((1R)-1-{[(benzyloxy)carbonyl]amino}-3-phenylpropyl)phosphinic acid | 924896-60-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: ((1R)-1-{[(benzyloxy)carbonyl]amino}-3-phenylpropyl)phosphinic acid
• 英文别名: (1-(((benzyloxy)carbonyl)amino)-3-phenylpropyl)phosphinic acid
• CAS: 924896-60-6
• 化学式: C₁₇H₂₀NO₄P
• 分子量: 333.324
• InChiKey: NKIJHPAMPARFRD-MRXNPFEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.34
• 重原子数：
  23.0
• 可旋转键数：
  7.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  75.63
• 氢给体数：
  2.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  ((1R)-1-{[(benzyloxy)carbonyl]amino}-3-phenylpropyl)phosphinic acid 在 氢溴酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 六甲基二硅氮烷 作用下， 以 二氯甲烷 、 溶剂黄146 为溶剂， 反应 55.33h， 生成 ((1R)-1-amino-3-phenylpropyl){2′-[((2″S)-1″-amino-4″-methyl-1″-oxopentan-2″-yl)carbamoyl]-4′,4′-diphenylbutyl}phosphinic acid
  参考文献：
  名称：

  Optimization and Structure–Activity Relationships of Phosphinic Pseudotripeptide Inhibitors of Aminopeptidases That Generate Antigenic Peptides

  摘要：

  The oxytocinase subfamily of M1 aminopeptidases, Consisting of ER aminopeptidase 1 (ERAP1), ER aminopeptidase 2 (ERAP2), and insulin-regulated aminopeptidase (IRAP), plays critical roles in the generation of antigenic peptides and indirectly regulates human adaptive immune responses. We have previously,demonstrated that phosphinic pseudotripeptides can constitute potent inhibitors of this group of enzymes. In this study, we used synthetic methodologies able to furnish a series of stereochemically defined phosphinic pseudotripeptides and demonstrate that side chains at P-1' and P-2' positions are Critical determinants in driving potency and selectivity. We identified low nanomolar inhibitors of ERAP2 and IRAP that display selectivity of more than 2 and 3 orders of magnitude, respectively. Cellular analysis demonstrated that one of the compounds that is a selective IRAP inhibitor can reduce IRAP-dependent but not, ERAP1-dependent cross-presentation by dendritic cells with nanomolar efficacy. Our results encourage further preclinical development of phosphinic pseudotripeptides as regulators of adaptive immune responses.

  DOI：

  10.1021/acs.jmedchem.6b01031
• 作为产物：
  描述：

  苯丙醛 在 盐酸 、 氢溴酸 、 亚膦酸 、 sodium carbonate 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 29.59h， 生成 ((1R)-1-{[(benzyloxy)carbonyl]amino}-3-phenylpropyl)phosphinic acid
  参考文献：
  名称：

  研究次膦酸三肽模拟物 DG013A 作为 M1-氨基肽酶 ERAP1 的工具化合物抑制剂

  摘要：

  ERAP1 是一种锌依赖性 M1-氨基肽酶，可从肽的N末端修剪亲脂性氨基酸。由于其在抗原加工和适应性免疫反应调节中的重要性，高度多态性 ERAP1 的失调与自身免疫性疾病和癌症有关。为了检验这一假设并确定 ERAP1 在这些疾病领域的作用，高亲和力、细胞渗透性和选择性的化学探针至关重要。 DG013A 1是一种次膦酸三肽模拟抑制剂，据报道对 ERAP1 具有低纳摩尔亲和力。然而，这种化学型是与各种金属依赖性肽酶结合的特殊结构，并且含有高电荷次膦酸部分，因此尚不清楚它是否会表现出化学探针所需的高选择性和被动渗透性。因此，我们设计了一种新的立体选择性路线来合成 DG013A 1类似物库，以确定该化合物作为细胞化学探针的适用性，以验证 ERAP1 作为药物发现靶点。

  DOI：

  10.1016/j.bmcl.2021.128050

文献信息

• Practical Synthesis of Phosphinic Dipeptides by Tandem Esterification of Aminophosphinic and Acrylic Acids under Silylating Conditions
  作者：Paraskevi Kokkala、Kostas Voreakos、Angelos Lelis、Konstantinos Patiniotis、Nikolaos Skoulikas、Laurent Devel、Angeliki Ziotopoulou、Eleni Kaloumenou、Dimitris Georgiadis

  DOI：10.3390/molecules27041242

  日期：——

  acrylic acids and (R)-α-aminophosphinic acids, and high yields were achieved in all cases. In most examples reported herein, the isolation of biologically relevant (R,S)-diastereoisomers became possible by simple crystallization from the crude products, thus enhancing the operational simplicity of the proposed method. Finally, functional groups corresponding to acidic or basic natural amino acids are also

  在本报告中，提出了一种制备 5 型次膦酸二肽的合成方案。这些化合物可作为开发药用相关锌金属蛋白酶和天冬氨酰蛋白酶的高效膦肽抑制剂的重要组成部分。所提出的方法基于 α-氨基次膦酸和丙烯酸在甲硅烷基化条件下的串联酯化，以便随后参与 P-Michael 反应。通过使用多种容易获得的丙烯酸和 (R)-α-氨基次膦酸来研究转化的范围，并且在所有情况下都实现了高产率。在本文报道的大多数例子中，生物学相关的 (R,S)-非对映异构体的分离成为可能通过从粗产物中简单结晶，从而提高了所提出方法的操作简单性。最后，对应于酸性或碱性天然氨基酸的官能团也与反应条件相容。基于以上所述，我们预计所提出协议的实用性将有助于发现药理上有用的生物活性次膦酸肽。
• ERAP2 Inhibition Induces Cell-Surface Presentation by MOLT-4 Leukemia Cancer Cells of Many Novel and Potentially Antigenic Peptides
  作者：Ioannis Temponeras、George Stamatakis、Martina Samiotaki、Dimitris Georgiadis、Harris Pratsinis、George Panayotou、Efstratios Stratikos

