(2E)-3-(3-bromo-4-hydroxyphenyl)-2-[(oxan-2-yloxy)imino]-propanoic Acid

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: (2E)-3-(3-bromo-4-hydroxyphenyl)-2-[(oxan-2-yloxy)imino]-propanoic Acid
• 英文别名: (E)-3-(3-bromo-4-hydroxyphenyl)-2-{[(tetrahydro-2H-pyran-2-yl)oxy]imino}propanoic acid；(2E)-3-(3-bromo-4-hydroxyphenyl)-2-(oxan-2-yloxyimino)propanoic acid
• 化学式: C₁₄H₁₆BrNO₅
• 分子量: 358.189
• InChiKey: VATRKDOFAKHTDJ-LFIBNONCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  88.4
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2E)-3-(3-bromo-4-hydroxyphenyl)-2-[(oxan-2-yloxy)imino]-propanoic Acid 在 盐酸 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醚 、 二氯甲烷 为溶剂， 反应 6.0h， 生成 帕马普林A
  参考文献：
  名称：

  New synthetic strategies towards psammaplin A, access to natural product analogues for biological evaluation

  摘要：

  开发了新的合成路线以制备天然产物海绵抑素A（psammaplin A）及其多样化的类似物，这些类似物用于生物学评估。这些路线采用廉价且商业可获得的起始原料，并能合成目前报道方法难以获得的psammaplin A类似物。初步生物学研究表明，这些化合物是目前所发现的最强效的非肽类组蛋白去乙酰化酶1（HDAC1，I类）抑制剂。有趣的是，psammaplin A及其我们的合成类似物在体外显示出I类选择性，这对于设计和合成未来同工型选择性抑制剂具有重要意义。

  DOI：

  10.1039/c0ob00824a
• 作为产物：
  描述：

  3-溴-4-羟基苯甲醛 在 吡啶 、 盐酸 、 水 、 sodium acetate 作用下， 反应 3.0h， 生成 (2E)-3-(3-bromo-4-hydroxyphenyl)-2-[(oxan-2-yloxy)imino]-propanoic Acid
  参考文献：
  名称：

  New synthetic strategies towards psammaplin A, access to natural product analogues for biological evaluation

  摘要：

  开发了新的合成路线以制备天然产物海绵抑素A（psammaplin A）及其多样化的类似物，这些类似物用于生物学评估。这些路线采用廉价且商业可获得的起始原料，并能合成目前报道方法难以获得的psammaplin A类似物。初步生物学研究表明，这些化合物是目前所发现的最强效的非肽类组蛋白去乙酰化酶1（HDAC1，I类）抑制剂。有趣的是，psammaplin A及其我们的合成类似物在体外显示出I类选择性，这对于设计和合成未来同工型选择性抑制剂具有重要意义。

  DOI：

  10.1039/c0ob00824a

文献信息

• Synthesis and biological activity of selenopsammaplin A and its analogues as antitumor agents with DOT1L inhibitory activity
  作者：Hae Ju Han、Woong Sub Byun、Gyu Ho Lee、Won Kyung Kim、Kyungkuk Jang、Sehun Yang、Jewon Yang、Min Woo Ha、Suckchang Hong、Jeeyeon Lee、Jongheon Shin、Ki Bong Oh、Sang Kook Lee、Hyeung-geun Park

  DOI：10.1016/j.bmc.2021.116072

  日期：2021.4

  cells and inhibitory activity toward DOT1L for antitumor potential. All synthetic selenopsammaplin A analogues exhibited the higher cytotoxicity compared to psammaplin A with up to 6 – 60 times depending on cancer cells, and most analogues showed significant inhibitory activities against DOT1L. Among the prepared analogues, the phenyl analogue (10) possessed the most potent activity with both cytotoxicity

  Disruptor of telomer silencing-1 like (DOT1L) 是一种组蛋白 H3 甲基转移酶，可特异性催化组蛋白 H3 赖氨酸 79 残基的甲基化。最近的研究结果表明，DOT1L 异常过度表达，而上调的 DOT1L 引起人乳腺癌细胞的增殖和转移。因此，DOT1L 抑制剂被认为是治疗乳腺癌的一种有前景的策略。本研究首次报道了非核苷 DOT1L 抑制剂 selenopsammaplin A 及其类似物。Selenopsammaplin A 是新设计和合成的，由 3-bromo-4-hydroxybenzaldahyde 分 8 步以 25% 的总产率合成，并制备了 13 个 selenopsammaplin A 类似物，用于研究它们对癌细胞的细胞毒性和对 DOT1L 的抑制活性的构效关系研究。抗肿瘤潜力。与 psammaplin A 相比，所有合成的 selenopsammaplin
• An Unusual Natural Product Primary Sulfonamide: Synthesis, Carbonic Anhydrase Inhibition, and Protein X-ray Structures of Psammaplin C
  作者：Prashant Mujumdar、Kanae Teruya、Kathryn F. Tonissen、Daniela Vullo、Claudiu T. Supuran、Thomas S. Peat、Sally-Ann Poulsen

