(S)-N-methylcanadine | 690949-61-2

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 原小檗碱生物碱及其衍生物
• 英文名称: (S)-N-methylcanadine
• 英文别名: (1S)-16,17-dimethoxy-13-methyl-5,7-dioxa-13-azoniapentacyclo[11.8.0.02,10.04,8.015,20]henicosa-2,4(8),9,15(20),16,18-hexaene
• CAS: 690949-61-2
• 化学式: C₂₁H₂₄NO₄
• 分子量: 354.426
• InChiKey: IPABSWBNWMXCHM-LBOXEOMUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  36.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-N-methylcanadine 在 CYP₈₂X₂ 、 CYP₈₂Y₁ 、 还原型辅酶II(NADPH)四钠盐 作用下， 以 aq. buffer 为溶剂， 反应 0.83h， 生成 1,13-dihydroxy-N-methylcanadine
  参考文献：
  名称：

  [EN] COMPOSITIONS AND METHODS FOR MAKING NOSCAPINE AND SYNTHESIS INTERMEDIATES THEREOF
  [FR] COMPOSITIONS ET PROCÉDÉS DE FABRICATION DE NOSCAPINE ET D'INTERMÉDIAIRES DE SYNTHÈSE DE CELLE-CI

  摘要：

  制备治疗化合物诺斯卡平和诺斯卡平合成中间体的方法包括将选自第一类肉桂碱衍生物、第一类罂粟碱衍生物和纳科汀半缩醛的诺斯卡平途径前体与来自CYP82Y1、CYP82X1、AT1、CYP82X2、OMT、CXE1和NOS组中至少一种酶中的至少一种接触。

  公开号：

  WO2015021561A1
• 作为产物：
  描述：

  坎那定; 氢化小蘖碱 、 S-腺苷蛋氨酸 生成 (S)-N-methylcanadine 、 S-(5'-腺苷)-L-高半胱氨酸
  参考文献：
  名称：

  四氢原小ization碱顺式-N-甲基转移酶的分子克隆和表征，该酶参与罂粟生物碱的生物合成。

  摘要：

  S-腺苷-1-甲硫氨酸：四氢小ber碱顺式-N-甲基转移酶（EC 2.1.1.122）催化将（S）-stylopine转化为季铵生物碱（S）-cis-N-甲基stylopine，这是关键步骤生物碱在植物中的生物合成 在诱导剂处理的罂粟细胞培养物表达的序列标签数据库中鉴定了全长cDNA，该cDNA编码的蛋白质分别与罂粟和黄连的coclaurine N-甲基转移酶表现出45％和48％的氨基酸同一性。系统发育分析表明，该蛋白质属于独特的酶进化枝，包括椰菜碱N-甲基转移酶，拟南芥基因At4g33110和At4g33120的谓词翻译产物，和细菌S-腺苷-L-蛋氨酸依赖性环丙烷脂肪酸合酶。cDNA在大肠杆菌中的表达产生了一种重组酶，该酶能够将原小al碱生物碱苯乙烯，Canadine和tetrahydropalmatine转化为其相应的N-甲基化衍生物。然而，原小ber碱生物碱四羟基小b碱和苦参碱，以及

  DOI：

  10.1074/jbc.m611908200

文献信息

• Targeted metabolite and transcript profiling for elucidating enzyme function: isolation of novel <i>N‐</i>methyltransferases from three benzylisoquinoline alkaloid‐producing species
  作者：David K. Liscombe、Jörg Ziegler、Jürgen Schmidt、Christian Ammer、Peter J. Facchini

