(2S,3R)-4-[bis-(tert-butyl)oxyphosphinyl]-2-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-3-methylbutanoic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: (2S,3R)-4-[bis-(tert-butyl)oxyphosphinyl]-2-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-3-methylbutanoic acid
• 英文别名: (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(di-tert-butoxyphosphoryl)-3-methylbutanoic acid；(2S,3R)-4-[di-(tert-butyl)-oxyphosphinyl]-N-Fmoc-L-valine；N-Fmoc-Pmab(Ot-Bu)₂-OH；(2S,3R)-4-[di-(tert-butyl-oxy)-phosphinyl]-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valine；(2S,3R)-4-[di(tert-butoxy)oxyphosphinyl]-N-Fmoc-L-valine；N-Fmoc,O,O-(bis-(tert-butyl))-Pmab；Fmoc-L-Pmab(tBu)2-OH；(2S,3R)-4-[bis[(2-methylpropan-2-yl)oxy]phosphoryl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methylbutanoic acid
• 化学式: C₂₈H₃₈NO₇P
• 分子量: 531.586
• InChiKey: AENLXSUZQOUSJS-UUOWRZLLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  37
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  FMOC-O-叔丁基-L-丝氨酸 、 N-Fmoc-N'-三苯甲基-L-组氨酸 、 Fmoc-L-脯氨酸 、 Fmoc-L-亮氨酸 、 1-乙酰基咪唑 、 (2S,3R)-4-[bis-(tert-butyl)oxyphosphinyl]-2-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-3-methylbutanoic acid 在 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 哌啶 作用下， 以 N-甲基吡咯烷酮 为溶剂， 生成 [(2R,3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-acetylpyrrolidine-2-carbonyl]amino]-4-methylpentanoyl]amino]-3-[3-(8-phenyloctyl)imidazol-4-yl]propanoyl]amino]-3-hydroxypropanoyl]amino]-4-amino-2-methyl-4-oxobutyl]phosphonic acid
  参考文献：
  名称：

  Investigation of Unanticipated Alkylation at the N(π) Position of a Histidyl Residue Under Mitsunobu Conditions and Synthesis of Orthogonally Protected Histidine Analogues

  摘要：

  We had previously reported that Mitsunobu-based introduction of alkyl substituents onto the imidazole N(pi)-position of a key histidine residue in phosphothreonine-containing peptides can impart high binding affinity against the polo-box domain of polo-like kinase 1. Our current paper investigates the mechanism leading to this N(pi)-alkylation and provides synthetic methodologies that permit the facile synthesis of histidine N(pi)-modified peptides. These agents represent new and potentially important tools for biological studies.

  DOI：

  10.1021/jo201599c
• 作为产物：
  描述：

  二叔丁基亚磷酸盐 在 4-二甲氨基吡啶 、 lithium hydroxide monohydrate 、 偶氮二异丁腈 、 水 、 三正丁基氢锡 、 三乙胺 、 N,N-二异丙基乙胺 、 柠檬酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， 100.0 ℃ 、101.33 kPa 条件下， 反应 3.41h， 生成 (2S,3R)-4-[bis-(tert-butyl)oxyphosphinyl]-2-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-3-methylbutanoic acid
  参考文献：
  名称：

  Peptide mimetic ligands of polo-like kinase 1 polo box domain and methods of use

  摘要：

  提供了一种新型化合物，通过波洛盒结构结合波洛样激酶。在某些实施例中，这些新型化合物是PEG化肽。根据本发明，这些PEG化肽表现出高PBD结合亲和力。在某些实施例中，这些PEG化肽在整个细胞系统中也表现出活性。本发明还提供了一种通过波洛盒结构结合波洛样激酶且具有降低阴离子电荷的化合物。此外，还提供了PEG化肽的设计和/或合成方法以及使用这些方法。本发明提供了这些化合物的使用方法和合成方法。

  公开号：

  US10266565B2

文献信息

• Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain – binding peptide macrocycles
  作者：David Hymel、Kohei Tsuji、Robert A. Grant、Ramesh M. Chingle、Dominique L. Kunciw、Michael B. Yaffe、Terrence R. Burke

  DOI：10.1039/d1ob01120k

  日期：——

  phospho-dependent PPIs, such as the polo-like kinase 1 (Plk1) polo-box domain (PBD), a phosphorylated protein residue can provide high-affinity recognition and binding to target protein hot spots. Developing antagonists of the Plk1 PBD can be particularly challenging if one relies solely on interactions within and proximal to the phospho-binding pocket. Fortunately, the affinity of phospho-dependent PPI antagonists

  靶向蛋白质-蛋白质相互作用（PPI）已成为抗癌治疗开发的一个重要发现领域。对于磷酸依赖性 PPI，例如 polo 样激酶 1 (Plk1) polo-box 结构域 (PBD)，磷酸化蛋白残基可以提供高亲和力识别并与目标蛋白热点结合。如果仅依赖于磷酸结合袋内部及其附近的相互作用，那么开发 Plk1 PBD 拮抗剂可能会特别具有挑战性。幸运的是，通过利用磷酸结合位点和配体结合时可能揭示的隐藏“神秘”口袋中的相互作用，可以显着增强磷酸依赖性 PPI 拮抗剂的亲和力。在我们当前的论文中，我们描述了针对 Plk1 PBD 的大环肽模拟物的设计和合成，其特征是一种新的谷氨酸类似物，同时充当闭环连接，提供对神秘结合袋的访问，同时在同时实现磷酸苏氨酸 (pT) 残基的正确定向，以在标志性磷酸结合袋中实现最佳相互作用。用这种新的氨基酸类似物制备的大环化合物引入了开链线性母肽中未发现的额外氢键相互作用。值得
• PEPTIDE MIMETIC LIGANDS OF POLO-LIKE KINASE 1 POLO BOX DOMAIN AND METHODS OF USE
  申请人：Burke, JR. Terrence R.

