methyl 2-methoxy-7-methyl-2-oxo-4,5-dihydro-3H-1,2lambda5-oxaphosphepine-6-carboxylate | 1225020-25-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 英文名称: methyl 2-methoxy-7-methyl-2-oxo-4,5-dihydro-3H-1,2lambda5-oxaphosphepine-6-carboxylate
• 英文别名: methyl 2-methoxy-7-methyl-2-oxo-4,5-dihydro-3H-1,2λ5-oxaphosphepine-6-carboxylate
• CAS: 1225020-25-6
• 化学式: C₉H₁₅O₅P
• 分子量: 234.189
• InChiKey: GYEHUGPUFOMJON-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  61.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl 2-methoxy-7-methyl-2-oxo-4,5-dihydro-3H-1,2lambda5-oxaphosphepine-6-carboxylate 在 18-冠醚-6 、 potassium carbonate 、 sodium iodide 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 反应 48.75h， 生成 methyl 7-methyl-2-octadecoxy-2-oxo-4,5-dihydro-3H-1,2lambda5-oxaphosphepine-6-carboxylate
  参考文献：
  名称：

  Synthesis and Kinetic Evaluation of Cyclophostin and Cyclipostins Phosphonate Analogs As Selective and Potent Inhibitors of Microbial Lipases

  摘要：

  A new series-of customizable diastereomeric cis- and trans-monocyclic enol-phosphonate analogs to Cyclophostin and Cyclipostins were synthesized. Their potencies and mechanisms of inhibition. toward six representative lipolytic enzymes belonging to distinct lipase families Were examined. With Mammalian gastric and pancreatic lipases no inhibition occurred with any of the compounds tested. Conversely, Fusarium solani Cutinase and. lipases from, Mycobacterium tuberculosis (Rv0183 and LipY) were all fully. inactivated. The best inhibitors displayed a cis conformation (H and OMe) and exhibited higher inhibitory activities than the lipase inhibitor Orlistat toward the same enzymes. Our results have revealed that chemical group at the gamma-carbon the phosphonate ring strongly impacts the inhibitory efficiency, leading to a significant improvement in selectivity toward a target lipase over another. The powerful and selective inhibition of microbial (fungal and mycobacterial) lipases suggests that these seven-membered monocyclic enol-phosphonates should provide useful leads for the development of novel and highly selective antimicrobial agents.

  DOI：

  10.1021/jm301216x
• 作为产物：
  描述：

  methyl 2-acetyl-5-(dimethoxyphosphoryl)pent-4-enoate 在 吡啶 、 palladium 10% on activated carbon 、 氢气 、 sodium iodide 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 6.0h， 生成 methyl 2-methoxy-7-methyl-2-oxo-4,5-dihydro-3H-1,2lambda5-oxaphosphepine-6-carboxylate
  参考文献：
  名称：

  [EN] FLUORESCENT LABELED INHIBITORS
  [FR] INHIBITEURS MARQUÉS PAR FLUORESCENCE

  摘要：

  本文提供了一系列荧光标记的膦酸酯和磷酸酯化合物，可用作亲和探针来检测某些酶，包括脂肪酶。同时还提供了制备和使用这些化合物的方法。

  公开号：

  WO2015127381A1

文献信息

• Synthesis and kinetic analysis of some phosphonate analogs of cyclophostin as inhibitors of human acetylcholinesterase
  作者：Supratik Dutta、Raj K. Malla、Saibal Bandyopadhyay、Christopher D. Spilling、Cynthia M. Dupureur

  DOI：10.1016/j.bmc.2010.01.063

  日期：2010.3

  Two new monocyclic analogs of the natural AChE inhibitor cyclophostin and two exocyclic enol phosphates were synthesized. The potencies and mechanisms of inhibition of the bicyclic and monocyclic enol phosphonates and the exocyclic enol phosphates toward human AChE are examined. One diastereoisomer of the bicyclic phosphonate exhibits an IC50 of 3 μM. Potency is only preserved when the cyclic enol

  合成了天然 AChE 抑制剂环磷蛋白的两种新单环类似物和两种环外烯醇磷酸酯。检查了双环和单环烯醇膦酸酯和环外烯醇磷酸酯对人 AChE 的抑制效力和机制。双环膦酸酯的一种非对映异构体的 IC 50为 3 μM。只有当环状烯醇膦酸酯完整并与酯结合时，才能保留效力。动力学分析表明所有活性化合物的结合和缓慢失活步骤。质谱分析表明活性位点 Ser 确实被双环膦酸酯磷酸化。
• Synthesis and Biological Characterization of Fluorescent Cyclipostins and Cyclophostin Analogues: New Insights for the Diagnosis of Mycobacterial-Related Diseases
  作者：Morgane Sarrazin、Benjamin P. Martin、Romain Avellan、Giri Raj Gnawali、Isabelle Poncin、Hugo Le Guenno、Christopher D. Spilling、Jean-François Cavalier、Stéphane Canaan

  DOI：10.1021/acsinfecdis.2c00448

  日期：2022.12.9

  nontuberculous mycobacteria infections, predominantly due to Mycobacterium abscessus, than the healthy population. Because M. abscessus infections are a major cause of clinical decline and morbidity in CF patients, improving treatment and the detection of this mycobacterium in the context of a polymicrobial culture represents a critical component to better manage patient care. We report here the synthesis of fluorescent

