cyclo-[Arg-Gly-Asp-Gly-(3-Amb)]

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: cyclo-[Arg-Gly-Asp-Gly-(3-Amb)]
• 英文别名: cyclo(Arg-Gly-Asp-Gly-Mamb)；2-[(8S,14S)-14-[3-(diaminomethylideneamino)propyl]-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentazabicyclo[15.3.1]henicosa-1(21),17,19-trien-8-yl]acetic acid
• 化学式: C₂₂H₃₀N₈O₇
• 分子量: 518.53
• InChiKey: FJJAYVDQBXRRIJ-GJZGRUSLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.1
• 重原子数：
  37
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  247
• 氢给体数：
  8
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3-氰基苯甲酸 在 palladium on activated charcoal 盐酸 、 氢气 、 三乙胺 作用下， 以 乙醇 、 水 为溶剂， 反应 38.0h， 生成 cyclo-[Arg-Gly-Asp-Gly-(3-Amb)]
  参考文献：
  名称：

  Template-Constrained Cyclic Peptides: Design of High-Affinity Ligands for GPIIb/IIIa

  摘要：

  Although peptides adopt a large ensemble of conformations in aqueous solution, they are generally believed to bind to a receptor in a unique conformation. Thus, there is considerable interest in devising methods to restrict the conformational freedom of peptides. One such approach involves tying the amino and carboxy terminal ends of the peptide onto a semirigid template that will lock the intervening peptide backbone into a single conformer or a family of related conformers. This general strategy has been tested using the tripeptide sequence Arg-Gly-Asp (RGD), which binds with low affinity to the platelet glycoprotein IIb/IIIa (GPIIb/IIIa or alpha(IIb)beta(3)) Mimics of RGD are of interest as antithrombotics because of their ability to inhibit the aggregation of platelets. Prior to this study, other workers (Samanen et al. J. Med. Chem. 1991, 34, 3114-3125) prepared a disulfide-containing cyclic pentapeptide that bound to GPIIb/IIIa with an affinity of approximately 0.1 mu M. NMR analysis of the solution conformation of this peptide suggested that replacing the disulfide-containing portion of the cycle with the amino acid m-(aminomethyl)benzoic acid would lead to a more rigid structure. Indeed, introduction of this template into a cyclic ROD-containing peptide resulted in compounds with high affinity for the receptor. Further, systematic inclusion of additional conformational constraints in the form of N-alpha- and C-alpha-alkyl groups led to a peptide with an affinity of approximately 100 pM for binding to the receptor. This peptide also showed good activity in the platelet aggregation assay at oral doses as low as 0.1 mg/kg.

  DOI：

  10.1021/ja00087a007

文献信息

• The Development and Application of a Novel Safety-Catch Linker for BOC-Based Assembly of Libraries of Cyclic Peptides^,¹
  作者：Gregory T. Bourne、Simon W. Golding、Ross P. McGeary、Wim D. F. Meutermans、Alun Jones、Garland R. Marshall、Paul F. Alewood、Mark L. Smythe

  DOI：10.1021/jo010580y

  日期：2001.11.1

  Cyclic peptides are appealing targets in the drug-discovery process. Unfortunately, there currently exist no robust solid-phase strategies that allow the synthesis of large arrays of discrete cyclic peptides. Existing strategies are complicated, when synthesizing large libraries, by the extensive workup that is required to extract the cyclic product from the deprotection/cleavage mixture. To overcome

  在药物发现过程中，环肽是有吸引力的靶标。不幸的是，目前尚不存在鲁棒的固相策略，其不能合成大量的离散环肽。在合成大型文库时，现有策略很复杂，因为需要进行大量的后处理才能从脱保护/裂解混合物中提取环状产物。为了克服这个问题，我们开发了一个新的安全捕获链接器。本文所述的安全捕获概念涉及使用受保护的邻苯二酚衍生物，其中在肽合成过程中羟基之一被苄基掩盖，从而使接头失活为氨解作用。接头的这种掩盖衍生物允许线性前体的BOC固相肽组装。环化之前，接头被激活，线性肽使用常用条件（TFMSA）脱保护，导致脱保护的肽与接头的活化形式连接。清除剂和脱保护加合物可通过简单的洗涤和过滤除去。在中和N-末端胺后，伴随从树脂上裂解的环化反应在DMF溶液中产生环肽。后处理是简单的溶剂去除。为了举例说明该策略，合成了几种针对生长抑素和整联蛋白受体的环肽。通过这项初步研究并显示该方法的优势，我们能够合成包含400多个成员的环状
• Template-Constrained Cyclic Peptides: Design of High-Affinity Ligands for GPIIb/IIIa
  作者：Sharon Jackson、W. DeGrado、A. Dwivedi、A. Parthasarathy、A. Higley、J. Krywko、A. Rockwell、J. Markwalder、G. Wells

  DOI：10.1021/ja00087a007

  日期：1994.4

  Although peptides adopt a large ensemble of conformations in aqueous solution, they are generally believed to bind to a receptor in a unique conformation. Thus, there is considerable interest in devising methods to restrict the conformational freedom of peptides. One such approach involves tying the amino and carboxy terminal ends of the peptide onto a semirigid template that will lock the intervening peptide backbone into a single conformer or a family of related conformers. This general strategy has been tested using the tripeptide sequence Arg-Gly-Asp (RGD), which binds with low affinity to the platelet glycoprotein IIb/IIIa (GPIIb/IIIa or alpha(IIb)beta(3)) Mimics of RGD are of interest as antithrombotics because of their ability to inhibit the aggregation of platelets. Prior to this study, other workers (Samanen et al. J. Med. Chem. 1991, 34, 3114-3125) prepared a disulfide-containing cyclic pentapeptide that bound to GPIIb/IIIa with an affinity of approximately 0.1 mu M. NMR analysis of the solution conformation of this peptide suggested that replacing the disulfide-containing portion of the cycle with the amino acid m-(aminomethyl)benzoic acid would lead to a more rigid structure. Indeed, introduction of this template into a cyclic ROD-containing peptide resulted in compounds with high affinity for the receptor. Further, systematic inclusion of additional conformational constraints in the form of N-alpha- and C-alpha-alkyl groups led to a peptide with an affinity of approximately 100 pM for binding to the receptor. This peptide also showed good activity in the platelet aggregation assay at oral doses as low as 0.1 mg/kg.