Bush E D, Trager W F
J Med Chem. 1985 Aug;28(8):992-6. doi: 10.1021/jm00146a004.
Optically pure analogues of (R)- and (S)-warfarin selectively deuterated in either the 6-, 7-, or 8-position were prepared and incubated with microsomal preparations from either nontreated, phenobarbital-pretreated, or beta-naphthoflavone-pretreated male Sprague-Dawley rats. The amount of deuterium retained and the relative amount of hydroxylated product formed (6-, 7-, 8-, or 4'-hydroxywarfarin) from each of the six substrates for each of the treatments were determined by capillary gas chromatography-mass spectrometry. The degree of deuterium retention in all products from all substrates was largely independent of both absolute configuration and induction state. Conversely, the relative amounts of product formed were highly dependent upon both absolute configuration and induction state. These results suggest that all the hydroxylation reactions proceed through an addition rearrangement step prior to or in the absence of epoxide formation, which appears to be dictated by the nature of the heme-Fe3+-oxene complex. In contrast, the position of hydroxylation or regioselectivity appears to be primarily dependent upon the nature of the apoprotein.
制备了在6、7或8位选择性氘代的（R）-和（S）-华法林的光学纯类似物，并与来自未处理、苯巴比妥预处理或β-萘黄酮预处理的雄性Sprague-Dawley大鼠的微粒体制剂一起孵育。通过毛细管气相色谱-质谱法测定每种处理的六种底物中每种底物保留的氘量以及形成的羟基化产物（6-、7-、8-或4'-羟基华法林）的相对量。所有底物的所有产物中的氘保留程度在很大程度上与绝对构型和诱导状态无关。相反，形成的产物相对量高度依赖于绝对构型和诱导状态。这些结果表明，所有羟基化反应在环氧形成之前或不存在环氧形成的情况下通过加成重排步骤进行，这似乎由血红素-Fe3+-氧烯复合物的性质决定。相比之下，羟基化位置或区域选择性似乎主要取决于脱辅基蛋白的性质。
