8-羟基依法韦仑 | 205754-33-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 中文名称: 8-羟基依法韦仑
• 中文别名: 8-羟基依法韦伦
• 英文名称: 8-Hydroxyefavirenz
• 英文别名: (4S)-6-chloro-4-(2-cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1H-3,1-benzoxazin-2-one
• CAS: 205754-33-2
• 化学式: C₁₄H₉ClF₃NO₃
• 分子量: 331.679
• InChiKey: OOVOMPCQLMFEDT-ZDUSSCGKSA-N

物化性质

• 熔点：
  144-154°C
• 沸点：
  373.6±42.0 °C(Predicted)
• 密度：
  1?+-.0.1 g/cm3(Predicted)
• 溶解度：
  乙腈：可溶； DMSO：可溶；甲醇：可溶

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  58.6
• 氢给体数：
  2
• 氢受体数：
  6

ADMET

代谢

8-羟基依非韦伦已知的人类代谢物包括8,14-二羟基-依非韦伦和(2S,3S,4S,5R)-6-[[(4S)-6-氯-4-(2-环丙基乙炔基)-2-氧代-4-(三氟甲氧基)-1H-3,1-苯并氧氮杂-8-基]氧基]-3,4,5-三羟基氧杂环己烷-2-羧酸。

8-hydroxyefavirenz has known human metabolites that include 8,14-dihydroxy-efavirenz and (2S,3S,4S,5R)-6-[[(4S)-6-chloro-4-(2-cyclopropylethynyl)-2-oxo-4-(trifluoromethyl)-1H-3,1-benzoxazin-8-yl]oxy]-3,4,5-trihydroxyoxane-2-carboxylic acid.

来源:NORMAN Suspect List Exchange

安全信息

• 储存条件：
  -20°C，密封保存于干燥处。

制备方法与用途

8-羟基依法韦仑(8-OH-EFV)是伊法韦仑(HY-10572)的主要代谢产物，能够通过依赖JNK和BimEL的机制诱导原代人肝细胞凋亡。此外，8-羟基依法韦仑在癌症研究中也有应用价值。

反应信息

• 作为反应物：
  描述：

  8-羟基依法韦仑 在 lithium hydroxide 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 8-Hydroxyefavirenz Glucuronide
  参考文献：
  名称：

  Synthesis and biological activities of potential metabolites of the non-nucleoside reverse transcriptase inhibitor Efavirenz

  摘要：

  Studies on the biotransformation of the clinically important non-nucleoside reverse transcriptase inhibitor efavirenz have shown that oxidation and secondary conjugation are important components of the processing of this molecule in vivo. We have synthesized metabolites of efavirenz to confirm their structure and to evaluate their activity as antivirals. (C) 2001 DuPont Pharmaceuticals Company. Published by Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(01)00012-9
• 作为产物：
  描述：

  依法韦仑 在 bis(methanesulfonyl)peroxide 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 aq. phosphate buffer 为溶剂， 反应 16.5h， 生成 8-羟基依法韦仑
  参考文献：
  名称：

  后期芳烃碳氢氧合

  摘要：

  尽管在药物发现和开发中需要代谢物合成，但用于形成氧化芳族 CO 键的合成方法很少。我们报告了一种用于芳烃后期 CO 键形成的新方法。即使对于高度官能化的底物，该反应也以优异的官能团耐受性进行。所得的甲磺酸芳基酯提供了获取潜在的人类药物代谢物的途径，并可直接用于安装 CF 键以阻断代谢热点。试剂双（甲磺酰基）过氧化物和底物芳烃之间的电荷转移相互作用可能与芳烃相对于其他官能团的化学选择性官能化有关。

  DOI：

  10.1021/jacs.8b09208

文献信息

• Biomimetic oxidation of aromatic xenobiotics: synthesis of the phenolic metabolites from the anti-HIV drug efavirenz
  作者：Riccardo Wanke、David A. Novais、Shrika G. Harjivan、M. Matilde Marques、Alexandra M. M. Antunes

  DOI：10.1039/c2ob25212k

  日期：——

  We report the oxidation of the first line anti-HIV drug efavirenz (EFV), mediated by a bio-inspired nonheme Fe-complex. Depending upon the experimental conditions this system can be tuned either to yield the major EFV metabolite, 8-hydroxy-EFV, in enantiomerically pure form or to mimic cytochrome P450 (CYP) activity, yielding 8-hydroxy-EFV and 7-hydroxy-EFV, the two phenolic EFV metabolites reported to be formed in vivo. The successful oxidation of the anti-estrogen tamoxifen and the equine estrogen equilin into their CYP-mediated metabolites supports the general application of bio-inspired nonheme Fe-complexes in mirroring CYP activity.

