4-Hydroxy-Bufuralol | 61470-08-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: 4-Hydroxy-Bufuralol
• 英文别名: 2-[2-(Tert-butylamino)-1-hydroxyethyl]-7-ethyl-1-benzofuran-4-ol
• CAS: 61470-08-4
• 化学式: C₁₆H₂₃NO₃
• 分子量: 277.364
• InChiKey: VWEQAYFMBKZBLK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  65.6
• 氢给体数：
  3
• 氢受体数：
  4

ADMET

代谢

4-羟基丁呋洛尔是丁呋洛尔的人类已知代谢物。

4-Hydroxybufuralol is a known human metabolite of Bufuralol.

来源:NORMAN Suspect List Exchange

反应信息

• 作为产物：
  描述：

  丁呋洛尔 在 glucose-6-phosphate dehydrogenase 、 DL-dithiothreitol 、 human cytochrome P₄₅₀ 2D₆ 、 烟酰胺腺嘌呤双核苷酸磷酸盐 、 1,2-二十二酰基-sn-glycero-3-胆碱磷酸 、 NADPH---hemoprotein reductase 作用下， 以 aq. phosphate buffer 为溶剂， 反应 0.03h， 生成 4-Hydroxy-Bufuralol
  参考文献：
  名称：

  人细胞色素P450 4A11的血红素硫醇亚磺酰化作用起催化抑制作用的氧化还原开关作用。

  摘要：

  细胞色素P450（P450，CYP）4A11是一种人类脂肪酸ω-羟化酶，可催化花生四烯酸氧化为类二十烷酸20-羟基二十碳四烯酸（20-HETE），这在调节血压方面起着重要作用。P450 4A11的变体与高血压和对降压药的耐药性有关，而20-HETE具有分别与血管收缩和利尿增加有关的降压和降压特性。这些生理活动可能受氧化还原环境的影响，但机理尚不清楚。在这里，我们发现还原剂（例如二硫苏糖醇和三（2-羧乙基）膦）可以大大增强P450 4A11的催化活性，但不能增强其他10种人类P450的催化活性。相反，加入H2O2会减弱P450 4A11的催化活性。通过定点诱变消除了潜在的P450 4A11的八个Cys残基中的五个的催化作用。使用同位素编码的二甲基二酮/碘二甲基酮标记策略和肽的质谱分析，我们证明了血红素硫醇半胱氨酸（Cys-457）以H 2 O 2浓度依赖性方式被选择性地亚磺酰化。可以通过还原

  DOI：

  10.1074/jbc.m117.792200

文献信息

• CYP2D6 Allelic Variants *34, *17-2, *17-3, and *53 and a Thr309Ala Mutant Display Altered Kinetics and NADPH Coupling in Metabolism of Bufuralol and Dextromethorphan and Altered Susceptibility to Inactivation by SCH 66712
  作者：Sarah M. Glass、Cydney M. Martell、Alexandria K. Oswalt、Victoria Osorio-Vasquez、Christi Cho、Michael J. Hicks、Jacqueline M. Mills、Rina Fujiwara、Michael J. Glista、Sharat S. Kamath、Laura Lowe Furge

  DOI：10.1124/dmd.117.079871

  日期：2018.8

  Metabolic phenotype can be affected by multiple factors, including allelic variation and interactions with inhibitors. Human CYP2D6 is responsible for approximately 20% of cytochrome P450–mediated drug metabolism but consists of more than 100 known variants; several variants are commonly found in the population, whereas others are quite rare. Four CYP2D6 allelic variants—three with a series of mutations distal to the active site (*34, *17-2, *17-3) and one ultra-metabolizer with mutations near the active site (*53), along with reference *1 and an active site mutant of *1 (Thr309Ala)—were expressed, purified, and studied for interactions with the typical substrates dextromethorphan and bufuralol and the inactivator SCH 66712. We found that *34, *17-2, and *17-3 displayed reduced enzyme activity and NADPH coupling while producing the same metabolites as *1, suggesting a possible role for Arg296 in NADPH coupling. A higher-activity variant, *53, displayed similar NADPH coupling to *1 but was less susceptible to inactivation by SCH 66712. The Thr309Ala mutant showed similar activity to that of *1 but with greatly reduced NADPH coupling. Overall, these results suggest that kinetic and metabolic analysis of individual CYP2D6 variants is required to understand their possible contributions to variable drug response and the complexity of personalized medicine.

  代谢表型可能受到多种因素的影响，包括等位基因变异和与抑制剂的相互作用。人类 CYP2D6 负责约 20% 的细胞色素 P450 介导的药物代谢，但由 100 多种已知变体组成；几种变体在人群中很常见，而其他变体则相当罕见。四种 CYP2D6 等位基因变体 - 三种在活性位点远端具有一系列突变（*34、*17-2、*17-3），一种超代谢型在活性位点附近具有突变（*53），以及参考* 1 和 *1 的活性位点突变体 (Thr309Ala) 被表达、纯化，并研究了与典型底物右美沙芬和布呋洛尔以及灭活剂 SCH 66712 的相互作用。我们发现 *34、*17-2 和 *17- 3 显示酶活性和 NADPH 偶联降低，同时产生与 *1 相同的代谢物，表明 Arg296 在 NADPH 偶联中可能发挥作用。较高活性的变体 *53 表现出与 *1 相似的 NADPH 偶联，但不太容易被 SCH 66712 失活。Thr309Ala 突变体表现出与 *1 相似的活性，但 NADPH 偶联大大降低。总体而言，这些结果表明需要对单个 CYP2D6 变体进行动力学和代谢分析，以了解它们对可变药物反应和个性化医疗的复杂性的可能贡献。
• Functional influence of human CYP2D6 allelic variations: P34S, E418K, S486T, and R296C
  作者：Joohwan Kim、Young-Ran Lim、Songhee Han、Jung-Soo Han、Young-Jin Chun、Chul-Ho Yun、Chang Hoon Lee、Donghak Kim

