寡霉素A | 579-13-5

• 物质功能分类: 原料药 - 抗生素类药物 - 其它抗生素类药
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯类和类似物
• 中文名称: 寡霉素A
• 中文别名: 氯化芍药素
• 英文名称: oligomycin A
• 英文别名: oligomycin；(1R,4E,5'S,6S,6'S,7R,8S,10R,11R,12S,14R,15S,16R,18E,20E,22R,25S,27R,28S,29R)-22-ethyl-7,11,14,15-tetrahydroxy-6'-[(2R)-2-hydroxypropyl]-5',6,8,10,12,14,16,28,29-nonamethylspiro[2,26-dioxabicyclo[23.3.1]nonacosa-4,18,20-triene-27,2'-oxane]-3,9,13-trione
• CAS: 579-13-5
• 化学式: C₄₅H₇₄O₁₁
• 分子量: 791.076
• InChiKey: MNULEGDCPYONBU-AWJDAWNUSA-N

物化性质

• 熔点：
  150-151℃
• 沸点：
  886.3±65.0 °C(Predicted)
• 密度：
  1.14
• 溶解度：
  溶于DMSO、乙醇或丙酮

计算性质

• 辛醇/水分配系数(LogP)：
  7.1
• 重原子数：
  56
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  180
• 氢给体数：
  5
• 氢受体数：
  11

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  Xn,T
• 安全说明：
  S36/37
• 危险类别码：
  R22,R20/21/22,R68/20/21/22
• WGK Germany：
  3
• 海关编码：
  29419090
• 包装等级：
  III
• 危险类别：
  6.1(b)
• 危险品运输编号：
  UN 2811

制备方法与用途

生物活性

Oligomycin A (MCH 32) 是一种ATP合成酶抑制剂，作用于线粒体膜的耦合过程，能够抑制氧化磷酸化和所有ATP依赖性反应。

靶点

Target	Value
ATP合成酶	（细胞裂解物实验）

体外研究

Oligomycin A 是一种ATP合成酶的抑制剂，能够抑制氧化磷酸化及所有发生在线粒体内膜上的ATP依赖性过程。该化合物通过阻断其质子通道（Fo亚基），从而抑制ATP的生成；这对ADP通过氧化磷酸化转化为ATP是必要的。Oligomycin A对ATP合成的抑制会显著降低电子传递链中的电子流，尽管由于质子泄漏或线粒体解偶联过程，电子流不会完全停止。在一组癌细胞中，100纳克/毫升的Oligomycin在1小时内可完全抑制氧化磷酸化活性，并且在6小时后引起不同程度的糖酵解。此外，在黑色素瘤中，Oligomycin能够抑制线粒体呼吸作用，使其对治疗更加敏感，并阻断慢循环、长期肿瘤维持所需的慢生长黑色素瘤细胞的出现。

反应信息

• 作为反应物：
  描述：

  寡霉素A 在 potassium fluoride 、 1,3-双(2,6-二异丙苯基)-2,2-二氟-2,3-二氢-1H-咪唑 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以70%的产率得到33-epi-33-fluoro-33-deoxyoligomycin A
  参考文献：
  名称：

  Late-Stage Deoxyfluorination of Alcohols with PhenoFluor

  摘要：

  An operationally simple protocol for the selective deoxyfluorination of structurally complex alcohols is presented. Several fluorinated derivatives of natural products and pharmaceuticals have been prepared to showcase the potential of the method for late-stage diversification and its functional group compatibility. A series of simple guidelines for predicting the selectivity in substrates with multiple alcohols is given.

