苄达明 N-氧化物 | 36504-71-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 中文名称: 苄达明 N-氧化物
• 中文别名: 苄达明N-氧化物
• 英文名称: Benzydamine N-Oxide
• 英文别名: 3-(1-benzylindazol-3-yl)oxy-N,N-dimethylpropan-1-amine oxide
• CAS: 36504-71-9
• 化学式: C₁₉H₂₃N₃O₂
• 分子量: 325.411
• InChiKey: VHKKEFPZHPEYJK-UHFFFAOYSA-N

物化性质

• 溶解度：
  可溶于氯仿（少许）、DMSO（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  45.1
• 氢给体数：
  0
• 氢受体数：
  3

安全信息

• 海关编码：
  2933990090

制备方法与用途

苄胺N-氧化物是苄胺的代谢产物，可用来测量含黄素的单加氧酶活性。

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  苄达明	benzydamine	642-72-8	C19H23N3O	309.411

反应信息

• 作为产物：
  描述：

  苄达明 以 aq. phosphate buffer 为溶剂， 生成 苄达明 N-氧化物
  参考文献：
  名称：

  Human Flavin-Containing Monooxygenase 3 on Graphene Oxide for Drug Metabolism Screening

  摘要：

  人黄素单加氧酶 3 (hFMO3) 是一种膜结合肝蛋白，属于第二重要的 1 相药物代谢酶类，以其活性形式固定在氧化石墨烯 (GO) 上，以增强电化学响应。为了提高蛋白质稳定性并确保固定化酶的电催化活性，使用双十二烷基二甲基溴化铵 (DDAB) 来模拟生物膜的脂质层，并充当 GO 纳米材料和 hFMO3 生物组分之间的界面。掠射角衰减全反射傅里叶变换红外（GATR-FT-IR）实验证实了蛋白质二级结构和折叠的保存。通过循环伏安法对玻碳电极上的 GO 和 DDAB 固定化酶进行电化学表征，确定了氧化还原电位、电子转移速率和表面覆盖度等多个参数。该系统在药物筛选中的生物技术应用通过固定化酶对两种治疗药物苯扎明（非甾体类抗炎药）和他莫昔芬（广泛用于乳腺癌治疗和化学预防的抗雌激素）的 N 氧化而得到成功证明。

  DOI：

  10.1021/ac504535y

文献信息

• Biotransformation of benzydamine by microsomes and precision-cut slices prepared from cattle liver
  作者：A. Santi、P. Anfossi、N. G. Coldham、F. Capolongo、M. J. Sauer、C. Montesissa

  DOI：10.1080/00498250110085827

  日期：2002.1

  1. Benzydamine (BZ), a non-steroidal anti-inflammatory drug used in human and veterinary medicine, is not licensed for use in food-producing species. Biotransformation of BZ in cattle has not been reported previously and is investigated here using liver microsomes and precision-cut liver slices.2. BZ was metabolized by cattle liver microsomes to benzydamine N-oxide (BZ-NO) and monodesmethyl-BZ (Nor-BZ). Both reactions followed Michaelis-Menten kinetics (K-m = 76.4 +/- 16.0 and 58.9 +/- 6.4 muM, V-max = 6.5 +/- 0.8 and 7.4 +/- 0: 5 nmol mg(1) min(1), respectively); sensitivity to heat and pH suggested that the N-oxidation is catalysed by the flavin-containing monooxygenases.3. BZ-NO and Nor-BZ were the most abundant products derived from liver slice incubations, and nine other BZ metabolites were found and tentatively identified by LC-MS. Desbenzylated and hydroxylated BZ-NO analogues and a hydroxylated product of BZ were detected, which have been reported in other species. Product ion mass spectra of other metabolites, which are described here for the first time, indicated the formation of a BZ N(+-)glucuronide and five hydroxylated and N+-glucuronidated derivatives of BZ, BZ-NO and Nor-BZ.4. The results indicate that BZ is extensively metabolized in cattle. Clearly, differences in metabolism compared with, for example, rat and human, will need to be considered in the event of submission for marketing authorization for use in food animals.
• Whole-cell dependent biosynthesis of N- and S-oxides using human flavin containing monooxygenases expressing budding yeast
  作者：Yuuka Masuyama、Miyu Nishikawa、Kaori Yasuda、Toshiyuki Sakaki、Shinichi Ikushiro