  DOI：10.1111/j.1365-313x.2009.03980.x

  日期：2009.11

  An integrated approach using targeted metabolite profiles and modest EST libraries each containing approximately 3500 unigenes was developed in order to discover and functionally characterize novel genes involved in plant‐specialized metabolism. EST databases have been established for benzylisoquinoline alkaloid‐producing cell cultures of Eschscholzia californica, Papaver bracteatum and Thalictrum flavum, and are a rich repository of alkaloid biosynthetic genes. ESI‐FTICR‐MS and ESI‐MS/MS analyses facilitated unambiguous identification and relative quantification of the alkaloids in each system. Manual integration of known and candidate biosynthetic genes in each EST library with benzylisoquinoline alkaloid biosynthetic networks assembled from empirical metabolite profiles allowed identification and functional characterization of four N‐methyltransferases (NMTs). One cDNA from T. flavum encoded pavine N‐methyltransferase (TfPavNMT), which showed a unique preference for (±)‐pavine and represents the first isolated enzyme involved in the pavine alkaloid branch pathway. Correlation of the occurrence of specific alkaloids, the complement of ESTs encoding known benzylisoquinoline alkaloid biosynthetic genes and the differential substrate range of characterized NMTs demonstrated the feasibility of bilaterally predicting enzyme function and species‐dependent specialized metabolite profiles.

  摘要 为了发现参与植物特化代谢的新基因并确定其功能特征，我们开发了一种综合方法，利用目标代谢物图谱和适度的EST文库（每个文库包含约3500个单体基因）。已经建立了苄基异喹啉生物碱生产细胞培养物的 EST 数据库，这些细胞培养物包括 Eschscholzia californica、Papaver bracteatum 和 Thalictrum flavum，它们是生物碱生物合成基因的丰富宝库。ESI-FTICR-MS 和 ESI-MS/MS 分析有助于对每个系统中的生物碱进行明确鉴定和相对定量。将每个 EST 文库中的已知和候选生物合成基因与根据经验代谢物图谱组装的苄基异喹啉生物碱生物合成网络进行人工整合，可以鉴定出 4 个 N-甲基转移酶（NMT）并确定其功能特征。其中一个来自 T. flavum 的 cDNA 编码了帕维因 N-甲基转移酶（TfPavNMT），该酶对 (±)- 帕维因有独特的偏好，代表了参与帕维因生物碱分支途径的第一个分离酶。特定生物碱的出现、编码已知苄基异喹啉生物碱生物合成基因的ESTs的补充以及特征NMTs的不同底物范围之间的相关性证明了双边预测酶功能和依赖物种的特殊代谢物特征的可行性。
• Complete biosynthesis of noscapine and halogenated alkaloids in yeast
  作者：Yanran Li、Sijin Li、Kate Thodey、Isis Trenchard、Aaron Cravens、Christina D. Smolke

  DOI：10.1073/pnas.1721469115

  日期：2018.4.24

  over 30 enzymes from plants, bacteria, mammals, and yeast itself, including 7 plant endoplasmic reticulum (ER)-localized enzymes. Optimization directed to tuning expression of pathway enzymes, host endogenous metabolic pathways, and fermentation conditions led to an over 18,000-fold improvement from initial noscapine titers to ∼2.2 mg/L. By feeding modified tyrosine derivatives to the optimized noscapine-producing

  从简单的构建模块微生物生物合成植物天然产物是实现高价值化合物的大规模生产和修饰的一种有前景的方法。最近，从罂粟中生物合成诺斯卡品（一种潜在的抗癌化合物）的途径被阐明为一个 10 基因簇。在这里，我们展示了在酿酒酵母中从头生产那斯卡品，通过重建生物合成途径，该途径包含来自植物、细菌、哺乳动物和酵母本身的 30 多种酶，其中包括 7 种植物内质网 (ER) 定位酶。针对途径酶表达、宿主内源代谢途径和发酵条件进行优化，使那可品滴度从最初的滴度提高了 18,000 倍以上，达到约 2.2 mg/L。通过将修饰的酪氨酸衍生物喂入优化的那可品生产菌株中，我们进一步证明了卤化苄基异喹啉生物碱的微生物生产。这项工作凸显了微生物生物合成平台支持合成有价值的新型生物碱化合物的潜力，这可以促进基于生物碱的药物发现和开发。
• CYP82Y1 Is N-Methylcanadine 1-Hydroxylase, a Key Noscapine Biosynthetic Enzyme in Opium Poppy
  作者：Thu-Thuy T. Dang、Peter J. Facchini