  DOI：

  10.1021/ja3125405
• 作为产物：
  描述：

  C₄₅H₇₆O₁₂ 在 OlmO from Streptomyces avermectinius VL₁₀₀₁ 作用下， 以 aq. buffer 为溶剂， 反应 1.0h， 生成 寡霉素A
  参考文献：
  名称：

  聚酮类抗生素生物合成中的酶催化螺缩醛形成

  摘要：

  许多聚酮化合物的生物合成中的一个关键步骤是螺缩醛（螺缩酮）的立体定向形成。我们在此报告大环聚酮化合物骨霉素和寡霉素的生物合成中的螺缩醛形成涉及新型螺缩醛环化酶的催化。来自骨霉素生物合成基因簇 (BGC) 的 OssO 与 OlmO 同源，OlmO 是寡霉素 BGC 的未注释基因的产物。删除olmO消除了寡霉素的产生并导致分离出缺乏螺缩醛结构的寡霉素样代谢物。纯化的OlmO 催化主要代谢物完全转化为寡霉素C。OssO 和OlmO 的晶体结构揭示了一个不寻常的10 链β-桶。三个保守的极性残基在 β-桶形腔中聚集在一起，并且这些残基中的任何一个的位点特异性突变都消除或大大降低了 OlmO 活性，支持一般酸/一般碱催化在螺缩醛形成中的作用。

  DOI：

  10.1021/jacs.2c03313

文献信息

• The first examples of chemical modification of oligomycin A
  作者：Lyudmila N Lysenkova、Konstantin F Turchin、Valery N Danilenko、Alexander M Korolev、Maria N Preobrazhenskaya

  DOI：10.1038/ja.2009.112

  日期：2010.1

  The first examples of chemical modification of antibiotic oligomycin A are described. The interaction of oligomycin A with hydroxylamine yielded six-membered nitrone annelated with the antibiotic at the positions 3,4,5,6,7. The reaction with 1-aminopyridinium iodide in pyridine led to pyrazolo[1,5-a]pyridine conjugated with the antibiotic at the positions 2 and 3 (product of addition to the C2–C3 double bond followed by spontaneous oxidation). The structures of the compounds obtained were supported by NMR and mass spectrometry methods including the 15N-labeling of compounds.

  本文描述了抗生素寡霉素A的化学修饰的首批实例。寡霉素A与羟胺的相互作用产生了六元氮酮，该氮酮在3、4、5、6、7位与抗生素环化。在吡啶中与1-氨基吡啶鎓碘化物的反应产生了吡唑并[1,5-a]吡啶，该化合物在2和3位与抗生素共轭（C2-C3双键加成产物，随后发生自发氧化）。所获得化合物的结构得到了核磁共振和质谱分析方法的支持，包括化合物的15N标记。
• Stereochemistries and Biological Properties of Oligomycin A Diels–Alder Adducts
  作者：Olga A. Omelchuk、Vadim I. Malyshev、Michael G. Medvedev、Lyudmila N. Lysenkova、Nikita M. Belov、Lyubov G. Dezhenkova、Natalia E. Grammatikova、Alexander M. Scherbakov、Andrey E. Shchekotikhin

  DOI：10.1021/acs.joc.1c00296

  日期：2021.6.18

  the carbonyl group of the dienophile. Biological studies showed that the Diels–Alder modification of the Oligomycin A diene system resulted in a complex antiproliferative potential pattern. The synthesized adducts were determined to be more active against the triple-negative (ERα, PR, and HER2 negative) breast cancer cell line MDA-MB-231 and lung carcinoma cell line A-549 compared to Oligomycin A. Meanwhile

  Oligomycin A 是一种有效的抗生素和抗肿瘤剂。然而，其高毒性和低生物利用度限制了其应用。在本研究中，我们获得了具有苯醌和N-苄基马来酰亚胺的 Oligomycin A Diels-Alder 加合物，并通过结合1具有分子力学构象分析和量子化学反应建模的 H 和 ROESY NMR 数据。后者表明加合物立体化学受 Oligomycin A 侧链异丙醇部分与亲二烯体羰基的氢键控制。生物学研究表明，Oligomycin A 二烯系统的 Diels-Alder 修饰导致了复杂的抗增殖潜力模式。与 Oligomycin A 相比，合成的加合物对三阴性（ERα、PR 和 HER2 阴性）乳腺癌细胞系 MDA-MB-231 和肺癌细胞系 A-549 的活性更高。同时，Oligomycin A 是比其衍生物更有效地对抗髓性白血病细胞系 K-562 和乳腺癌细胞系 MCF-7。因此，
• Antiplasmodial compounds
  申请人：UNIVERSITY OF CENTRAL FLORIDA RESEARCH FOUNDATION, INC.

