具有芳香族氨基酸羟化酶辅因子活性的四氢生物蝶呤的合成类似物。

Synthetic analogues of tetrahydrobiopterin with cofactor activity for aromatic amino acid hydroxylases.

作者信息

Bigham E C, Smith G K, Reinhard J F, Mallory W R, Nichol C A, Morrison R W

出版信息

J Med Chem. 1987 Jan;30(1):40-5. doi: 10.1021/jm00384a007.

Abstract

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.

摘要

已通过泰勒方法，由吡嗪邻氨基腈经胍环化、在氢氧化钠水溶液中水解以及在三氟乙酸（TFA）中用铂催化氢化，合成了具有6 - 烷氧基甲基取代基的四氢生物蝶呤（THB）类似物3a - j，其中取代基为从甲基到辛基的直链和支链烷基。这些化合物中最佳的3b，是苯丙氨酸羟化酶、酪氨酸羟化酶（V = THB的154%）和色氨酸羟化酶的优良辅因子，不会使底物结合不稳定（Kmtyr = 23 microM），并且可被二氢蝶啶还原酶循环利用（V = THB的419%）。这些化合物正在作为生物蝶呤缺乏症疾病中辅因子替代物进行评估。