Synthetic analogues of tetrahydrobiopterin with cofactor activity for aromatic amino acid hydroxylases.
Tetrahydrobiopterin (THB) analogues with 6-alkoxymethyl substituents, 3a-j, where the substituents were straight- and branched-chain alkyl ranging from methyl to octyl, have been synthesized by the Taylor method from pyrazine ortho amino nitriles by guanidine cyclization, hydrolysis in aqueous NaOH, and catalytic hydrogenation over Pt in trifluoroacetic acid (TFA). The best of these compounds, 3b, is an excellent cofactor for phenylalanine hydroxylase, tyrosine hydroxylase (V = 154% of THB), and tryptophan hydroxylase, does not destablize the binding of substrate (Kmtyr = 23 microM), and is recycled by dihydropteridine reductase (V = 419% of THB). The compounds are being evaluated as cofactor replacements in biopterin-deficiency diseases.
D000313:Adrenal Medulla / Q000201:enzymology; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D001933:Brain Stem / Q000201:enzymology; D002417:Cattle; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D010651:Phenylalanine Hydroxylase / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship; D014365:Tryptophan Hydroxylase / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D007202:Indicators and Reagents; D001708:Biopterins; D010651:Phenylalanine Hydroxylase; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase