1'-羟基丁呋洛尔 | 57704-16-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 中文名称: 1'-羟基丁呋洛尔
• 中文别名: 4-氨基-5-(甲氧基羰基)噻吩-2-羧酸；2-(叔丁基氨基)-1-[7-(1-羟乙基)-1-苯并呋喃-2-基]乙醇；1’-羟基丁呋洛尔；1"-羟基丁呋洛尔
• 英文名称: 1-hydroxybufuralol
• 英文别名: 1’-hydroxybufuralol；hydroxybufuralol；1′ -hydroxybufuralol；1'-Hydroxybufuralol；2-(tert-butylamino)-1-[7-(1-hydroxyethyl)-1-benzofuran-2-yl]ethanol
• CAS: 57704-16-2
• 化学式: C₁₆H₂₃NO₃
• 分子量: 277.364
• InChiKey: GTYMTYBCXVOBBB-UHFFFAOYSA-N

物化性质

• 熔点：
  41-49°C
• 沸点：
  433.0±40.0 °C(Predicted)
• 密度：
  1.139±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（轻微）、DMSO（轻微）、甲醇（轻微、加热）

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 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

制备方法与用途

生物活性方面，1'-羟基苯福林是 bufuralol 的主要代谢产物，能够反映 CYP2D6 酶的活性。

反应信息

• 作为产物：
  描述：

  丁呋洛尔 在 glucose dehydrogenase 、 葡萄糖 、 nicotinamide adenine dinucleotide phosphate 、 sodium citrate 、 magnesium chloride 作用下， 以 aq. phosphate buffer 为溶剂， 反应 0.17h， 生成 1'-羟基丁呋洛尔
  参考文献：
  名称：

  人类细胞色素P450 2D6的双位点饱和诱变导致区域选择性甾体羟基化

  摘要：

  人细胞色素P450 2D6（CYP2D6）是主要的人类药物代谢酶之一，优选对含有碱性氮原子的底物起作用。睾丸激素-与其他类固醇一样-是非典型底物，仅通过CYP2D6代谢较差。本研究旨在研究两个活性位点残基216和483对CYP2D6羟化类固醇（例如睾丸激素）的能力的影响。这两个位置的所有400种可能的组合突变均已生成，并在巴斯德毕赤酵母中单独表达。采用全细胞生物转化结合HPLC-MS分析，确定每个单个CYP2D6变体的睾丸激素羟化酶活性和区域选择性。覆盖整个序列空间，CYP2D6变体具有增强的活性，到目前为止，未知的睾丸激素羟化反应中的区域偏好被确定。最有趣的是，与先前有关突变蛋白F483I的文献报道相反，突变F483G导致2β位发生优选的羟基化，而野生型CYP2D6的主要产物6β-羟基睾丸激素的缓慢形成被进一步降低。已经有两个点突变足以将CYP2D6转化为甾醇羟化酶，该酶的睾丸激素羟化率

  DOI：

  10.1111/febs.12270

文献信息

• Inhibition of Human Drug Metabolizing Cytochrome P450 by Buprenorphine.
  作者：Ken Umehara、Yoshihiko Shimokawa、Gohachiro Miyamoto

  DOI：10.1248/bpb.25.682

  日期：——

  The effects of buprenorphine, a powerful mixed agonist/antagonist analgesic, on several cytochrome P450 (CYP) isoform specific reactions in human liver microsomes were investigated to predict drug interaction of buprenorphine in vivo from in vitro data. The following eight CYP-catalytic reactions were used in this study: CYP1A1/2-mediated 7-ethoxyresorufin O-deethylation, CYP2A6-mediated coumarin 7-hydroxylation, CYP2B6-mediated 7-benzyloxyresorufin O-debenzylation, CYP2C8/9-mediated tolbutamide methylhydroxylation, CYP2C19-mediated S-mephenytoin 4-hydroxylation, CYP2D6-mediated bufuralol 1′-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, and CYP3A4-mediated testosterone 6β-hydroxylation. Buprenorphine strongly inhibited the CYP3A4- and CYP2D6-catalyzed reactions with Ki values of 14.7 μM and 21.4 μM, respectively. The analgesic also weakly inhibited specific reactions catalyzed by CYP1A1/2 (Ki=132 μM), CYP2B6 (Ki=133 μM), CYP2C19 (Ki=146 μM), CYP2C8/9 (IC50>300 μM), and CYP2E1 (IC50>300 μM), but not CYP2A6 mediated pathway. In consideration of the Ki values obtained in this study and the therapeutic concentration of buprenorphine in human plasma, buprenorphine would not be predicted to cause clinically significant interactions with other CYP-metabolized drugs.

  本研究调查了强效混合激动剂/拮抗剂镇痛药丁丙诺啡在人肝微粒体中对几种细胞色素P450（CYP）同工酶特异性反应的影响，旨在从体外数据预测丁丙诺啡在体内的药物相互作用。本研究使用了以下八种CYP催化反应：CYP1A1/2介导的7-乙氧基罗丹明O-脱乙基化、CYP2A6介导的香豆素7-羟化、CYP2B6介导的7-苄氧基罗丹明O-脱苄基化、CYP2C8/9介导的甲苯磺丁脲甲基羟化、CYP2C19介导的S-美芬妥英4-羟化、CYP2D6介导的布非洛尔1′-羟化、CYP2E1介导的氯唑沙宗6-羟化和CYP3A4介导的睾酮6β-羟化。丁丙诺啡对CYP3A4和CYP2D6催化反应显示出强烈抑制作用，Ki值分别为14.7 μM和21.4 μM。该镇痛药还对CYP1A1/2（Ki=132 μM）、CYP2B6（Ki=133 μM）、CYP2C19（Ki=146 μM）、CYP2C8/9（IC50>300 μM）和CYP2E1（IC50>300 μM）介导的特异性反应表现出弱抑制作用，但不包括CYP2A6介导的通路。综合本研究获得的Ki值和丁丙诺啡在人血浆中的治疗浓度，预计丁丙诺啡不会引起与其他CYP代谢药物临床意义上的显著相互作用。
• Double site saturation mutagenesis of the human cytochrome P450 2D6 results in regioselective steroid hydroxylation
  作者：Martina Geier、Andreas Braun、Patrik Fladischer、Piotr Stepniak、Florian Rudroff、Christian Hametner、Marko D. Mihovilovic、Anton Glieder

