(2S,3S)-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester | 1344157-79-4

• 物质功能分类: 医药中间体 - 原料药中间体
• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: (2S,3S)-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester
• 英文别名: (2S,3S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-3-methoxypyrrolidine-2-carboxylic acid；(2S,3S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-3-methoxypyrrolidine-2-carboxylic acid
• CAS: 1344157-79-4
• 化学式: C₂₁H₂₁NO₅
• 分子量: 367.401
• InChiKey: DCSGGCNCYLELKJ-OALUTQOASA-N

物化性质

• 沸点：
  564.3±50.0 °C(Predicted)
• 密度：
  1.35±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S,3S)-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester 、 Ac-Val-Asp(OtBu)-Val-OH 、 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 21.0h， 以12 mg的产率得到(3S)-3-((S)-2-acetamido-3-methylbutanamido)-4-(((2S)-1-((2S,3S)-2-(((3S)-2-hydroxy-5-oxotetrahydrofuran-3-yl)carbamoyl)-3-methoxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid
  参考文献：
  名称：

  Exploiting differences in caspase-2 and -3 S2 subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors

  摘要：

  Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P-2 residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-L-proline along with four additional scaffold variants were selected as P-2 elements for their predicted ability to clash sterically with a residue of the caspase-3 S-2 pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and similar to 200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.08.020
• 作为产物：
  描述：

  (2S,3S)-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester 2-methyl ester 在 盐酸 、 水 、 silver(l) oxide 作用下， 以 1,4-二氧六环 、 1,2-二氯乙烷 为溶剂， 反应 42.0h， 生成 (2S,3S)-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester
  参考文献：
  名称：

  Exploiting differences in caspase-2 and -3 S2 subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors

  摘要：

  Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P-2 residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-L-proline along with four additional scaffold variants were selected as P-2 elements for their predicted ability to clash sterically with a residue of the caspase-3 S-2 pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and similar to 200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.08.020

文献信息

• 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 SERVIC

  公开号：US20160039872A1

  公开（公告）日：2016-02-11

  The invention provides novel compounds that may serve as anticancer therapeutics. The compounds of the invention bind to polo-like kinases through the polo-box domain. In certain embodiments, the compounds of the invention are POM-protected peptide derivatives. The use of cationic bis-alkyl his residues in combination with a mono POM-protected pho-phoryl group results in a peptide possessing an overall neutral charge. The peptide derivatives of the invention have achieved both good efficacy and an enhanced bioavailability. The invention also provides methods of use, compositions, and kits thereof. Further, the invention provides a novel method of design and/or synthesis of phosphoryl-derived peptide derivatives useful as therapeutic agents.

  该发明提供了可能用作抗癌治疗的新化合物。该发明的化合物通过波洛盒结构结合到波洛样激酶。在某些实施方式中，该发明的化合物是POM保护的肽衍生物。在结合了阳离子双烷基组氨酸残基和单个POM保护的磷酸化基团的情况下，得到的肽具有整体中性电荷。该发明的肽衍生物既具有良好的疗效又具有增强的生物利用度。该发明还提供了使用方法、组合物和相关试剂盒。此外，该发明提供了一种新的设计和/或合成磷酸化肽衍生物的方法，这些衍生物可用作治疗剂。
• 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。
• US9175038B2
  申请人：——

  公开号：US9175038B2

  公开（公告）日：2015-11-03
• Exploiting differences in caspase-2 and -3 S2 subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors
  作者：Michel C. Maillard、Frederick A. Brookfield、Stephen M. Courtney、Florence M. Eustache、Mark J. Gemkow、Rebecca K. Handel、Laura C. Johnson、Peter D. Johnson、Mark A. Kerry、Florian Krieger、Mirco Meniconi、Ignacio Muñoz-Sanjuán、Jordan J. Palfrey、Hyunsun Park、Sabine Schaertl、Malcolm G. Taylor、Derek Weddell、Celia Dominguez

  DOI：10.1016/j.bmc.2011.08.020

  日期：2011.10

  Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P-2 residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-L-proline along with four additional scaffold variants were selected as P-2 elements for their predicted ability to clash sterically with a residue of the caspase-3 S-2 pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and similar to 200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD. (C) 2011 Elsevier Ltd. All rights reserved.