Preparation of 2-amino-4(3H)-oxopyrimido[5,4-b] [1,4]thiazines (5-thiapterins) and their evaluation as cofactors for phenylalanine hydroxylase.
Reaction of diethyl chloromalonate with beta-mercapto amines, 9, gave 1,4-thiazin-3-ones, 10, which were alkylated exclusively at the lactam oxygen with triethyloxonium tetrafluoroborate and subsequently condensed with guanidine to give the first reported 5-thiapterins, 8. Oxidation of 8 with m-chloroperoxybenzoic acid gave the S-oxides, 12. Both 8 and 12 were found to be good inhibitors of rat liver phenylalanine hydroxylase competitive with 6-methyltetrahydropterin, with 8 exhibiting lower Ki's than the corresponding 12. The 8-thiapterin 4 was a much poorer inhibitor.
D000818:Animals; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D010651:Phenylalanine Hydroxylase / Q000378:metabolism*; D011622:Pterins / Q000378:metabolism*; D051381:Rats
D011622:Pterins; D010651:Phenylalanine Hydroxylase