  DOI：10.1111/febs.12270

  日期：2013.7

  hydroxylase activity and regioselectivity of every single CYP2D6 variant was determined. Covering the whole sequence space, CYP2D6 variants with improved activity and so far unknown regio‐preference in testosterone hydroxylation were identified. Most intriguingly and in contrast to previous literature reports about mutein F483I, the mutation F483G led to preferred hydroxylation at the 2β‐position, while

  人细胞色素P450 2D6（CYP2D6）是主要的人类药物代谢酶之一，优选对含有碱性氮原子的底物起作用。睾丸激素-与其他类固醇一样-是非典型底物，仅通过CYP2D6代谢较差。本研究旨在研究两个活性位点残基216和483对CYP2D6羟化类固醇（例如睾丸激素）的能力的影响。这两个位置的所有400种可能的组合突变均已生成，并在巴斯德毕赤酵母中单独表达。采用全细胞生物转化结合HPLC-MS分析，确定每个单个CYP2D6变体的睾丸激素羟化酶活性和区域选择性。覆盖整个序列空间，CYP2D6变体具有增强的活性，到目前为止，未知的睾丸激素羟化反应中的区域偏好被确定。最有趣的是，与先前有关突变蛋白F483I的文献报道相反，突变F483G导致2β位发生优选的羟基化，而野生型CYP2D6的主要产物6β-羟基睾丸激素的缓慢形成被进一步降低。已经有两个点突变足以将CYP2D6转化为甾醇羟化酶，该酶的睾丸激素羟化率
• Expression and Characterization of Cynomolgus Monkey Cytochrome CYP3A4 in a Novel Human Embryonic Kidney Cell–Based Mammalian System
  作者：Sindhuja Selvakumar、Priyadeep Bhutani、Kaushik Ghosh、Prasad Krishnamurthy、Sanjith Kallipatti、Sabariya Selvam、Manjunath Ramarao、Sandhya Mandlekar、Michael W. Sinz、A. David Rodrigues、Murali Subramanian

  DOI：10.1124/dmd.113.055491

  日期：2014.3

  Cynomolgus monkeys are a commonly used species in preclinical drug discovery, and have high genetic similarity to humans, especially for the drug-metabolizing cytochrome P450s. However, species differences are frequently observed in the metabolism of drugs between cynomolgus monkeys and humans, and delineating these differences requires expressed CYPs. Toward this end, cynomolgus monkey CYP3A4 (c3A4) was cloned and expressed in a novel human embryonic kidney 293-6E cell suspension system. Following the preparation of microsomes, the kinetic profiles of five known human CYP3A4 (h3A4) substrates (midazolam, testosterone, terfenadine, nifedipine, and triazolam) were determined. All five substrates were found to be good substrates of c3A4, although some differences were observed in the K m values. Overall, the data suggest a strong substrate similarity between c3A4 and h3A4. Additionally, c3A4 exhibited no activity against non-h3A4 probe substrates, except for a known human CYP2D6 substrate (bufuralol), which suggests potential metabolism of human cytochrome CYP2D6-substrates by c3A4. Ketoconazole and troleandomycin showed similar inhibitory potencies toward c3A4 and h3A4, whereas non-h3A4 inhibitors did not inhibit c3A4 activity. The availability of a c3A4 preparation, in conjunction with commercially available monkey liver microsomes, will support further characterization of the cynomolgus monkey as a model to assess CYP3A-dependent clearance and drug-drug interactions.

  猴是临床前药物发现中常用的物种，其基因与人类高度相似，尤其是药物代谢细胞色素 P450s。然而，在猴与人之间的药物代谢过程中经常会观察到物种差异，要确定这些差异需要表达的 CYPs。为此，研究人员克隆了猴 CYP3A4（c3A4），并在新型人胚肾 293-6E 细胞悬浮系统中进行了表达。制备微粒体后，测定了五种已知人类 CYP3A4（h3A4）底物（咪达唑仑、睾酮、特非那定、硝苯地平和三唑仑）的动力学特征。尽管 K m 值存在一些差异，但所有五种底物都是 c3A4 的良好底物。总体而言，数据表明 c3A4 和 h3A4 底物具有很强的相似性。此外，除了已知的人类 CYP2D6 底物（糠醛醇）外，c3A4 对非 h3A4 探针底物没有表现出活性，这表明 c3A4 对人类细胞色素 CYP2D6 底物有潜在的代谢作用。酮康唑和曲安奈德霉素对 c3A4 和 h3A4 的抑制效力相似，而非 h3A4 抑制剂对 c3A4 活性没有抑制作用。c3A4制剂和市售猴肝微粒体的出现将有助于进一步确定猴作为模型的特性，以评估CYP3A依赖性清除和药物相互作用。
• 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。