  公开号：US20120065146A1

  公开（公告）日：2012-03-15

  Found in various eukaryotic organisms, polo-like kinases (collectively, Plks) are a conserved subfamily of Ser/Thr protein kinases that play critical roles in cell proliferation. Provided herein are compounds that specifically inhibit the activity of Plks, specifically Plk1. Further provided herein are methods for use of the compounds for the treatment of hyperproliferative disorders, particularly cancer. Also provided are uses of the compounds for the preparation of a medicament.

  在各种真核生物中发现的波罗样激酶（Plks）是一类保守的Ser / Thr蛋白激酶亚家族，它们在细胞增殖中发挥关键作用。本文提供了特异性抑制Plks，特别是Plk1活性的化合物。本文还提供了使用这些化合物治疗高增殖性疾病，特别是癌症的方法。此外，还提供了使用这些化合物制备药物的用途。
• Peptide and peptide mimetic binding antagonists of polo-like kinase 1 polo box domain and methods of use
  申请人：The United States of America, as represented by the Secretary, Department of Health & Human Services

  公开号：US10905769B2

  公开（公告）日：2021-02-02

  The description provides novel compounds that may serve as anticancer therapeutics. The compounds of the description bind to polo-like kinases through the polo-box domain. The peptide derivatives of the description have achieved improved efficacy in biochemical assays against Plk1. Exemplary compounds of the description include macrocyclic peptidomimetics with high affinity and selectivity for polo-like kinases, which may provide the basis for a new genre of anticancer therapeutics. Other exemplary compounds of the description include bi-valent compounds with that bind to polo-like kinases through both kinase domain and polo-box domain simultaneously by incorporating additional moieties that target Plk1 kinase domain, which significantly enhances affinitity relative and may provide the basis for a new genre of anticancer therapeutics. The description also provides methods of use, methods of preparation, compositions, and kits thereof. Further, the description provides a novel method of design and/or synthesis of phosphoryl-derived peptide derivatives useful as therapeutic agents.

  说明提供了可用作抗癌疗法的新型化合物。所述化合物通过 polo-box 结构域与 polo-like 激酶结合。描述中的肽衍生物在生化试验中对 Plk1 的疗效有所提高。本发明的示例化合物包括对polo-like激酶具有高亲和力和选择性的大环肽拟化物，可为新型抗癌疗法奠定基础。本发明的其他示例化合物包括双价化合物，它们通过加入靶向 Plk1 激酶结构域的附加分子，同时通过激酶结构域和 polo-box 结构域与 polo-like 激酶结合，从而显著增强了亲和性，并可为新型抗癌疗法奠定基础。说明还提供了使用方法、制备方法、组合物及其试剂盒。此外，该描述还提供了一种设计和/或合成可用作治疗剂的磷酸衍生肽衍生物的新方法。
• Preparation of orthogonally protected (2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid (Pmab) as a phosphatase-stable phosphothreonine mimetic and its use in the synthesis of polo-box domain-binding peptides
  作者：Fa Liu、Jung-Eun Park、Kyung S. Lee、Terrence R. Burke

  DOI：10.1016/j.tet.2009.09.093

  日期：2009.11

  Reported herein is the first stereoselective synthesis of (2S,3R)-4-[bis-(tert-butyloxy)phosphinyl]-2-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-3-methylbutanoic acid [(N-Fmoc, O,O-(bis-(tert-butyl))-Pmab), 4] as a hydrolytically-stable phosphothreonine mimetic bearing orthogonal protection compatible with standard solid-phase protocols. The synthetic approach used employs Evans' oxazolidinone for chiral induction. Also presented is the application of 4 in the solid-phase synthesis of polo-like kinase 1 (Plk1) polo box domain (PBD)-binding peptides. These Pmab-containing pepticles retain PBD binding efficacy similar to a parent pThr containing peptide. Reagent 4 should be a highly useful reagent for the preparation of signal transduction-directed pepticles. Published by Elsevier Ltd.
• PEPTIDE AND PEPTIDE MIMETIC BINDING ANTAGONISTS OF POLO-LIKE KINASE 1 POLO BOX DOMAIN AND METHODS OF USE
  申请人：The United States of America, as represented by theSecretary, Department of Health &Human Services

  公开号：US20180296686A1

  公开（公告）日：2018-10-18

  The description provides novel compounds that may serve as anticancer therapeutics. The compounds of the description bind to polo-like kinases through the polo-box domain. The peptide derivatives of the description have achieved improved efficacy in biochemical assays against Plk1. Exemplary compounds of the description include macrocyclic peptidomimetics with high affinity and selectivity for polo-like kinases, which may provide the basis for a new genre of anticancer therapeutics. Other exemplary compounds of the description include bi-valent compounds with that bind to polo-like kinases through both kinase domain and polo-box domain simultaneously by incorporating additional moieties that target Plk1 kinase domain, which significantly enhances affinitity relative and may provide the basis for a new genre of anticancer therapeutics. The description also provides methods of use, methods of preparation, compositions, and kits thereof. Further, the description provides a novel method of design and/or synthesis of phosphoryl-derived peptide derivatives useful as therapeutic agents.