tert-butyl 2-(3-(3-(3,4-dimethoxyphenyl)-1-hydroxypropyl)phenoxy)acetate | 1323151-35-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 直链 1,3-二芳基丙烷
• 英文名称: tert-butyl 2-(3-(3-(3,4-dimethoxyphenyl)-1-hydroxypropyl)phenoxy)acetate
• 英文别名: tert-butyl 2-[3-[(1S)-3-(3,4-dimethoxyphenyl)-1-hydroxypropyl]phenoxy]acetate
• CAS: 1323151-35-4
• 化学式: C₂₃H₃₀O₆
• 分子量: 402.488
• InChiKey: LTSMVCSYXYLQNM-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  29
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  74.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl 2-(3-(3-(3,4-dimethoxyphenyl)-1-hydroxypropyl)phenoxy)acetate 在 4-二甲氨基吡啶 、 叠氮磷酸二苯酯 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 20.0 ℃ 、100.0 kPa 条件下， 反应 12.0h， 生成 tert-butyl 2-(3-(3-(3,4-dimethoxyphenyl)-1-((S)-1-(3,3-dimethyl-2-oxopentanoyl)piperidine-2-carboxamido)propyl)phenoxy)acetate
  参考文献：
  名称：

  Evaluation of Synthetic FK506 Analogues as Ligands for the FK506-Binding Proteins 51 and 52

  摘要：

  The FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Both proteins have been implicated in prostate cancer. Furthermore, single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products that bind to these proteins indiscriminately but with nanomolar affinity. We here report the cocrystal structure of FKBP51 with a simplified alpha-ketoamide analogue derived from FK506 and the first structure-activity relationship analysis for FKBP51 and FKBP52 based on this compound. In particular, the tert-pentyl group of this ligand was systematically replaced by a cyclohexyl ring system, which more closely resembles the pyranose ring in the high-affinity ligands rapamycin and FK506. The interaction with FKBPs was found to be surprisingly tolerant to the stereochemistry of the attached cyclohexyl substituents. The molecular basis for this tolerance was elucidated by X-ray cocrystallography.

  DOI：

  10.1021/jm201746x
• 作为产物：
  描述：

  溴乙酸叔丁酯 在 sodium tetrahydroborate 、 potassium carbonate 作用下， 以 丙酮 为溶剂， 反应 20.0h， 生成 tert-butyl 2-(3-(3-(3,4-dimethoxyphenyl)-1-hydroxypropyl)phenoxy)acetate
  参考文献：
  名称：

  Evaluation of Synthetic FK506 Analogues as Ligands for the FK506-Binding Proteins 51 and 52

  摘要：

  The FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Both proteins have been implicated in prostate cancer. Furthermore, single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products that bind to these proteins indiscriminately but with nanomolar affinity. We here report the cocrystal structure of FKBP51 with a simplified alpha-ketoamide analogue derived from FK506 and the first structure-activity relationship analysis for FKBP51 and FKBP52 based on this compound. In particular, the tert-pentyl group of this ligand was systematically replaced by a cyclohexyl ring system, which more closely resembles the pyranose ring in the high-affinity ligands rapamycin and FK506. The interaction with FKBPs was found to be surprisingly tolerant to the stereochemistry of the attached cyclohexyl substituents. The molecular basis for this tolerance was elucidated by X-ray cocrystallography.

  DOI：

  10.1021/jm201746x

文献信息

• Targeted Covalent Inhibition of <i>Plasmodium</i> FK506 Binding Protein 35
  作者：Thomas C. Atack、Donald D. Raymond、Christa A. Blomquist、Charisse Flerida Pasaje、Patrick R. McCarren、Jamie Moroco、Henock B. Befekadu、Foxy P. Robinson、Debjani Pal、Lisl Y. Esherick、Alessandra Ianari、Jacquin C. Niles、William R. Sellers

  DOI：10.1021/acsmedchemlett.0c00272

  日期：2020.11.12

  protein 35, FKBP35, has been implicated as an essential malarial enzyme. Rapamycin and FK506 exhibit antiplasmodium activity in cultured parasites. However, due to the highly conserved nature of the binding pockets of FKBPs and the immunosuppressive properties of these drugs, there is a need for compounds that selectively inhibit FKBP35 and lack the undesired side effects. In contrast to human FKBPs, FKBP35

  FK506结合蛋白35，FKBP35，已被认为是必需的疟疾酶。雷帕霉素和FK506在培养的寄生虫中表现出抗疟原虫活性。然而，由于FKBP的结合口袋的高度保守的性质和这些药物的免疫抑制特性，需要选择性地抑制FKBP35并且缺乏不良副作用的化合物。与人FKBP相比，FKBP35在雷帕霉素结合口袋附近包含一个半胱氨酸C106，为开发靶向疟原虫FKBP35的共价抑制剂提供了机会。在这里，我们合成了FKBP35的抑制剂，表明它们在模型细胞环境中直接结合FKBP35，选择性地共价修饰C106，并在血阶段培养的寄生虫中表现出抗疟原虫活性。
• Design and Combinatorial Development of Shield-1 Peptide Mimetics Binding to Destabilized FKBP12
  作者：Daniel Madsen、Frederik P. Jørgensen、Daniel Palmer、Milena E. Roux、Jakob V. Olsen、Mikael Bols、Sanne Schoffelen、Frederik Diness、Morten Meldal

  DOI：10.1021/acscombsci.9b00197

  日期：2020.3.9

  rapid structure evaluation prior to off-bead resynthesis. Subsequently, a series of 19 compounds were prepared and tested using a competitive fluorescence polarization assay, which led to the discovery of peptide ligands with low micromolar binding affinity towards the DD. The methodology represents a rapid approach for identification of a novel structure scaffold, where the screening and initial structure

  在计算设计的基础上，已针对由小三肽和三唑封端的N末端组成的微粒编码的PEGA1900珠制备了聚焦的单珠单化合物文库。针对人FKBP12蛋白的双点突变版本（称为去稳定结构域（DD））筛选了该文库。受解码的文库命中率的启发，在新颖的珠上检测方法中筛选了非天然肽结构，这对于在离珠重新合成之前进行快速结构评估很有用。随后，制备了19种化合物，并使用竞争荧光偏振分析法进行了测试，这导致发现了对DD具有低微摩尔结合亲和力的肽配体。该方法代表了一种鉴定新型结构支架的快速方法，
• Small-Molecule Hydrophobic Tagging of Fusion Proteins and Induced Degradation of Same
  申请人：Yale University

  公开号：US20140302523A1

  公开（公告）日：2014-10-09

  The present invention includes compounds that are useful in perturbing or disrupting the function of a transmembrane or intracellular protein, whereby binding of a compound to the transmembrane or intracellular protein induces proteasomal degradation of the transmembrane or intracellular protein. The present invention further includes a method of inducing proteasomal degradation of a transmembrane or intracellular protein. The present invention further includes a method of identifying or validating a protein of interest as a therapeutic target for treatment of a disease state or condition.

  本发明包括一些化合物，这些化合物有助于扰乱或破坏跨膜或胞内蛋白的功能，其中化合物与跨膜或胞内蛋白的结合诱导跨膜或胞内蛋白的蛋白酶体降解。本发明还包括一种诱导跨膜或胞内蛋白的蛋白酶体降解的方法。本发明还包括一种鉴定或验证感兴趣蛋白作为治疗疾病状态或病情的治疗靶点的方法。