  囊性纤维化 (CF) 患者感染非结核分枝杆菌的风险显着高于健康人群，主要由脓肿分枝杆菌引起。由于脓肿分枝杆菌感染是 CF 患者临床衰退和发病的主要原因，因此在多微生物培养背景下改善治疗和检测这种分枝杆菌是更好地管理患者护理的关键组成部分。我们在这里报告了四种活性环磷蛋白和环磷蛋白类似物（ CyC ）的荧光丹酰衍生物的合成，并提供了有关CyC缺乏对抗革兰氏阴性和革兰氏阳性细菌活性的新见解，尤其是它们对抗革兰氏阴性和革兰氏阳性细菌的作用方式。巨噬细胞内脓肿分枝杆菌细胞。我们的结果指出，细胞内活性CyC在巨噬细胞内的酸性区室中积累，这种积累似乎对于将其递送至含有分枝杆菌的吞噬体至关重要，因此，对于其对抗细胞内复制的脓肿分枝杆菌的抗菌作用至关重要，并且修饰通过破坏内溶酶体 pH 值来实现这种细胞内定位会强烈影响CyC 的积累和功效。此外，我们发现这些荧光化合物可以成为有效的探针，以高灵敏度特异性标
• Direct capture, inhibition and crystal structure of <scp>HsaD</scp> (Rv3569c) from <i>M. tuberculosis</i>
  作者：Sarah Barelier、Romain Avellan、Giri Raj Gnawali、Patrick Fourquet、Véronique Roig‐Zamboni、Isabelle Poncin、Vanessa Point、Yves Bourne、Stéphane Audebert、Luc Camoin、Christopher D. Spilling、Stéphane Canaan、Jean‐François Cavalier、Gerlind Sulzenbacher

  DOI：10.1111/febs.16645

  日期：2023.3

  lipid metabolism. Here, we report the synthesis of new CyC alkyne-containing inhibitors (CyCyne) and their use for the direct fishing of target proteins in M. tb culture via bio-orthogonal click-chemistry activity-based protein profiling (CC-ABPP). This approach led to the capture and identification of a variety of enzymes, and many of them involved in lipid or steroid metabolisms. One of the captured enzymes

  结核病病原体结核分枝杆菌( M. tb )的一个特点是其代谢宿主来源的脂质的能力。然而，这种代谢背后的酶和机制仍然很大程度上未知。我们之前报道过环磷蛋白和环后蛋白 ( CyC ) 类似物是一种新的有效抗分枝杆菌分子家族，与主要参与细菌脂质代谢的 (Ser/Cys) 酶发生特异性共价反应。在这里，我们报告了新型CyC炔烃抑制剂 ( CyC yne )的合成，以及它们通过基于生物正交点击化学活性的蛋白质分析 (CC-ABPP)直接捕获结核分枝杆菌培养物中靶蛋白的用途。这种方法导致了多种酶的捕获和鉴定，其中许多酶参与脂质或类固醇代谢。捕获的酶之一 HsaD (Rv3569c) 是结核分枝杆菌在巨噬细胞内生存所必需的，因此是潜在的治疗靶点。这促使我们通过生化和结构方法相结合，进一步探索和验证CyC类似物抑制 HsaD 的特异性。我们证实CyC与催化 Ser 114残基共价结合，导致酶活性完全丧失。这些数据得到了四种
• Synthesis and comparison of the biological activity of monocyclic phosphonate, difluorophosphonate and phosphate analogs of the natural AChE inhibitor cyclophostin
  作者：Benjamin P. Martin、Elena Vasilieva、Cynthia M. Dupureur、Christopher D. Spilling

  DOI：10.1016/j.bmc.2015.10.044

  日期：2015.12

  New monocyclic phosphate, phosphonate and difluorophosphonate analogs of the natural AChE inhibitor cyclophostin were synthesized and their activity toward human AChE examined. Surprisingly, the phosphate, phosphonate, and difluorophosphonate analogs all showed diminished activity when compared with the natural product. (C) 2015 Elsevier Ltd. All rights reserved.
• Synthesis and Kinetic Evaluation of Cyclophostin and Cyclipostins Phosphonate Analogs As Selective and Potent Inhibitors of Microbial Lipases
  作者：Vanessa Point、Raj K. Malla、Sadia Diomande、Benjamin P. Martin、Vincent Delorme、Frederic Carriere、Stephane Canaan、Nigam P. Rath、Christopher D. Spilling、Jean−François Cavalier

  DOI：10.1021/jm301216x

  日期：2012.11.26

  A new series-of customizable diastereomeric cis- and trans-monocyclic enol-phosphonate analogs to Cyclophostin and Cyclipostins were synthesized. Their potencies and mechanisms of inhibition. toward six representative lipolytic enzymes belonging to distinct lipase families Were examined. With Mammalian gastric and pancreatic lipases no inhibition occurred with any of the compounds tested. Conversely, Fusarium solani Cutinase and. lipases from, Mycobacterium tuberculosis (Rv0183 and LipY) were all fully. inactivated. The best inhibitors displayed a cis conformation (H and OMe) and exhibited higher inhibitory activities than the lipase inhibitor Orlistat toward the same enzymes. Our results have revealed that chemical group at the gamma-carbon the phosphonate ring strongly impacts the inhibitory efficiency, leading to a significant improvement in selectivity toward a target lipase over another. The powerful and selective inhibition of microbial (fungal and mycobacterial) lipases suggests that these seven-membered monocyclic enol-phosphonates should provide useful leads for the development of novel and highly selective antimicrobial agents.