  我们报道了一线抗 HIV 药物依非韦伦 (EFV) 的氧化，该氧化是由仿生非血红素铁复合物介导的。根据实验条件，可以调整该系统以产生对映体纯形式的主要 EFV 代谢物 8-羟基-EFV，或模拟细胞色素 P450 (CYP) 活性，产生 8-羟基-EFV 和 7-羟基-EFV ，据报道在体内形成两种酚类 EFV 代谢物。抗雌激素他莫昔芬和马雌激素马烯雌酮成功氧化成其 CYP 介导的代谢物，支持了仿生非血红素铁复合物在镜像 CYP 活性中的普遍应用。
• Characterization of marmoset CYP2B6: cDNA cloning, protein expression and enzymatic functions
  作者：Kei Mayumi、Nobumitsu Hanioka、Kazufumi Masuda、Akiko Koeda、Shinsaku Naito、Atsuro Miyata、Shizuo Narimatsu

  DOI：10.1016/j.bcp.2013.01.024

  日期：2013.4

  The common marmoset is a promising species for evaluating the safety of drug candidates. To further understand the capacity for drug metabolism in marmosets, a cDNA encoding a CYP2B enzyme was cloned from the total RNA fraction of marmoset liver by 3'- and 5'-RACE methods. Nucleotide and deduced amino acid sequences showed 90.8 and 86.2% identity, respectively, with human CYP2B6. The marmoset CYP2B6 (marCYP2B6) protein was expressed in insect cells, and its enzymatic properties were compared with those of human (humCYP2B6) and cynomolgus monkey (cynCYP2B6) orthologs in liver and insect cell microsomes. Enzymatic functions were examined for the oxidation of 7-ethoxy-4-(trifluoromethyl)coumarin (7-ETC), bupropion (BUP) and efavirenz (EFV). The kinetic profiles for the oxidation of the three substrates by liver microsomal fractions were similar between humans and cynomolgus monkeys (biphasic for 7-ETC and monophasic for BUP and EFV), but that of marmosets was unique (monophasic for 7-ETC and biphasic for BUP and EFV). Recombinant enzymes, humCYP2B6 and cynCYP2B6, also yielded similar kinetic profiles for the oxidation of the three substrates, whereas marCYP2B6 showed activity only for 7-ETC hydroxylation. In silico docking simulations suggested that two amino acid residues, Val-114 and Leu-367, affect the activity of marCYP2B6. In fact, a marCYP2B6 mutant with substitutions V114I and L367V exhibited BUP hydroxylase activity that was 4-fold higher than that of humCYP2B6, while its EFV 8-hydroxylase activity was only 10% that of the human enzyme. These results indicate that the amino acids at positions 114 and 367 affect the enzymatic capacity of marmoset CYP2B6. (C) 2013 Elsevier Inc. All rights reserved.
• The phenolic metabolites of the anti-HIV drug efavirenz: Evidence for distinct reactivities upon oxidation with Frémy's salt
  作者：Shrika G. Harjivan、Riccardo Wanke、João L. Ferreira da Silva、M. Matilde Marques、Alexandra M.M. Antunes

  DOI：10.1016/j.ejmech.2013.12.022

  日期：2014.3

  Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor administered as first line treatment against HIV-1. The major drawbacks of EFV therapy are neurotoxicity and hepatotoxicity, which may result from bioactivation to reactive metabolites capable of reacting with bionucleophiles. We investigated the in vitro oxidation of the phenolic EFV metabolites, 7-hydroxy-efavirenz (7-OH-EFV) and 8hydroxy-efavirenz (8-OH-EFV), with Fremy's salt. A quinoline derivative, 6-chloro-2-cyclopropy1-4-(trifluoromethyl)quinolin-7-ol, presumably stemming from a radical rearrangement, was selectively obtained from 7-OH-EFV in 10% yield. In contrast, when subjected to the same oxidation conditions, 8-OH-EFV was considerably more prone to oxidative degradation and yielded multiple products. Among these, a quinone imine derivative was tentatively identified upon LC-ESI-MS/MS analysis of the reaction mixture. These observations demonstrate a remarkable difference in the reactivities of the two phenolic EFV metabolites under oxidative conditions. Moreover, taking into consideration the toxicological significance of quinone imine derivatives, these findings may explain earlier reports that 8-OH-EFV is a more potent toxicant than 7-OH-EFV in model test systems. (C) 2014 Elsevier Masson SAS. All rights reserved.
• Late-Stage Aromatic C–H Oxygenation
  作者：Jonas Börgel、Lalita Tanwar、Florian Berger、Tobias Ritter

  DOI：10.1021/jacs.8b09208

  日期：2018.11.28

  Synthetic methods for oxidative aromatic C-O bond formation are sparse, despite their demand in metabolite synthesis for drug discovery and development. We report a novel methodology for late-stage C-O bond formation of arenes. The reaction proceeds with excellent functional group tolerance even for highly functionalized substrates. The resulting aryl mesylates provide access to potential human metabolites

  尽管在药物发现和开发中需要代谢物合成，但用于形成氧化芳族 CO 键的合成方法很少。我们报告了一种用于芳烃后期 CO 键形成的新方法。即使对于高度官能化的底物，该反应也以优异的官能团耐受性进行。所得的甲磺酸芳基酯提供了获取潜在的人类药物代谢物的途径，并可直接用于安装 CF 键以阻断代谢热点。试剂双（甲磺酰基）过氧化物和底物芳烃之间的电荷转移相互作用可能与芳烃相对于其他官能团的化学选择性官能化有关。
• Synthesis and biological activities of potential metabolites of the non-nucleoside reverse transcriptase inhibitor Efavirenz
  作者：Jay A. Markwalder、David D. Christ、Abdul Mutlib、Beverly C. Cordova、Ronald M. Klabe、Steven P. Seitz

  DOI：10.1016/s0960-894x(01)00012-9

  日期：2001.3

  Studies on the biotransformation of the clinically important non-nucleoside reverse transcriptase inhibitor efavirenz have shown that oxidation and secondary conjugation are important components of the processing of this molecule in vivo. We have synthesized metabolites of efavirenz to confirm their structure and to evaluate their activity as antivirals. (C) 2001 DuPont Pharmaceuticals Company. Published by Elsevier Science Ltd. All rights reserved.