  DOI：10.1007/s12272-013-0212-5

  日期：2013.12

  CYP2D6 is responsible for the oxidative metabolism of 20–25 % of clinical drugs and its genetic polymorphisms can significantly influence the drug metabolism. In this study, we analyzed the functional activities of four nonsynonymous single nucleotide polymorphisms from CYP2D6*52 allele, which were recently found, and one found frequently in CYP2D6 alleles. Recombinant variant enzymes of E418K, S486T, and R296C were successfully expressed in Escherichia coli and purified. However, a CYP holoenzyme spectrum of P34S variant was not detected in E. coli whole cell level. Structural analysis indicated that P34S mutation seemed to perturb a highly conserved proline-rich N-terminus of CYP2D6. Steady state kinetic analyses showed the significant reductions of enzymatic activities in E418K and R296C variants. In the case of bufuralol 1’-hydroxylation, a novel mutant, E418K, showed 32 % decrease in catalytic efficiency (k cat/K m) mainly due to the decrease of k cat value. R296C showed much greater reduction in the catalytic efficiency (9 % of wild-type) due to both of a decrease of k cat value and an increase of K m value. In the case of dextromethorphan O-demethylation, E418K showed both of a decrease of k cat value and an increase K m value to result in ~43 % reduction of catalytic efficiency. A highly decreased catalytic efficiency (~6 % of wild-type) in the mutant of R296C also was observed mainly due to the dramatic change of k cat value of dextromethorphan O-demethylation. These results suggested that individuals carrying these allelic variants are likely to have the altered metabolic abilities of many clinical drugs therefore, these polymorphisms of CYP2D6 should be much concerned for reliable drug treatment.

  CYP2D6负责20-25%临床药物的氧化代谢，其基因多态性可显着影响药物代谢。在本研究中，我们分析了最近发现的 CYP2D6*52 等位基因的 4 个非同义单核苷酸多态性的功能活性，以及​​ CYP2D6 等位基因中常见的一个。 E418K、S486T、R296C的重组变体酶在大肠杆菌中成功表达并纯化。然而，在大肠杆菌全细胞水平中未检测到 P34S 变体的 CYP 全酶谱。结构分析表明，P34S 突变似乎扰乱了 CYP2D6 高度保守的富含脯氨酸的 N 末端。稳态动力学分析显示 E418K 和 R296C 变体的酶活性显着降低。就丁呋洛尔 1'-羟基化而言，一种新型突变体 E418K 的催化效率 (k cat/K m) 降低了 32%，这主要是由于 k cat 值的降低。由于 k cat 值的降低和 K m 值的增加，R296C 显示催化效率大幅降低（野生型的 9%）。在右美沙芬 O-去甲基化的情况下，E418K 显示 k cat 值降低和 K m 值增加，导致催化效率降低约 43%。在 R296C 突变体中也观察到催化效率大幅下降（约野生型的 6%），这主要是由于右美沙芬 O-去甲基化的 k cat 值的急剧变化。这些结果表明，携带这些等位基因变异的个体可能具有许多临床药物的代谢能力改变，因此，CYP2D6的这些多态性应该受到可靠药物治疗的高度关注。
• Heme–thiolate sulfenylation of human cytochrome P450 4A11 functions as a redox switch for catalytic inhibition
  作者：Matthew E. Albertolle、Donghak Kim、Leslie D. Nagy、Chul-Ho Yun、Ambra Pozzi、Üzen Savas、Eric F. Johnson、F. Peter Guengerich

  DOI：10.1074/jbc.m117.792200

  日期：2017.7

  dithiothreitol and tris(2-carboxyethyl)phosphine) strongly enhanced the catalytic activity of P450 4A11, but not of 10 other human P450s tested. Conversely, added H2O2 attenuated P450 4A11 catalytic activity. Catalytic roles of five of the potentially eight implicated Cys residues of P450 4A11 were eliminated by site-directed mutagenesis. Using an isotope-coded dimedone/iododimedone-labeling strategy and

  细胞色素P450（P450，CYP）4A11是一种人类脂肪酸ω-羟化酶，可催化花生四烯酸氧化为类二十烷酸20-羟基二十碳四烯酸（20-HETE），这在调节血压方面起着重要作用。P450 4A11的变体与高血压和对降压药的耐药性有关，而20-HETE具有分别与血管收缩和利尿增加有关的降压和降压特性。这些生理活动可能受氧化还原环境的影响，但机理尚不清楚。在这里，我们发现还原剂（例如二硫苏糖醇和三（2-羧乙基）膦）可以大大增强P450 4A11的催化活性，但不能增强其他10种人类P450的催化活性。相反，加入H2O2会减弱P450 4A11的催化活性。通过定点诱变消除了潜在的P450 4A11的八个Cys残基中的五个的催化作用。使用同位素编码的二甲基二酮/碘二甲基酮标记策略和肽的质谱分析，我们证明了血红素硫醇半胱氨酸（Cys-457）以H 2 O 2浓度依赖性方式被选择性地亚磺酰化。可以通过还原