2-Amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline | 107609-70-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2-Amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline
• 英文别名: 8-CH2OH-IQX；3H-Imidazo(4,5-f)quinoxaline-8-methanol, 2-amino-3-methyl-；(2-amino-3-methylimidazo[4,5-h]quinoxalin-8-yl)methanol
• CAS: 107609-70-1
• 化学式: C₁₁H₁₁N₅O
• 分子量: 229.241
• InChiKey: NXPOYXGJMFGPIL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  89.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-氨基-3,8-二甲基咪唑并[4,5-f]喹恶啉 在 liver S-9 protein from rats pretreated with PCB 、 β-烟酰胺腺嘌呤二核苷酸 、 还原型辅酶II(NADPH)四钠盐 、 glucose 6-phosphate dehydrogenase 作用下， 反应 3.0h， 生成 2-Amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline
  参考文献：
  名称：

  食源性诱变剂2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉在人体内的代谢。

  摘要：

  在五名人类志愿者中研究了2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（MeIQx）的代谢，这些志愿者的饮食等效为14C标记的MeIQx。尿中排泄的剂量范围为20.2％至58.6％，未代谢的MeIQx占剂量的0.7-2.8％。尿液中检测到5种主要代谢物，其中4种衍生物通过在线UV光谱和免疫亲和层析后的HPLC-MS表征。两种代谢物被鉴定为II期共轭物N2-（3,8-二甲基咪唑并[4,5-f]喹喔啉-2-基）氨基磺酸（MeIQx-N2-SO3（-））和N2-（β-1-葡糖二硬脂酰基）-2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（MeIQx-N2-Gl）。另外两个代谢物是细胞色素P450介导的（P450）氧化产物2-氨基-8-（羟甲基）-3-甲基咪唑[4，5-f]喹喔啉（8-CH2OH-MeIQx）和N2-（beta-1-glucosiduronyl）-N-hydroxy-2-amino-3

  DOI：

  10.1021/tx9701891

文献信息

• Regioselective Differences in C⁸- and N-Oxidation of 2-Amino-3,8-dimethylimidazo[4,5-<i>f</i>]quinoxaline by Human and Rat Liver Microsomes and Cytochromes P450 1A2
  作者：Robert J. Turesky、Véronique Parisod、Tuong Huynh-Ba、Sophie Langouët、F. Peter Guengerich

  DOI：10.1021/tx010035s

  日期：2001.7.1

  The metabolism of the mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was investigated with human and rat liver microsomes, recombinant human cytochrome P450 1A2 (P450 1A2) expressed in Escherichia coli cells, and rat P450 1A2. Human liver microsomes and human P450 1A2 catalyzed the oxidation of the exocyclic amine group of MeIQx to form the genotoxic product 2-(hydroxyamino)-3,8-dimethylimidazo[4

  用人和大鼠的肝微粒体，在大肠杆菌细胞中表达的重组人细胞色素P450 1A2（P450 1A2），研究了诱变剂2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（MeIQx）的代谢大鼠P450 1A2。人肝微粒体和人P450 1A2催化MeIQx环外胺基的氧化，形成遗传毒性产物2-（羟氨基）-3,8-二甲基咪唑并[4,5-f]喹喔啉（HONH-MeIQx）。人类P450 1A2还催化MeIQx的C（8）-甲基氧化形成2-氨基-（8-羟甲基）-3-甲基咪唑并[4,5-f]喹喔啉（8-CH（2）OH-IQx ），2-氨基-3-甲基咪唑并[4,5-f]喹喔啉-8-甲醛（IQx-8-CHO）和2-氨基-3-甲基咪唑并[4,5-f]喹喔啉-8-羧酸（IQx-8-COOH）。从而，MeIQx的化学稳定的C（8）-氧化产物可能是人类P450 1A2活性的有用生物标志物。当表示为每纳摩尔P450 1A2每分
• Metabolism of 2-Amino-3,8-dimethylimidazo[4,5-<i>f</i>]- quinoxaline in Human Hepatocytes:  2-Amino-3-methylimidazo[4,5-<i>f</i>]quinoxaline-8-carboxylic Acid Is a Major Detoxication Pathway Catalyzed by Cytochrome P450 1A2
  作者：Sophie Langouët、Dieter H. Welti、Nathalie Kerriguy、Laurent B. Fay、Tuong Huynh-Ba、Jovanka Markovic、F. Peter Guengerich、André Guillouzo、Robert J. Turesky