  DOI：10.1074/jbc.m113.505099

  日期：2014.1

  to noscapine have not been identified. We report the isolation and characterization of the cytochrome P-450 CYP82Y1, which catalyzes the 1-hydroxylation of N-methylcanadine to 1-hydroxy-N-methylcanadine. Comparison of transcript and metabolite profiles of eight opium poppy chemotypes revealed four cytochrome P-450s, three from the CYP82 and one from the CYP719 families, that were tightly correlated

  Noscapine 是一种苯酞异喹啉生物碱，因其有效的药理特性而被研究。尽管在一个多世纪前就已在结构上阐明，但尚未建立那可丁的生物合成。放射性示踪剂研究表明，那可品来源于原小檗碱生物碱 (S)-scoulerine，并已提议通过 (S)-N-methylcanadine 进行处理。然而，尚未确定参与将 N-甲基卡那丁转化为那可丁的途径中间体。我们报告了细胞色素 P-450 CYP82Y1 的分离和表征，该细胞色素 P-450 CYP82Y1 催化 N-甲基卡那丁的 1-羟基化为 1-羟基-N-甲基卡那丁。八种罂粟化学型的转录物和代谢物谱的比较揭示了四种细胞色素 P-450，三种来自 CYP82，一种来自 CYP719 家族，与那可丁的积累密切相关。重组 CYP82Y1 是唯一接受 (R,S)-N-methylcanadine 作为底物的酶，具有严格的特异性和高亲和力。正如预期的那样，CYP82Y1
• Compositions and methods for making noscapine and synthesis intermediates thereof
  申请人：Willow BioSciences Inc.

  公开号：US10793885B2

  公开（公告）日：2020-10-06

  Methods for the manufacture of the therapeutic chemical compound noscapine and noscapine synthesis intermediates comprising contacting a noscapine pathway precursor selected from a first canadine derivative, a first papaveroxine derivative and narcotine hemiacetal with at least one of the enzymes selected from the group CYP82Y1, CYP82X1, AT1, CYP82X2, OMT, CXE1 and NOS.

  生产治疗用化学合成物诺卡平和诺卡平合成中间体的方法，包括将选自第一卡那定衍生物、第一罂粟碱衍生物和麻醉品半缩醛的诺卡平途径前体与选自CYP82Y1、CYP82X1、AT1、CYP82X2、OMT、CXE1和NOS组的至少一种酶接触。
• Isolation and characterization of a cDNA encoding (S)-cis-N-methylstylopine 14-hydroxylase from opium poppy, a key enzyme in sanguinarine biosynthesis
  作者：Guillaume A.W. Beaudoin、Peter J. Facchini

  DOI：10.1016/j.bbrc.2012.12.129

  日期：2013.2

  Sanguinarine is a benzo[c]phenenthridine alkaloid with potent antimicrobial properties found commonly in plants of the Papaveraceae, including the roots of opium poppy (Papaver somniferum). Sanguinarine is formed from the central 1-benzylisoquinoline intermediate (S)-reticuline via the protoberberine alkaloid (S)-scoulerine, which undergoes five enzymatic oxidations and an N-methylation. The first four oxidations from (S)-scoulerine are catalyzed by cytochromes P450, whereas the final conversion involves a flavoprotein oxidase. All but gine gene in the biosynthetic pathway from (S)-reticuline to sanguinarine has been identified. In this communication, we report the isolation and characterization of (S)-cis-N-methylstylopine 14-hydroxylase (MSH) from opium poppy based on the transcriptional induction in elicitor-treated cell suspension cultures and root-specific expression of the corresponding gene. Along with protopine 6-hydroxylase, which catalyzes the subsequent and penultimate step in sanguinarine biosynthesis, MSH is a member of the CYP82N subfamily of cytochromes P450. The full-length MSH cDNA was expressed in Saccharomyces cerevisiae and the recombinant microsomal protein was tested for enzymatic activity using 25 benzylisoquinoline alkaloids representing a wide range of structural subgroups. The only enzymatic substrates were the N-methylated protoberberine alkaloids N-methylstylopine and N-methylcanadine, which were converted to protopine and allocryptopine, respectively. (C) 2013 Published by Elsevier Inc.