  DOI：10.1016/j.dmpk.2020.01.007

  日期：2020.6

  Flavin containing monooxygenases (FMOs) represent one of the predominant types of phase I drug metabolizing enzymes (DMEs), and thus play an important role in the metabolism of xeno- and endobiotics for the generation of their corresponding oxides. These oxides often display biological activities, however they are difficult to study since their chemical or biological synthesis is generally challenging even though only small amounts are required to evaluate their efficacy and safety. Previously, we constructed a DME expression system for cytochrome P450, UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) using yeast cells, and successfully produced xenobiotic metabolites in a whole-cell dependent manner. In this study, we developed a heterologous expression system for human FMOs, including FMO1-FMO5, in Saccharomyces cerevisiae and examined its N- and S-oxide productivity. The recombinant yeast cells expressed each of the FMO successfully, and the FMO4 transformant produced N- and S-oxide metabolites at several milligrams per liter within 24 h. This whole-cell dependent biosynthesis enabled the production of N- and S-oxides without the use of the expensive cofactor NADPH. Such novel yeast expression system could be a powerful tool for the production of oxide metabolites. (C) 2020 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
• Functional assessment of rat pulmonary flavin-containing monooxygenase activity
  作者：Yildiz Yilmaz、Gareth Williams、Nenad Manevski、Markus Walles、Stephan Krähenbühl、Gian Camenisch

  DOI：10.1080/00498254.2018.1469804

  日期：2019.5.4

  The expression of flavin-containing monooxygenase (FMO) varies extensively between human and commonly used preclinical species such as rat and mouse. The aim of this study was to investigate the pulmonary FMO activity in rat using benzydamine. Furthermore, the contribution of rat lung to the clearance of benzydamine was investigated using an in vivo pulmonary extraction model. Benzydamine N-oxygenation was observed in lung microsomes and lung slices. Thermal inactivation of FMO and CYP inhibition suggested that rat pulmonary N-oxygenation is predominantly FMO mediated while any contribution from CYPs is negligible. The predicted lung clearance (CLlung) estimated from microsomes and slices was 16 +/- 0.6 and 2.1 +/- 0.3 mL/min/kg, respectively. The results from in vivo pulmonary extraction indicated no pulmonary extraction following intravenous and intra-arterial dosing to rats. Interestingly, the predicted CLlung using rat lung microsomes corresponded to approximately 35% of rat CLliver suggesting that the lung makes a smaller contribution to the whole body clearance of benzydamine. Although benzydamine clearance in rat appears to be predominantly mediated by hepatic metabolism, the data suggest that the lung may also make a smaller contribution to its whole body clearance.
• Genetic variants of flavin-containing monooxygenase 3 (FMO3) in Japanese subjects identified by phenotyping for trimethylaminuria and found in a database of genome resources
  作者：Makiko Shimizu、Natsumi Koibuchi、Ami Mizugaki、Eiji Hishinuma、Sakae Saito、Masahiro Hiratsuka、Hiroshi Yamazaki

  DOI：10.1016/j.dmpk.2021.100387

  日期：2021.6
• Human Flavin-Containing Monooxygenase 3 on Graphene Oxide for Drug Metabolism Screening
  作者：Silvia Castrignanò、Gianfranco Gilardi、Sheila J. Sadeghi

  DOI：10.1021/ac504535y

  日期：2015.3.3

  Human flavin-containing monooxygenase 3 (hFMO3), a membrane-bound hepatic protein, belonging to the second most important class of phase-1 drug-metabolizing enzymes, was immobilized in its active form on graphene oxide (GO) for enhanced electrochemical response. To improve protein stabilization and to ensure the electrocatalytic activity of the immobilized enzyme, didodecyldimethylammonium bromide (DDAB) was used to mimic lipid layers of biological membranes and acted as an interface between GO nanomaterial and the hFMO3 biocomponent. Grazing angle attenuated total reflectance Fourier transform infrared (GATR-FT-IR) experiments confirmed the preservation of the protein secondary structure and fold. Electrochemical characterization of the immobilized enzyme with GO and DDAB on glassy carbon electrodes was carried out by cyclic voltammetry, where several parameters including redox potential, electron transfer rate, and surface coverage were determined. This system’s biotechnological application in drug screening was successfully demonstrated by the N-oxidation of two therapeutic drugs, benzydamine (nonsteroidal anti-inflammatory) and tamoxifen (antiestrogenic widely used in breast cancer therapy and chemoprevention), by the immobilized enzyme.

  人黄素单加氧酶 3 (hFMO3) 是一种膜结合肝蛋白，属于第二重要的 1 相药物代谢酶类，以其活性形式固定在氧化石墨烯 (GO) 上，以增强电化学响应。为了提高蛋白质稳定性并确保固定化酶的电催化活性，使用双十二烷基二甲基溴化铵 (DDAB) 来模拟生物膜的脂质层，并充当 GO 纳米材料和 hFMO3 生物组分之间的界面。掠射角衰减全反射傅里叶变换红外（GATR-FT-IR）实验证实了蛋白质二级结构和折叠的保存。通过循环伏安法对玻碳电极上的 GO 和 DDAB 固定化酶进行电化学表征，确定了氧化还原电位、电子转移速率和表面覆盖度等多个参数。该系统在药物筛选中的生物技术应用通过固定化酶对两种治疗药物苯扎明（非甾体类抗炎药）和他莫昔芬（广泛用于乳腺癌治疗和化学预防的抗雌激素）的 N 氧化而得到成功证明。