Synthetic Analogues of Tetrahydrobiopterin with Cofactor Activity for Aromatic Amino Acid Hydroxylases

Article abstract of DOI:10.1021/jm00384a007

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 Tylor 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=154percent of THB), and tryptophan hydroxylase, does not destabilize the binding of substrate (K_m^tyr=23 μM), and is recycled by dihydropteridine reductase (V=419percent of THB).The compounds are being evaluated as cofactor replacements in biopterin-deficiency diseases.