  公开号：US11230569B2

  公开（公告）日：2022-01-25

  Novel compositions and methods for the treatment and prevention of malaria are disclosed herein.

  本文公开了用于治疗和预防疟疾的新型组合物和方法。
• Synthesis, antimicrobial and antiproliferative properties of epi-oligomycin A, the (33<i>S</i>)-diastereomer of oligomycin A
  作者：Lyudmila N. Lysenkova、Oleg Y. Saveljev、Olga A. Omelchuk、George V. Zatonsky、Alexander M. Korolev、Natalya E. Grammatikova、Olga B. Bekker、Valery N. Danilenko、Lyubov G. Dezhenkova、Dilara A. Mavletova、Alexander M. Scherbakov、Andrey E. Shchekotikhin

  DOI：10.1080/14786419.2019.1608540

  日期：2020.11.1

  We describe the synthesis of epi-oligomycin A, a (33S)-diastereomer of the antibiotic oligomycin A. The structure of (33S)-oligomycin A was determined by elemental analysis, spectroscopic studies, including 1D and 2D NMR spectroscopy, and mass spectrometry. Isomerization of C33 hydroxyl group led to minor changes in the potency against Aspergillus niger, Candida spp., and filamentous fungi whereas the activity against Streptomyces fradiae decreased by approximately 20-fold compared to oligomycin A. We observed that 33-epi-oligomycin A had the same activity on the human leukemia cell line K562 as oligomycin A but was more potent for the multidrug resistant subline K562/4. Non-malignant cells were less sensitive to both oligomycin isomers. Finally, our results pointed at the dependence of the cytotoxicity of oligomycins on oxygen supply.
• Functional characterization of CYP107W1 from Streptomyces avermitilis and biosynthesis of macrolide oligomycin A
  作者：Songhee Han、Tan-Viet Pham、Joo-Hwan Kim、Young-Ran Lim、Hyoung-Goo Park、Gun-Su Cha、Chul-Ho Yun、Young-Jin Chun、Lin-Woo Kang、Donghak Kim

  DOI：10.1016/j.abb.2015.03.025

  日期：2015.6

  Streptomyces avermitilis contains 33 cytochrome P450 genes in its genome, many of which play important roles in the biosynthesis process of antimicrobial agents. Here, we characterized the biochemical function and structure of CYP107W1 from S. avermitilis, which is responsible for the 12-hydroxylation reaction of oligomycin C. CYP107W1 was expressed and purified from Escherichia coli.. Purified proteins exhibited the typical CO-binding spectrum of P450. Interaction of oligomycin C and oligomycin A (12-hydroxylated oligomycin C) with purified CYP107W1 resulted in a type I binding with K-d values of 14.4 +/- 0.7 mu M and 2.0 +/- 0.1 mu M, respectively. LC-mass spectrometry analysis showed that CYP107W1 produced oligomycin A by regioselectively hydroxylating C12 of oligomycin C. Steady-state kinetic analysis yielded a k(cat) value of 0.2 min(-1) and a K-m value of 18 mu M. The crystal structure of CYP107W1 was determined at 2.1 angstrom resolution. The overall P450 folding conformations are well conserved, and the open access binding pocket for the large macrolide oligomycin C was observed above the distal side of heme. This study of CYP107W1 can help a better understanding of clinically important P450 enzymes as well as their optimization and engineering for synthesizing novel antibacterial agents and other pharmaceutically important compounds. (C) 2015 Elsevier Inc. All rights reserved.