  DOI：10.3390/ijms23031913

  日期：——

  Recent studies have linked the activity of ER aminopeptidase 2 (ERAP2) to increased efficacy of immune-checkpoint inhibitor cancer immunotherapy, suggesting that pharmacological inhibition of ERAP2 could have important therapeutic implications. To explore the effects of ERAP2 inhibition on the immunopeptidome of cancer cells, we treated MOLT-4 T lymphoblast leukemia cells with a recently developed selective ERAP2 inhibitor, isolated Major Histocompatibility class I molecules (MHCI), and sequenced bound peptides by liquid chromatography tandem mass spectrometry. Inhibitor treatment induced significant shifts on the immunopeptidome so that more than 20% of detected peptides were either novel or significantly upregulated. Most of the inhibitor-induced peptides were 9mers and had sequence motifs and predicted affinity consistent with being optimal ligands for at least one of the MHCI alleles carried by MOLT-4 cells. Such inhibitor-induced peptides could serve as triggers for novel cytotoxic responses against cancer cells and synergize with the therapeutic effect of immune-checkpoint inhibitors.

  最近的研究将ER氨肽酶2（ERAP2）的活性与免疫检查点抑制剂癌症免疫治疗的疗效增加联系起来，表明ERAP2的药物抑制可能具有重要的治疗意义。为了探索ERAP2抑制对癌细胞免疫肽组的影响，我们使用最近开发的选择性ERAP2抑制剂处理MOLT-4 T淋巴母细胞白血病细胞，分离主要组织相容性I类分子（MHCI），并通过液相色谱串联质谱法对结合的肽进行测序。抑制剂处理引起了免疫肽组的显著变化，以至于检测到的肽中有超过20％是新颖的或明显上调的。大多数抑制剂诱导的肽是9mers，并具有序列模体和预测亲和力，与MOLT-4细胞携带的至少一种MHCI等位基因的最佳配体一致。这样的抑制剂诱导肽可能作为诱发对癌细胞的新型细胞毒反应的触发器，并与免疫检查点抑制剂的治疗效果协同作用。
• Diastereoselective Synthesis of Phosphinic Dipeptide Isosteres: Domino Chirality Transfer during a Stereocontrolled P-Michael Reaction
  作者：Angelos Lelis、Nikolaos Skoulikas、Mirto Papathanasopoulou、Kostas Voreakos、Dimitris Georgiadis

  DOI：10.1021/acs.orglett.3c02335

  日期：2023.9.15

  A highly diastereoselective P-Michael addition of chiral aminophosphinic acids to achiral acrylates has been developed, leading to phosphinic dipeptide isosteres in high yields and dr of up to >50:1. The method allows for the diastereoselective preparation of target compounds without the need for chiral auxiliaries or P-chiral substrates. A possible mechanistic explanation involves a domino chirality

  已开发出手性氨基次膦酸与非手性丙烯酸酯的高度非对映选择性 P-Michael 加成反应，可产生高产率的次膦二肽电子等排体，dr 高达 >50:1。该方法允许非对映选择性制备目标化合物，而不需要手性助剂或 P-手性底物。一种可能的机制解释涉及从氨基次膦酸到 P 中心的多米诺骨牌手性转移，通过关键的二苯甲基酯基团放大，然后转移到 α-碳。
• Late-Stage Diversification of Phosphinic Dehydroalanine Pseudopeptides Based on a Giese-Type Radical C-Alkylation Strategy
  作者：Kostas Voreakos、Laurent Devel、Dimitris Georgiadis

  DOI：10.1021/acs.orglett.9b00857

  日期：2019.6.21

  A straightforward, late-stage diversification strategy for the installation of side chains on readily accessible unsaturated phosphinopeptidic scaffolds based on a Giese-type addition of alkyl radicals has been investigated. Among different alternatives, the preferred methodology is operationally simple as it can be carried out in an open flask with no need for protection of acidic moieties. Direct application to the synthesis of SPPS-compatible building blocks or to longer peptides is also reported.
• High-performance liquid chromatographic enantiomer separation and determination of absolute configurations of phosphinic acid analogues of dipeptides and their α-aminophosphinic acid precursors
  作者：Michael Lämmerhofer、Dieter Hebenstreit、Elena Gavioli、Wolfgang Lindner、Artur Mucha、Paweł Kafarski、Piotr Wieczorek

  DOI：10.1016/s0957-4166(03)00537-8

  日期：2003.9

  The enantiomers of N-benzyloxycarbonyl-phospinic pseudodipeptides and their N-benzyloxycarbonyl-alpha-aminophosphinic acid precursors as well as various other structural analogues were separated oil a set of cinchona alkaloid-derived chiral anion-exchangers by HPLC in the reversed-phase mode. Semi-preparative scale chromatography provided single enantiomers in 100 mg quantities. The configurations of the enantiomers were assigned indirectly by enantioselective chromatography on the basis of the elution order and was confirmed by enantiomeric reference compounds. (C) 2003 Elsevier Ltd. All rights reserved.