mycocyclosin | 1373441-32-7

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: mycocyclosin
• 英文别名: (1S,14S)-6,9-dihydroxy-15,17-diazatetracyclo[12.2.2.13,7.18,12]icosa-3(20),4,6,8,10,12(19)-hexaene-16,18-dione
• CAS: 1373441-32-7
• 化学式: C₁₈H₁₆N₂O₄
• 分子量: 324.336
• InChiKey: PYDUENRHWXNYLP-KBPBESRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  24
• 可旋转键数：
  0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  98.7
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  L-酪氨酸 在 ammonium hydroxide 、 甲酸 、 氯化亚砜 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 五甲基苯 、 碘 、 potassium carbonate 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 、 三氟乙酸 、 联硼酸频那醇酯 作用下， 以 乙醇 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 73.0h， 生成 mycocyclosin
  参考文献：
  名称：

  Total Synthesis of Mycocyclosin

  摘要：

  The first total synthesis of mycocyclosin, a diketopiperazine natural product isolated from M. tuberculosis, is described. While direct oxidative coupling of tyrosine phenolic groups was unsuccessful, construction of the highly strained bicyclic framework was successfully accomplished through an intramolecular Miyaura-Suzuki cross-coupling to generate the biaryl linkage.

  DOI：

  10.1021/ol300831t

文献信息

• Scalable Synthesis of Mycocyclosin
  作者：Xu Zhu、Christopher C. McAtee、Corinna S. Schindler

  DOI：10.1021/acs.orglett.8b00894

  日期：2018.5.18

  We report herein the scalable total synthesis of the secondary metabolite, mycocyclosin, initially isolated from Mycobacterium tuberculosis. Mycocylosin bears a highly strained 3,3′-dityrosine biaryl system which arises biosynthetically from an intramolecular oxidative dehydrogenative cross-coupling of cyclo(l-Tyr-l-Tyr) (cYY) catalyzed by the P450 enzyme CYP121. CYP121 is found exclusively in M. tuberculosis

  我们在这里报告了最初从结核分枝杆菌中分离出来的次要代谢产物麦考环素的可扩展总合成方法。Mycocylosin带有一个高度应变3,3'-联芳基dityrosine系统，其从一个分子内氧化性生物合成产生脱氢交叉耦合环的（升-Tyr-升-Tyr）（CYY）由P450酶CYP121催化。CYP121仅在结核分枝杆菌中发现。通过Pd（II）催化的大环化，可扩展获得麦考环素和相关衍生物的途径，有望促进这些化合物作为新型结核病抗微生物剂的生物学评估。
• Substrate-Assisted Hydroxylation and <i>O</i>-Demethylation in the Peroxidase-like Cytochrome P450 Enzyme CYP121
  作者：Romie C. Nguyen、Yu Yang、Yifan Wang、Ian Davis、Aimin Liu

  DOI：10.1021/acscatal.9b04596

  日期：2020.1.17

  spectroscopies and X-ray crystallography. We found that cYF-4-OMe can function as a substrate of CYP121 using the established assay via the peroxide shunt. Analysis of the enzymatic reaction revealed an O-demethylation of cYF-4-OMe instead of cyclization, yielding cYY and formaldehyde. A hydroxylated substrate, cYF-4-OMeOH, is expected to be the intermediate product, which was trapped and structurally characterized

