-3-amino-2-fluoropropanoic acids have been synthesized and used to provide an assay which shows that catabolism of the anti-cancer drug 5-fluorouracil (1; R = F) proceeds with the same absolute stereochemistry as is found in catabolism of thymine (1; R =Me).