cyclohexyl 2-((5S,11S,14R)-14-ethyl-12-methyl-4,7,10,13,16-pentaoxo-11-(3-(3-tosylguanidino)propyl)-3,6,9,12,15-pentaaza-1(1,3)-benzenacyclohexadecaphane-5-yl)acetate | 153346-63-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: cyclohexyl 2-((5S,11S,14R)-14-ethyl-12-methyl-4,7,10,13,16-pentaoxo-11-(3-(3-tosylguanidino)propyl)-3,6,9,12,15-pentaaza-1(1,3)-benzenacyclohexadecaphane-5-yl)acetate
• CAS: 153346-63-5
• 化学式: C₃₈H₅₂N₈O₉S
• 分子量: 796.945
• InChiKey: WVXWBQAHNOGSIP-AYQJTBPPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  56.0
• 可旋转键数：
  10.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  247.56
• 氢给体数：
  6.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  甲烷磺酸 、 cyclohexyl 2-((5S,11S,14R)-14-ethyl-12-methyl-4,7,10,13,16-pentaoxo-11-(3-(3-tosylguanidino)propyl)-3,6,9,12,15-pentaaza-1(1,3)-benzenacyclohexadecaphane-5-yl)acetate 在 三氟甲磺酸 、 苯甲醚 、 三氟乙酸 作用下， 生成 (5R,11R,14R)-11-{3-[(二氨基亚甲基)氨基]丙基}-14-乙基-12-甲基-4,7,10,13,16-五氧代-3,6,9,12,15-戊氮杂双环[15.3.1]二十一-1(21),17,19-三烯-5-羧酸甲烷磺酸酯(1:1)
  参考文献：
  名称：

  Facile detosylation of cyclic peptides. An effective synthesis of platelet glycoprotein IIb/IIIa inhibitors

  摘要：

  A general and effective synthesis of cyclic pentapeptides containing Arg-Gly-Asp sequence, which are potent antithrombotic agents, is reported.

  DOI：

  10.1016/s0040-4039(00)78178-0
• 作为产物：
  描述：

  Boc-D-Abu-N(Me)Arg(Tos)-Gly-OBn 在 palladium on activated charcoal 氢气 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 溶剂黄146 、 二乙胺 、 三氟乙酸 作用下， 以 二乙胺 为溶剂， 生成 cyclohexyl 2-((5S,11S,14R)-14-ethyl-12-methyl-4,7,10,13,16-pentaoxo-11-(3-(3-tosylguanidino)propyl)-3,6,9,12,15-pentaaza-1(1,3)-benzenacyclohexadecaphane-5-yl)acetate
  参考文献：
  名称：

  Facile detosylation of cyclic peptides. An effective synthesis of platelet glycoprotein IIb/IIIa inhibitors

  摘要：

  A general and effective synthesis of cyclic pentapeptides containing Arg-Gly-Asp sequence, which are potent antithrombotic agents, is reported.

  DOI：

  10.1016/s0040-4039(00)78178-0

文献信息

• 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.