  DOI：10.1021/tx000176e

  日期：2001.2.1

  8-dimethylimidazo[4,5-f]quinoxaline, which is formed by cytochrome P450 1A2 (P450 1A2), was found to be transformed into the N(2)-glucuronide conjugate, N(2)-(beta-1-glucosiduronyl)-2-(hydroxyamino)-3,8-dimethylimidazo[4,5-f]quinoxaline. The phase II conjugates N(2)-(3,8-dimethylimidazo[4,5-f]quinoxalin-2-yl)sulfamic acid and N(2)-(beta-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, as well

  诱变剂2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（MeIQx）的代谢途径在人类中仍未完全表征。在这项研究中，对人类原代肝细胞中MeIQx的代谢进行了研究。通过紫外线和质谱对六种代谢物进行了表征。新型代谢物还通过1H NMR光谱进行了表征。发现由细胞色素P450 1A2（P450 1A2）形成的致癌代谢物2-（羟氨基）-3,8-二甲基咪唑并[4,5-f]喹喔啉可转化为N（2）-葡糖醛酸共轭物，N（2）-（β-1-葡萄糖基十二烷基）-2-（羟基氨基）-3,8-二甲基咪唑并[4,5-f]喹喔啉。II期共轭N（2）-（3,8-二甲基咪唑并[4,5-f]喹喔啉-2-基）氨基磺酸和N（2）-（β-1-葡糖二硼酰基）-2-氨基-3， 8-二甲基咪唑并[4,5-f]喹喔啉 以及MeIQx和N-去甲基-MeIQx的7-氧代衍生物，2-氨基-3,8-二甲基-6-氢-7H-咪唑并[4,5-f]喹喔啉-7
• Metabolism of the Food-Borne Mutagen 2-Amino-3,8-dimethylimidazo[4,5-<i>f</i>]quinoxaline in Humans
  作者：Robert J. Turesky、R. Colin Garner、Dieter H. Welti、Janique Richoz、Steve H. Leveson、Karen H. Dingley、Kenneth W. Turteltaub、Laurent B. Fay

  DOI：10.1021/tx9701891

  日期：1998.3.1

  8-dimethylimidazo[4,5-f]quinoxalin-2-yl)sulfamic acid (MeIQx-N2-SO3(-)) and N2-(beta-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f ]quinoxaline (MeIQx-N2-Gl). Two other metabolites were the cytochrome P450-mediated (P450) oxidation products 2-amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline (8-CH2OH-MeIQx), and N2-(beta-1-glucosiduronyl)-N-hydroxy-2-amino-3,8-dimethylimidaz o[4,5-f]quinoxaline (NOH-MeIQx-N2-Gl)

  在五名人类志愿者中研究了2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（MeIQx）的代谢，这些志愿者的饮食等效为14C标记的MeIQx。尿中排泄的剂量范围为20.2％至58.6％，未代谢的MeIQx占剂量的0.7-2.8％。尿液中检测到5种主要代谢物，其中4种衍生物通过在线UV光谱和免疫亲和层析后的HPLC-MS表征。两种代谢物被鉴定为II期共轭物N2-（3,8-二甲基咪唑并[4,5-f]喹喔啉-2-基）氨基磺酸（MeIQx-N2-SO3（-））和N2-（β-1-葡糖二硬脂酰基）-2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（MeIQx-N2-Gl）。另外两个代谢物是细胞色素P450介导的（P450）氧化产物2-氨基-8-（羟甲基）-3-甲基咪唑[4，5-f]喹喔啉（8-CH2OH-MeIQx）和N2-（beta-1-glucosiduronyl）-N-hydroxy-2-amino-3
• A Comprehensive Approach to the Profiling of the Cooked Meat Carcinogens 2-Amino-3,8-dimethylimidazo[4,5-<i>f</i>]quinoxaline, 2-Amino-1-methyl-6-phenylimidazo[4,5-<i>b</i>]pyridine, and Their Metabolites in Human Urine
  作者：Dan Gu、Lynn McNaughton、David LeMaster、Brian G. Lake、Nigel J. Gooderham、Fred F. Kadlubar、Robert J. Turesky

