(4R,6E,10E,12Z)-16,18-dihydroxy-4-methyl-12-(2-oxo-2-piperidin-1-ylethoxy)imino-3-oxabicyclo[12.4.0]octadeca-1(14),6,10,15,17-pentaen-2-one | 1173889-47-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酯类和类似物
• 英文名称: (4R,6E,10E,12Z)-16,18-dihydroxy-4-methyl-12-(2-oxo-2-piperidin-1-ylethoxy)imino-3-oxabicyclo[12.4.0]octadeca-1(14),6,10,15,17-pentaen-2-one
• CAS: 1173889-47-8
• 化学式: C₂₅H₃₂N₂O₆
• 分子量: 456.539
• InChiKey: VZVRACFMIZZMJB-GEACGRFDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  33
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  109
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  在 polystyrene-sulfonic acid 作用下， 以 甲醇 为溶剂， 反应 4.0h， 以85%的产率得到(4R,6E,10E,12Z)-16,18-dihydroxy-4-methyl-12-(2-oxo-2-piperidin-1-ylethoxy)imino-3-oxabicyclo[12.4.0]octadeca-1(14),6,10,15,17-pentaen-2-one
  参考文献：
  名称：

  针对 HSP90 的 Pochonin 文库的不同合成和已鉴定抑制剂的体内功效。

  摘要：

  The heat shock protein 90 (HSP90) has emerged as one of the most exciting therapeutic target in recent years.[1, 2] Despite the seemingly ubiquitous function of this constitutively expressed chaperone, its role in stabilizing conformationally labile proteins has implications in pathologies ranging from oncology to neurodegenerative diseases. Most of HSP90’s endogenous clients[3] are key regulators of cell signaling which are destabilized and degraded in the absence of HSP90’s chaperoning activity. The dependence of transformed cells on HSP90 is further heightened by the fact that many oncogenic mutations, while increasing the activity of pro-growth signaling pathways, are less stable than their wild type counterpart and have an increased dependence on HSP90’s chaperoning activity.[4] A clinically relevant example is the heightened dependence of drug resistant Bcr-Abl mutants on HSP90’s activity and the fact that HSP90 inhibitors in combination with Abl inhibitors remain effective against such mutants.[5, 6] Accordingly, HSP90 inhibition provides a broad and effective target for anticancer treatment. Furthermore, HSP90 inhibitors can act synergistically with a cytotoxic agent.[7] HSP90 is also implicated in regulating the fate of a number of conformationally unstable proteins which underlie the development of neurodegenerative diseases.[8] It has been shown that HSP90 inhibitors can reduce protein aggregates in cellular and animal models of Huntington disease,[9] spinal and bulbar muscular atrophy,[10] Parkinson disease,[11] and other Tau protein-related neurodegenerative diseases.[12]

  DOI：

  10.1002/anie.200800233

文献信息

• [EN] POCHOXIME CONJUGATES USEFUL FOR THE TREATMENT OF HSP90 RELATED PATHOLOGIES<br/>[FR] DÉRIVÉS DE POCHOXIME CONVENANT POUR LE TRAITEMENT DE PATHOLOGIES EN RAPPORT AVEC HSP90
  申请人：UNIV STRASBOURG

  公开号：WO2012052843A1

  公开（公告）日：2012-04-26

  The present invention includes novel derivatives, analogs, and intermediates of the natural products radicicol, pochonins, pochoximes, and their syntheses. The present invention also provides a pharamceutical composition comprising the present compound and the use of the compound as inhibitors of kinases and of the enzyme family known as heat shock protein 90 (HSP90).

