macrocycle Lys-NMe-D-Phe-Phe-(Cbz)Lys-Leu | 1321841-96-6

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮
• 英文名称: macrocycle Lys-NMe-D-Phe-Phe-(Cbz)Lys-Leu
• 英文别名: Phe-N-Me-D-Phe-Lys-Leu-Lys(Cbz)
• CAS: 1321841-96-6
• 化学式: C₄₅H₆₁N₇O₇
• 分子量: 812.022
• InChiKey: DUNUHMVMOKGQQQ-GOXAKLKVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.52
• 重原子数：
  59.0
• 可旋转键数：
  17.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  201.06
• 氢给体数：
  6.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  macrocycle Lys-NMe-D-Phe-Phe-(Cbz)Lys-Leu 、 15-生物素-氨基-4,7,10,13-二氧杂壬酸N-羟基琥珀酰亚胺 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 以39%的产率得到macrocycle Phe-N-Me-D-Phe-Lys(Peg-biotin)-Leu-Lys(Cbz)
  参考文献：
  名称：

  Synthesis and evaluation of biotinylated sansalvamide A analogs and their modulation of Hsp90

  摘要：

  Described are the syntheses of three sansalvamide A derivatives that contain biotinylated tags at individual positions around the macrocycle. The tagged derivatives indicated in protein pull-down assays that they bind to Hsp90 at the same binding site (N-Middle domain) as the San A-amide peptide. Further, these compounds inhibit binding between Hsp90 and multiple C-terminal client proteins. This interaction is unique to the San A analogs indicating they can be tuned for selectivity against Hsp90 client/ co-chaperone proteins. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.06.083
• 作为产物：
  描述：

  NH2-(Boc)Lys-NMe-D-Phe-Phe-(Cbz)Lys-Leu-OH 在 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 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-) 、 三氟乙酸 、 3-(二乙氧基邻酰氧基)-1,2,3-苯并三嗪-4-酮 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 生成 macrocycle Lys-NMe-D-Phe-Phe-(Cbz)Lys-Leu
  参考文献：
  名称：

  Synthesis and evaluation of biotinylated sansalvamide A analogs and their modulation of Hsp90

  摘要：

  Described are the syntheses of three sansalvamide A derivatives that contain biotinylated tags at individual positions around the macrocycle. The tagged derivatives indicated in protein pull-down assays that they bind to Hsp90 at the same binding site (N-Middle domain) as the San A-amide peptide. Further, these compounds inhibit binding between Hsp90 and multiple C-terminal client proteins. This interaction is unique to the San A analogs indicating they can be tuned for selectivity against Hsp90 client/ co-chaperone proteins. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.06.083

文献信息

• Reinventing Hsp90 Inhibitors: Blocking C-Terminal Binding Events to Hsp90 by Using Dimerized Inhibitors
  作者：Yen Chin Koay、Hendra Wahyudi、Shelli R. McAlpine

  DOI：10.1002/chem.201603464

  日期：2016.12.19

  promising anticancer target. Classical inhibitors that block the binding of adenine triphosphate (ATP) to the N‐terminus of Hsp90 are highly toxic to cells and trigger a resistance mechanism within cells. This resistance mechanism comprises a large increase in prosurvival proteins, namely, heat shock protein 70 (Hsp70), heat shock protein 27 (Hsp27), and heat shock factor 1 (HSF‐1). Molecules that modulate

  热激蛋白90（Hsp90）是一种分子伴侣（90 kDa），起二聚体的作用。这种蛋白质有助于负责癌症发展和进程的400多种蛋白质的折叠，组装和稳定化。抑制Hsp90的功能将同时关闭多种癌症驱动的途径，因为致癌客户严重依赖Hsp90，这使得该分子伴侣成为有希望的抗癌靶标。阻止三磷酸腺嘌呤（ATP）与Hsp90 N末端结合的经典抑制剂对细胞具有高毒性，并会触发细胞内的抗药性机制。这种抗性机制包括大量的生存蛋白，即热休克蛋白70（Hsp70），热休克蛋白27（Hsp27）和热休克因子1（HSF-1）。调节Hsp90 C末端的分子可有效诱导癌细胞死亡，而无需激活耐药机制。在本文中，我们描述了一系列二聚化的C末端Hsp90调节剂的设计，合成和生物结合亲和力。我们表明，这些C末端调节剂的二聚体可协同抑制Hsp90相对于单体。
• A small molecule that preferentially binds the closed conformation of Hsp90
  作者：Leslie D. Alexander、James R. Partridge、David A. Agard、Shelli R. McAlpine

  DOI：10.1016/j.bmcl.2011.09.096

  日期：2011.12

  Described is the synthesis of three different fluorescein-tagged derivatives of a macrocycle, and their binding affinity to heat shock protein 90 (Hsp90). Using fluorescence polarization anisotropy, we report the binding affinity of these fluorescein-labeled compounds to Hsp90 in its open state and ATP-dependent closed state. We show that the compounds demonstrate a conformation-dependent preference for binding to the closed state. Published by Elsevier Ltd.