  CYP121是一种来自结核分枝杆菌的P450酶，可催化其天然底物环（1-Tyr-1-Tyr）（cYY）上两个芳香环之间的CC偶联反应，从而形成细胞存活所必需的产品Mycocyclosin。与典型的P450羟化酶不同，CYP121的行为像过氧化物酶一样，并能进行自由基介导的CC键形成。在这里，我们探讨了底物的酚氢是否是假定的氢原子抽象为自由基形成的位点。我们合成了一个单独的O-甲基化底物类似物cYF-4-OMe，并通过紫外可见和电子顺磁共振光谱法和X射线晶体学表征了其与CYP121的相互作用。我们发现使用过氧化物分流器建立的测定法可将cYF-4-OMe用作CYP121的底物。酶促反应的分析显示cYF-4-OMe的O-去甲基化而不是环化，产生cYY和甲醛。预期羟基化的底物cYF-4-OMeOH是中间产物，其被捕获并通过X射线晶体学对其结构进行了表征。我们进一步确定，通过18O标记研究，cYF-
• Identification and structural basis of the reaction catalyzed by CYP121, an essential cytochrome P450 in <i>Mycobacterium tuberculosis</i>
  作者：Pascal Belin、Marie Hélène Le Du、Alistair Fielding、Olivier Lequin、Mickaël Jacquet、Jean-Baptiste Charbonnier、Alain Lecoq、Robert Thai、Marie Courçon、Cédric Masson、Christophe Dugave、Roger Genet、Jean-Luc Pernodet、Muriel Gondry

  DOI：10.1073/pnas.0812191106

  日期：2009.5.5

  The gene encoding the cytochrome P450 CYP121 is essential for Mycobacterium tuberculosis . However, the CYP121 catalytic activity remains unknown. Here, we show that the cyclodipeptide cyclo(l-Tyr-l-Tyr) (cYY) binds to CYP121, and is efficiently converted into a single major product in a CYP121 activity assay containing spinach ferredoxin and ferredoxin reductase. NMR spectroscopy analysis of the reaction product shows that CYP121 catalyzes the formation of an intramolecular C-C bond between 2 tyrosyl carbon atoms of cYY resulting in a novel chemical entity. The X-ray structure of cYY-bound CYP121, solved at high resolution (1.4 Å), reveals one cYY molecule with full occupancy in the large active site cavity. One cYY tyrosyl approaches the heme and establishes a specific H-bonding network with Ser-237, Gln-385, Arg-386, and 3 water molecules, including the sixth iron ligand. These observations are consistent with low temperature EPR spectra of cYY-bound CYP121 showing a change in the heme environment with the persistence of the sixth heme iron ligand. As the carbon atoms involved in the final C-C coupling are located 5.4 Å apart according to the CYP121-cYY complex crystal structure, we propose that C-C coupling is concomitant with substrate tyrosyl movements. This study provides insight into the catalytic activity, mechanism, and biological function of CYP121. Also, it provides clues for rational design of putative CYP121 substrate-based antimycobacterial agents.

  编码细胞色素P450 CYP121的基因对结核分枝杆菌至关重要，然而CYP121的催化活性仍然未知。本文表明，环二肽环(cYY)与CYP121结合，并在含菠菜铁蛋白和铁蛋白还原酶的CYP121活性测定中被有效转化为单一主要产物。反应产物的NMR光谱分析表明，CYP121催化cYY的两个酪氨酸碳原子之间形成一个分子内的C-C键，从而形成一种新的化学实体。cYY结合CYP121的X射线结构在高分辨率(1.4Å)下解析，显示一个cYY分子在大的活性位点腔中具有完全占据。一个cYY酪氨酸接近血红素并与Ser-237、Gln-385、Arg-386和3个水分子(包括第六个铁配体)建立了特定的氢键网络。这些观察结果与cYY结合CYP121的低温EPR光谱一致，显示血红素环境发生了变化，第六个血红素铁配体仍然存在。由于CYP121-cYY复合物晶体结构中参与最终C-C偶联的碳原子相距5.4Å，因此我们提出C-C偶联与底物酪氨酸运动同时进行。本研究为了解CYP121的催化活性、机制和生物学功能提供了洞察，同时为理性设计假定的基于CYP121底物的抗分枝杆菌药物提供了线索。
• Total Synthesis of Mycocyclosin
  作者：James R. Cochrane、Jonathan M. White、Uta Wille、Craig A. Hutton

  DOI：10.1021/ol300831t

  日期：2012.5.4

  The first total synthesis of mycocyclosin, a diketopiperazine natural product isolated from M. tuberculosis, is described. While direct oxidative coupling of tyrosine phenolic groups was unsuccessful, construction of the highly strained bicyclic framework was successfully accomplished through an intramolecular Miyaura-Suzuki cross-coupling to generate the biaryl linkage.