((2S,3R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-hydroxy-4-phenylbutanoyl)-L-leucine | 1225383-33-4

• 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: ((2S,3R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-hydroxy-4-phenylbutanoyl)-L-leucine
• 英文别名: (S)-2-{(2S,3R)-3-[(9H-fluoren-9-yl)methoxy]carbonylamino-2-hydroxy-4-phenylbutanamido}-4-methylpentanoic acid；E3 ligase Ligand 8；(2S)-2-[[(2S,3R)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-2-hydroxy-4-phenylbutanoyl]amino]-4-methylpentanoic acid
• CAS: 1225383-33-4
• 化学式: C₃₁H₃₄N₂O₆
• 分子量: 530.621
• InChiKey: DYKHBFJZCIEBJE-PKTNWEFCSA-N

物化性质

• 沸点：
  815.8±65.0 °C(Predicted)
• 密度：
  1.252±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  39
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  125
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ((2S,3R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-hydroxy-4-phenylbutanoyl)-L-leucine 、 2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)乙酸叔丁酯 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 、 水 为溶剂， 以59.1 mg的产率得到tert-butyl 2-[2-(2-(2-[(S)-2-((2S,3R)-3-([(9H-fluoren-9-yl)methoxy]carbonyl amino)-2-hydroxy-4-phenylbutanamido)-4-methylpentanamido]ethoxy)ethoxy)ethoxy]acetate
  参考文献：
  名称：

  Design, synthesis and biological evaluation of nuclear receptor-degradation inducers

  摘要：

  Compounds that regulate the function(s) of nuclear receptors (NRs) are useful for biological studies and as candidate therapeutic agents. Most such compounds are agonists or antagonists. On the other hand, we have developed specific protein degradation inducers, which we designated as SNIPERs (Specific and Nongenetic IAPs-dependent Protein ERasers), for selective degradation of target proteins. SNIPERs are hybrid molecules consisting of an appropriate ligand for the protein of interest, coupled to a ligand for inhibitor of apoptosis proteins (IAPs), which target the bound protein for polyubiquitination and proteasomal degradation. We considered that protein knockdown with SNIPERs would be a promising alternative approach for modulating NR function. In this study, we designed and synthesized degradation inducers targeting retinoic acid receptor (RAR), estrogen receptor (ER), and androgen receptor (AR). These newly synthesized RAR, ER, and AR SNIPERs, 9, 11, and 13, respectively, were confirmed to significantly reduce the levels of the corresponding NRs in live cells. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.09.041
• 作为产物：
  描述：

  氯甲酸-9-芴基甲酯 、 乌苯美司 在 potassium carbonate 作用下， 以 四氢呋喃 、 水 为溶剂， 以97%的产率得到((2S,3R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-hydroxy-4-phenylbutanoyl)-L-leucine
  参考文献：
  名称：

  Protein Knockdown Using Methyl Bestatin−Ligand Hybrid Molecules: Design and Synthesis of Inducers of Ubiquitination-Mediated Degradation of Cellular Retinoic Acid-Binding Proteins

  摘要：

  Induction of selective degradation of target proteins by small molecules (protein knockdown) would be useful for biological research and treatment of various diseases. To achieve protein knockdown, we utilized the ubiquitin ligase activity of cellular inhibitor of apoptosis protein 1 (cIAP1), which is activated by methyl bestatin (MeBS, 2). We speculated that formation of an artificial (nonphysiological) complex of cIAP1 and a target protein would be induced by a hybrid molecule consisting of MeBS (2) linked to a ligand of the target protein, and this would lead to cIAP1-mediated ubiquitination and subsequent proteasomal degradation of the target protein. To verify this hypothesis, we focused on cellular retinoic acid-binding proteins (CRABP-I and -II) and designed hybrid molecules (compounds 4) consisting of MeBS (2) coupled via spacers of various lengths to all-trans retinoic acid (ATRA, 3), a ligand of CRABPs. Compounds 4 induced selective loss of CRABP-I and -II proteins in cells. We confirmed that 4b induced formation of a complex of cIAP1 and CRABP-II in vitro and induced proteasomal degradation of CRABP-II in cells. When neuroblastoma IMR-32 cells were treated with 4b, the level of CRABP-II was reduced and cell migration was inhibited, suggesting potential value of CRABP-II-targeting therapy for controlling tumor metastasis. Our results indicate that 4b possesses sufficient activity, permeability, and stability in cells to be employed in cellular assays. Hybrid molecules such as 4 should be useful not only as chemical tools for studying the biological/physiological functions of CRABPs but also as candidate therapeutic agents targeting CRABPs.

  DOI：

  10.1021/ja100691p

文献信息

• Development of Protein Degradation Inducers of Androgen Receptor by Conjugation of Androgen Receptor Ligands and Inhibitor of Apoptosis Protein Ligands
  作者：Norihito Shibata、Katsunori Nagai、Yoko Morita、Osamu Ujikawa、Nobumichi Ohoka、Takayuki Hattori、Ryokichi Koyama、Osamu Sano、Yasuhiro Imaeda、Hiroshi Nara、Nobuo Cho、Mikihiko Naito

  DOI：10.1021/acs.jmedchem.7b00168

  日期：2018.1.25

  Targeted protein degradation using small molecules is a novel strategy for drug development. We have developed hybrid molecules named specific and nongenetic inhibitor of apoptosis protein [IAP]-dependent protein erasers (SNIPERs) that recruit IAP ubiquitin ligases to degrade target proteins. Here, we show novel SNIPERs capable of inducing proteasomal degradation of the androgen receptor (AR). Through

  使用小分子进行有针对性的蛋白质降解是药物开发的新策略。我们已经开发了杂交分子，命名为凋亡蛋白[IAP]依赖蛋白橡皮擦（SNIPERs）的特异性和非遗传抑制剂，这些蛋白可以募集IAP泛素连接酶来降解目标蛋白。在这里，我们显示了新型的SNIPERs，能够诱导雄激素受体（AR）的蛋白酶体降解。通过在AR配体和IAP配体和接头处SNIPER（AR）分子的衍生化，我们开发了42a（SNIPER（AR）-51），该蛋白显示出针对AR的有效蛋白敲低活性。与AR蛋白的降解一致，42a抑制AR介导的基因表达和雄激素依赖性前列腺癌细胞的增殖。另外42a有效诱导前列腺癌细胞中的半胱天冬酶激活和凋亡，这在用AR拮抗剂处理的细胞中未观察到。这些结果表明，SNIPER（AR）可能是抗前列腺癌抗癌药物的先导，而前列腺癌表现出AR依赖性增殖。
• Development of target protein-selective degradation inducer for protein knockdown
  作者：Yukihiro Itoh、Minoru Ishikawa、Risa Kitaguchi、Shinichi Sato、Mikihiko Naito、Yuichi Hashimoto

  DOI：10.1016/j.bmc.2011.03.057

  日期：2011.5

  Our previous technique for inducing selective degradation of target proteins with ester-type SNIPER (Specific and Nongenetic Inhibitor-of-apoptosis-proteins (IAPs)-dependent Protein ERaser) degrades both the target proteins and IAPs. Here, we designed a small-molecular amide-type SNIPER to overcome this issue. As proof of concept, we synthesized and biologically evaluated an amide-type SNIPER which induces selective degradation of cellular retinoic acid binding protein II (CRABP-II), but not IAPs. Such small-molecular, amide-type SNIPERs that induce target protein-selective degradation without affecting IAPs should be effective tools to study the biological roles of target proteins in living cells. (C) 2011 Elsevier Ltd. All rights reserved.