  本发明包括天然产物radicicol、pochonins、pochoximes的新颖衍生物、类似物和中间体，以及它们的合成方法。本发明还提供了一种包含本化合物的药物组合物，以及将该化合物用作激酶抑制剂和热休克蛋白90（HSP90）酶家族的用途。
• Treatment Of Neurofibromatosis With Radicicol And Its Derivatives
  申请人：CHEN Ruihong

  公开号：US20100292218A1

  公开（公告）日：2010-11-18

  The present invention provides compounds of formulae Ia, Ia′, IIa, IIa′, IIIa, IIIa′, IVa, or Va and the therapeutic use thereof. The present invention also includes methods of treating NF2-deficient or NF1-deficient cells or neurodegenerative diseases with radicicol or its derivatives, such as one or more compounds of formula I, II, III, IV, V, Ia, Ia′, IIa, IIa′, IIIa, IIIa′, IVa, or Va. Furthermore, the present invention is directed to methods of inhibiting the growth of NF2-deficient or NF1-deficient tumors. The methods comprise contacting NF2-deficient or NF1-deficient tumor cells with radicicol or its derivatives, such as one or more compounds of formula I, II, III, IV, V, Ia, Ia′, IIa, IIa′, IIIa, IIIa′, IVa, or Va. The present invention is also directed to the combinational use of radicicol or its derivatives, such as one or more compounds of formula I, II, III, IV, V, Ia, Ia′, IIa, IIa′, IIIa, IIIa′, IVa, or Va with at least one additional active agent, such as one or more HSP90 inhibitors.

  本发明提供了Ia、Ia′、IIa、IIa′、IIIa、IIIa′、IVa或Va配方的化合物及其治疗用途。本发明还包括使用紫霉素或其衍生物，例如公式I、II、III、IV、V、Ia、Ia′、IIa、IIa′、IIIa、IIIa′、IVa或Va中的一个或多个化合物，治疗NF2缺陷或NF1缺陷细胞或神经退行性疾病的方法。此外，本发明还涉及抑制NF2缺陷或NF1缺陷肿瘤生长的方法。该方法包括使用紫霉素或其衍生物，例如公式I、II、III、IV、V、Ia、Ia′、IIa、IIa′、IIIa、IIIa′、IVa或Va中的一个或多个化合物接触NF2缺陷或NF1缺陷肿瘤细胞。本发明还涉及紫霉素或其衍生物，例如公式I、II、III、IV、V、Ia、Ia′、IIa、IIa′、IIIa、IIIa′、IVa或Va与至少一种其他活性剂，例如一种或多种HSP90抑制剂的联合使用。
• Synthesis of resorcylic acid lactones useful as therapeutic agents
  申请人：Winssinger Nicolas

  公开号：US10239856B2

  公开（公告）日：2019-03-26

  Disclosed are macrocyclic compounds of formulae I, I′, II, II′, III, III′, IV, and V, which are analogs of the pochonin resorcylic acid lactones, pharmaceutical compositions comprising the compounds, and methods and uses comprising the compounds for the treatment of diseases mediated by kinases and Heat Shock Protein 90 HSP90.

  所公开的是式 I、I′、II、II′、III、III′、IV 和 V 的大环化合物，它们是宝鸡素树脂酸内酯的类似物，包含这些化合物的药物组合物，以及包含这些化合物的用于治疗激酶和热休克蛋白 90 HSP90 介导的疾病的方法和用途。
• SYNTHESIS OF RESORCYLIC ACID LACTONES USEFUL AS THERAPEUTIC AGENTS
  申请人：Winssinger Nicolas

  公开号：US20110217335A1

  公开（公告）日：2011-09-08

  Disclosed are macrocyclic compounds of formulae I, I′, II, II′, III, III′, IV, and V, which are analogs of the pochonin resorcylic acid lactones, pharmaceutical compositions comprising the compounds, and methods and uses comprising the compounds for the treatment of diseases mediated by kinases and Heat Shock Protein 90 HSP90.
• POCHOXIME CONJUGATES USEFUL FOR THE TREATMENT OF HSP90 RELATED PATHOLOGIES
  申请人：Winssinger Nicolas

  公开号：US20140031302A1

  公开（公告）日：2014-01-30

  The present invention includes novel derivatives, analogs, and intermediates of the natural products radicicol, pochonins, pochoximes, and their syntheses. The present invention also provides a pharmaceutical composition comprising the present compound and the use of the compound as inhibitors of kinases and of the enzyme family known as heat shock protein 90 (HSP90).