鲁伯斯塔 | 169939-94-0

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 中文名称: 鲁伯斯塔
• 中文别名: 卢博滔林
• 英文名称: ruboxistaurin
• 英文别名: LY333531；((9S)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-dimetheno)dibenzo-[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20(19H)-dione；(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.17,14.02,6.08,13.022,27]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione
• CAS: 169939-94-0
• 化学式: C₂₈H₂₈N₄O₃
• 分子量: 468.555
• InChiKey: ZCBUQCWBWNUWSU-SFHVURJKSA-N

物化性质

• 沸点：
  744.4±60.0 °C(Predicted)
• 密度：
  1.34
• 溶解度：
  DMSO：50 mg/mL（106.71 mM；超声加热并加热至 60°C）

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  35
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  68.5
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

鲁博克西斯他林已知的人体代谢物包括N-去甲基LY333531。

Ruboxistaurin has known human metabolites that include N-desmethyl LY333531.

来源:NORMAN Suspect List Exchange

反应信息

• 作为产物：
  描述：

  tert-butyl-[(2S)-4-iodo-2-(2-iodoethoxy)butoxy]-diphenylsilane 在 吡啶 、 氢氧化钾 、 caesium carbonate 、 六甲基二硅氮烷 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 40.0h， 生成 鲁伯斯塔
  参考文献：
  名称：

  (S)-13-[(Dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno- 1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione (LY333531) and Related Analogues:  Isozyme Selective Inhibitors of Protein Kinase Cβ

  摘要：

  Protein kinase C (PKC) is a family of closely related serine and threonine kinases. Overactivation of some PKC isozymes has been postulated to occur in several disease states, including diabetic complications. Selective inhibition of overactivated PKC isozymes may offer a unique therapeutic approach to disease states such as diabetic retinopathy. A novel series of 14-membered macrocycles containing a N-N'-bridged bisindolylmaleimide moiety is described. A panel of eight cloned human PKC isozymes (alpha, beta I, beta II, gamma, delta, epsilon, zeta, eta) was used to identify the series and optimize the structure and associated activity relationship. The dimethylamine analogue LY333531 (1), (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione, inhibits the PKC beta I (IC50 = 4.7 nM) and PKC beta II (IC50 = 5.9 nM) isozymes and was 76- and 61-fold selective for inhibition of PKC beta I and PKC beta II in comparison to PKC alpha, respectively. The additional analogues described in the series are also selective inhibitors of PKC beta. LY333531 (1) exhibits ATP dependent competitive inhibition. of PKC beta I and is selective for PKC in comparison to other ATP dependent kinases (protein kinase A, calcium calmodulin, caesin kinase, src tyrosine kinase). The cellular activity of the series was assessed using bovine retinal capillary endothelial cells. Retinal endothelial cell dysfunction has been implicated in the development of diabetic retinopathy. Plasminogen activator activity stimulated by a phorbol ester (4 beta-phorbol 12,13-dibutyrate) in endothelial cells was inhibited by the compounds in the series with ED(50) values ranging from 7.5 to 0.21 mu M. A comparison of the PKC isozyme and related ATP dependent kinase inhibition profiles is provided for the series and compared to the profile for staurosporine, a nonselective PKC inhibitor. The cellular activity of the series is compared with that of the kinase inhibitor staurosporine.

  DOI：

  10.1021/jm950588y

文献信息

• Method of manufacturing ruboxistarin
  申请人：Zentiva, k.s.

  公开号：EP2181999A1

  公开（公告）日：2010-05-05

  Method of manufacturing ruboxistaurin, comprising the steps of preparation of L-2-deoxyribose 1-cyano-3,4-dibenzoate, followed by deprotection to 1-cyano L-2-deoxyribose, oxidative cleaving to (S)-4-hydroxy-2-(2-hydroxy-ethoxy)-butyronitrile and transformation to the methanesulfonic acid (S)-3-cyano-3-(2-methanesulfonyloxyethoxy)-propyl ester, then coupling with 1-substituted-3,4-bis(3-indolyl)maleimide leading to 9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13] oxadiazacyclohexadecine-18,20(19H)-dione, 6,7,10,11-tetrahydro-19-substituted-9(S)-cyano, followed by methylation of the amino group and deprotection forming 5,21:12,17-dimetheno-9H-dibenzo[e,k]furo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20-dione, 6,7,10,11-tetrahydro-9-[(dimethylamino)methyl]-, (S)- (9CI), and the final step consisting of imido preparation to form ruboxistaurin.

