Reduced 2-Methyl-4-Oxo, 2-Methylamino-4-Oxo, 2-Methylthio-4-Oxo and 2-Amino-4-Thioxo 6,7-Dimethylpteridines, and 6,8-Dimethylpterin as Substrates for Dihydropteridine Reductase

Abstract

The syntheses of unsubstituted (4), 6-methyl- (6), cis-6,7-dimethyl- (8), cis-2,6,7-trimethyl- (10), cis-6,7-dimethyl-2-thioxo-(1H)- (12) and cis-6,7-dimethyl-2-methylthio- (13) 5,6,7,8- tetrahydropteridin -4(3H)-one and the deuterated derivatives (5), (7), (9) and (14), and a cis and trans mixture of 2-amino-6,7-dimethyl-5,6,7,8- tetrahydropteridin-4(3H)- thione (11) are described. The existence of the transient quinonoid species (15)-(17) had been previously demonstrated by showing that they are substrates for the enzyme dihydropteridine reductase from human brain. We report that the transient quinonoid species cis-2,6,7-trimethyl-(18), cis-2-methylthio-6,7-dimethyl-(25), cis-2-methylamino-6,7-dimethyl-(26), and 2-amino-6,8-dimethyl-(29)7,8-dihydropteridin-4(6H)-one, and 2-amino- 6,7-dimethyl-7,8-dihydropteridin-4(6H)- thione (28), but not cis-6,7- dimethyl-2-thio-7,8-dihydropteridin-4(6H)-one (27) are substrates for this enzyme showing that a variety of substituents in position 2 of the pteridine ring can be tolerated, and confirming that the predominant tautomer (1) of the quinonoid species in aqueous solution is also the reactive tautomer at the active site of this enzyme.