(5-hydroxynorvaline)-2-cyclosporin

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (5-hydroxynorvaline)-2-cyclosporin
• 英文别名: cyclo[Ala-D-Ala-N(Me)Leu-N(Me)Leu-N(Me)Val-N(Me)Bmt(E)-Nva(OH)(OH)-Sar-N(Me)Leu-Val-N(Me)Leu]；(3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-30-(3-hydroxypropyl)-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone
• 化学式: C₆₃H₁₁₃N₁₁O₁₃
• 分子量: 1232.66
• InChiKey: LMYSMWRGUZMLGF-YVMZBLKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  87
• 可旋转键数：
  17
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  299
• 氢给体数：
  6
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  5(OH)Nva-MeLeu-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal-MeBmt-OH 在 4-二甲氨基吡啶 、 (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluoroborate 作用下， 以 二氯甲烷 为溶剂， 以26%的产率得到(5-hydroxynorvaline)-2-cyclosporin
  参考文献：
  名称：

  The Role of Water Molecules in the Structure-Based Design of (5-Hydroxynorvaline)-2-cyclosporin: Synthesis, Biological Activity, and Crystallographic Analysis with Cyclophilin A

  摘要：

  Analysis of the contact surface of the cyclophilin A (CypA)/cyclosporin A (CsA, 1) crystal structure delineates a unique cavity between both molecules in the vicinity of the Abu-2 side chain atoms of 1 (Abu pocket). Therefore, (5-hydroxynorvaline)-2-cyclosporin (2) was designed and prepared as a CsA derivative which could mediate additional interactions within the pocket. The X-ray crystal structure of the CypA/2 complex at 1.76 Angstrom resolution shows that 1 and 2 have identical backbone conformations and that the introduced hydroxypropyl chain makes indeed the expected supplemental interactions with CypA. However, 2 has 8-9-fold lower binding affinity than 1 for CypA. This results from a presumed unfavorable free energy change associated with the displacement of one of the tightly bound water molecules within the pocket and a change in prebinding equilibria. The role of the later was assessed by comparing the conformation distribution of 1 and 2 to that of norvaline-2-cyclosporin (3) and norvaline-2-(D-MeSer)-3-cyclosporin (4).

  DOI：

  10.1021/jm00017a020