  DOI：10.1021/acs.jmedchem.6b00443

  日期：2016.6.9

  the synthesis of psammaplin C and evaluate the inhibition profile against therapeutically relevant carbonic anhydrase (CA) zinc metalloenzymes. The compound exhibited unprecedented inhibition of an important cancer-associated isozyme, hCA XII, with a Ki of 0.79 nM. The compound also displayed good isoform selectivity for hCA XII over other CAs. We present the first reported protein X-ray crystal structures

  帕马普林C是仅两种描述的天然产物伯磺酰胺之一。在这里，我们报告了psammaplin C的合成，并评估了对治疗相关的碳酸酐酶（CA）锌金属酶的抑制作用。该化合物对一种重要的癌症相关同工酶hCA XII的K i抑制作用史无前例。为0.79 nM。该化合物还显示出对hCA XII优于其他CA的良好同工型选择性。我们目前首次报道了与人类CA复杂的psammaplin C的蛋白质X射线晶体结构。我们设计了易于结晶的hCA II酶以模拟hCA IX和hCA XII结合位点，然后利用蛋白质X射线晶体学确定psammaplin C在hCA II，hCA IX和hCA XII模拟活性位点内的结合姿势，全部到高分辨率。这是首次评估天然产物伯磺酰胺抑制剂的抑制作用以及与CA的结合。
• Defining the Mechanism of Action and Enzymatic Selectivity of Psammaplin A against Its Epigenetic Targets
  作者：Matthias G. J. Baud、Thomas Leiser、Patricia Haus、Sharon Samlal、Ai Ching Wong、Robert J. Wood、Vanessa Petrucci、Mekala Gunaratnam、Siobhan M. Hughes、Lakjaya Buluwela、Fabrice Turlais、Stephen Neidle、Franz-Josef Meyer-Almes、Andrew J. P. White、Matthew J. Fuchter

  DOI：10.1021/jm2016182

  日期：2012.2.23

  Psammaplin A (11c) is a marine metabolite previously reported to be a potent inhibitor of two classes of epigenetic enzymes: histone deacetylases and DNA methyltransferases. The design and synthesis of a focused library based on the psammaplin A core has been carried out to probe the molecular features of this molecule responsible for its activity. By direct in vitro assay of the free thiol generated upon reduction of the dimeric psammaplin scaffold, we have unambiguously demonstrated that 11c functions as a natural prodrug, with the reduced form being highly potent against HDAC1 in vitro (IC50 0.9 nM). Furthermore, we have shown it to have high isoform selectivity, being 360-fold selective for HDAC1 over HDAC6 and more than 1000-fold less potent against HDAC7 and HDAC8. SAR around our focused library revealed a number of features, most notably the oxime functionality to be important to this selectivity. Many of the compounds show significant cytotoxicity in A549, MCF7, and W138 cells, with the SAR of cytotcodcity correlating to HDAC inhibition. Furthermore, compound treatment causes upregulation of histone acetylation but little effect on tubulin acetylation. Finally, we have found no evidence for 11c functioning as a DNMT inhibitor.
• Combinatorial Synthesis through Disulfide Exchange: Discovery of Potent Psammaplin A Type Antibacterial Agents Active against Methicillin-ResistantStaphylococcus aureus (MRSA)
  作者：K. C. Nicolaou、Robert Hughes、Jeffrey A. Pfefferkorn、Sofia Barluenga、A. J. Roecker

  DOI：10.1002/1521-3765(20011001)7:19<4280::aid-chem4280>3.0.co;2-3

  日期：2001.10.1

  Psammaplin A is a symmetrical bromotyrosine -derived disulfide natural product isolated from the Psammaplysilla sponge, which exhibits in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Inspired by the structure of this marine natural product, a combinatorial scrambling strategy for the construction of heterodimeric disulfide analogues was developed and applied to the construction of a 3828-membered library starting from 88 homodimeric disulfides. These psammaplin A analogues were screened directly against various gram positive bacterial strains leading to the discovery of a series of potent antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA), Among the most active leads derived from these studies are compounds 104. 105, 113, 115, 123, and 128. The present, catalytically-induced. disulfide exchange strategy may be extendable to other types of building blocks bearing thiol groups facilitating the construction of diverse discovery-oriented combinatorial libraries.
• EP3708563
  申请人：——

  公开号：——

  公开（公告）日：——