  生产鲁博西他林的方法，包括以下步骤：制备L-2-去氧核糖-1-氰-3,4-二苯甲酸酯，然后去保护成为1-氰基L-2-去氧核糖，氧化断裂成(S)-4-羟基-2-(2-羟基乙氧基)-丁腈，并转化为甲磺酸(S)-3-氰基-3-(2-甲磺酰氧乙氧基)-丙基酯，然后与1-取代-3,4-双(3-吲哚基)马来酰亚胺偶联，得到9H,18H-5,21:12,17-二甲烯二苯并[e,k]吡咯并[3,4-h][1,4,13]噁二氮杂环十六烷-18,20(19H)-二酮，6,7,10,11-四氢-19-取代-9(S)-氰基，然后甲基化氨基团并去保护，形成5,21:12,17-二甲烯-9H-二苯并[e,k]呋喃[3,4-h][1,4,13]噁二氮杂环十六烷-18,20-二酮，6,7,10,11-四氢-9-[(二甲氨基)甲基]-，(S)- (9CI)，最后一步是制备亚砜以形成鲁博西他林。
• Regenerative therapy
  申请人：Medizinische Universität Wien

  公开号：EP2177218A1

  公开（公告）日：2010-04-21

  The present invention relates to the use of an agent capable of enhancing the PKA-p38-CREB pathway, suppressing the Fyn-RhoA-Rock and/or PKC-alpha-MARCKS pathways or Ephrin-B3 for the manufacture of a pharmaceutical composition for the treatment of damaged myelin sheaths, characterized in that, the agent neutralizes the effect of inhibitors of the regeneration of damaged myelin sheaths by oligodendrocytes, and wherein the inhibitors are selected from myelin associated inhibitors, in particular Ephrin-B3, and inhibitors of the glial scar, in particular Sema3A, and kits suitable for the treatment of damaged myelin sheaths.

  本发明涉及一种能够增强PKA-p38-CREB通路、抑制Fyn-RhoA-Rock和/或PKC-α-MARCKS通路或Ephrin-B3的制剂在制造治疗受损髓鞘的药物组合物中的用途，其特征在于：该制剂能中和抑制少突胶质细胞再生受损髓鞘的抑制剂的作用，其中抑制剂选自髓鞘相关抑制剂，特别是 Ephrin-B3，以及胶质瘢痕抑制剂，特别是 Sema3A，以及适用于治疗受损髓鞘的试剂盒。
• METHOD FOR SUPPRESSING DIFFERENTIATION OF PLURIPOTENT STEM CELLS
  申请人：Kaneka Corporation

  公开号：EP4105319A1

  公开（公告）日：2022-12-21

  Pluripotent stem cells are suspension-cultured with the undifferentiated state thereof maintained. In suspension culture of pluripotent stem cells, the undifferentiated state is maintained by the presence of a PKC inhibitor, especially, a PKCβ inhibitor, and a tankyrase inhibitor (TNKS inhibitor).

  多能干细胞是在保持未分化状态下进行悬浮培养的。在多能干细胞的悬浮培养过程中，PKC 抑制剂（尤其是 PKCβ 抑制剂）和罐酸酶抑制剂（TNKS 抑制剂）的存在可维持多能干细胞的未分化状态。
• Methods for diagnosing and treating cancer by means of the expression status and mutational status of NRF2 and downstream target genes of said gene
  申请人：Genentech, Inc.

  公开号：US11066709B2

  公开（公告）日：2021-07-20

  The invention provides methods of identifying a subject having cancer, such as lung cancer, by analyzing expression levels of one or more NRF2 splice variants or NRF2 target genes. The invention also provides methods of treating cancer in a subject with a NRF2 pathway antagonist, wherein the subject expresses one or more NRF2 splice variants or overexpresses one or more NRF2 target genes.

  本发明提供了通过分析一种或多种NRF2剪接变体或NRF2靶基因的表达水平来鉴定癌症（如肺癌）受试者的方法。本发明还提供了用NRF2通路拮抗剂治疗受试者癌症的方法，其中受试者表达一种或多种NRF2剪接变体或过度表达一种或多种NRF2靶基因。
• PIM kinase inhibitor compositions, methods, and uses thereof
  申请人：Snap Bio, Inc.

  公开号：US11319320B2

  公开（公告）日：2022-05-03

  This application relates to compounds of formulae (I) and (II) and compositions thereof useful as inhibitors of PIM kinases. Also provided are methods of synthesis and methods of use of PIM inhibitors in treating individuals suffering from cancerous malignancies.

  本申请涉及作为 PIM 激酶抑制剂的式 (I) 和 (II) 化合物及其组合物。还提供了 PIM 抑制剂的合成方法和用于治疗癌症恶性肿瘤患者的方法。