Heimark L D, Trager W F
J Med Chem. 1984 Aug;27(8):1092-5. doi: 10.1021/jm00374a027.
An octanol/water model system and circular dichroism (CD) spectroscopy have been used to study the solution conformation of warfarin in aqueous and lipid environments. Upon partitioning of (S)-warfarin from buffer pH 7.4 into octanol, the position of the absorption band due to the alpha, beta-unsaturated carbonyl chromophore shifts from 210 nm in the aqueous phase to 220 nm in the octanol phase. The shift is coupled to an increase in the molecular ellipticity of the band, suggesting the formation of a dissymmetric chromophore. Comparison of CD spectra of conformationally fixed analogues of warfarin to that of warfarin in solution suggests that the compound shifts from the open side chain keto form in the aqueous phase at pH 7.4 to the cyclic hemiketal form after partitioning into the lipid octanol phase. On the basis of these results, the hemiketal form is proposed as the preferred solution conformation of warfarin in the lipid environment of the active site of cytochrome P-450 and the relationship between solution conformation and stereoselectivity of warfarin metabolism by beta-naphthoflavone inducible cytochrome P-450 is discussed.
采用正辛醇/水模型系统和圆二色（CD）光谱法研究了华法林在水性和脂质环境中的溶液构象。当（S）-华法林从pH 7.4的缓冲液分配到正辛醇中时，由于α，β-不饱和羰基发色团引起的吸收带位置从水相中的210 nm移至正辛醇相中的220 nm。该位移与该带的分子椭圆率增加相关联，表明形成了不对称发色团。将华法林构象固定类似物的CD光谱与溶液中华法林的CD光谱进行比较表明，该化合物在pH 7.4的水相中从开放侧链酮形式转变为分配到脂质正辛醇相后转变为环状半缩酮形式。基于这些结果，提出半缩酮形式是华法林在细胞色素P-450活性位点的脂质环境中的优选溶液构象，并讨论了溶液构象与β-萘黄酮诱导的细胞色素P-450对华法林代谢的立体选择性之间的关系。