  DOI：10.1021/tx900436m

  日期：2010.4.19

  A targeted liquid chromatography/tandem mass spectrometry-based metabolomics type approach, employing a triple stage quadrupole mass spectrometer in the product ion scan and selected reaction monitoring modes, was established to profile 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and their principal metabolites in the urine of omnivores. A mixed-mode reverse phase cation exchange resin enrichment procedure was employed to isolate MeIQx and its oxidized metabolites, 2-amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline (8-CH2OH-IQx) and 2-amino-3-methylimidazo[4,5-f]quinoxaline-8-carboxylic acid (IQx-8-COOH), which are produced by cytochrome P450 1A2 (P450 1A2). The phase II conjugates N-2-(beta-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and N-2-(3,8-dimethylimidazo[4,5-f]quinoxalin-2-yl)-sulfamic acid were measured indirectly, following acid hydrolysis to form MeIQx. The enrichment procedure permitted the simultaneous analysis of PhIP, N-2-(beta-1-glucosiduronyl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, N3-(beta-1-glucosiduronyl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, 2-amino-1-methyl-6-(4'-hydroxy)-phenylimidazo[4,5-b]pyridine (4'-HO-PhIP), and the isomeric N-2- and N3-glucuronide conjugates of the carcinogenic metabolite, 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (HONH-PhIP), which is formed by P450 1A2. The limit of quantification (LOQ) for MeIQx. PhIP, and 4'-HO-PhIP was similar to 5 pg/mL; the LOQ values for 8-CH2OH-IQx and IQx-8-COOH were, respectively, <15 and <25 pg/mL, and the LOQ values for the glucuronide conjugates of PhIP and HONH-PhIP were 50 pg/mL. The metabolism was extensive; less than 9% of the dose was eliminated in urine as unaltered MeIQx, and <1% was eliminated as unaltered PhIP. Phase II conjugates of the parent amines accounted for up to 12% of the dose of MeIQx and up to 2% of the dose of PhIP. 8-CH2OH-IQx and IQx-8-COOH accounted for up to 76% of the dose of MeIQx, and the isomeric glucuronide conjugates of HONH-PhIP accounted for up to 33% of the dose of PhIP that were eliminated in urine within 10 h of meat consumption. P450 1A2 significantly contributes to the metabolism of both HAAs but with marked differences in substrate specificity. P450 1A2 primarily catalyzes the detoxification of MeIQx by oxidation of the 8-methyl group, whereas it catalyzes the bioactivation of PhIP by oxidation of the exocyclic amine group.
• Cytochrome P450-Mediated Metabolism and DNA Binding of 2-Amino-1,7-dimethylimidazo[4,5-<i>g</i>]quinoxaline and Its Carcinogenic Isomer 2-Amino-3,8-dimethylimidazo[4,5-<i>f</i>]quinoxaline in Mice
  作者：Robert J. Turesky、Erin E. Bessette、Deborah Dunbar、Rosa G. Liberman、Paul L. Skipper

  DOI：10.1021/tx2004536

  日期：2012.2.20

  2-Amino-1,7-dimethylimidazo[4,5-g]quinoxaline (MeIgQx) is a recently discovered heterocyclic aromatic amine (HAA) that is formed during the cooking of meats. MeIgQx is an isomer of 2-amino-3,8-dimethylmidazo[4,5-f]quinoxaline (MeIQx), a rodent carcinogen and possible human carcinogen that also occurs in cooked meats. MeIgQx is a bacterial mutagen, but knowledge about its metabolism and carcinogenic potential is lacking. Metabolism studies on MeIgQx and MeIQx were conducted with human and mouse liver microsomes, and recombinant human P450s. DNA binding studies were also investigated in mice to ascertain the genotoxic potential of MeIgQx in comparison to MeIQx. Both HAAs underwent comparable rates of N-oxidation to form genotoxic N-hydroxylated metabolites with mouse liver microsomes (0.2-0.3 nmol/min/mg protein). The rate of N-oxidation of MeIQx was 4-fold greater than the rate of N-oxidation of MeIgQx with human liver microsomes (1.7 vs 0.4 nmol/min/mg protein). The rate of N-oxidation, by recombinant human P450 1A2, was comparable for both substrates (6 pmol/min/pmol P450 1A2). MeIgQx also underwent N-oxidation by human P450s 1A1 and 1B1 at appreciable rates, whereas MeIQx was poorly metabolized by these P450s. The potential of MeIgQx and MeIQx to form DNA adducts was assessed in female C57BL/6 mice given [C-14]-MeIgQx (10 mu Ci, 9.68 mg/kg body wt) or [C-14]-MeIQx (10 mu Ci, 2.13 mg/kg body wt). DNA adduct formation in the liver, pancreas, and colorectum was measured by accelerator mass spectrometry at 4, 24, or 48 h post-treatment Variable levels of adducts were detected in all organs. The adduct levels were similar for both HAAs, when adjusted for dose, and ranged from 1 to 600 adducts per 10(7) nudeotides per mg/kg dose. Thus, MeIgQx undergoes metabolic activation and binds to DNA at levels that are comparable to MeIQx. Given the high amounts of MeIgQx formed in cooked meats, further investigations are warranted to assess the carcinogenic potential of this HAA.