(6R,9AR)-REL-六氢-6-[(4-羟基苯基)甲基]-8-(1-萘基甲基)-4,7-二氧代-N-(苯基甲基)-2H-吡嗪并[1,2-A]嘧啶-1(6H)-甲酰胺 | 780757-88-2

• 物质功能分类: 生物化工 - 抑制剂 - 干细胞及Wnt信号通路(Stem Cells & Wnt)
• 分子结构分类: 有机化合物 - 苯类化合物
• 中文名称: (6R,9AR)-REL-六氢-6-[(4-羟基苯基)甲基]-8-(1-萘基甲基)-4,7-二氧代-N-(苯基甲基)-2H-吡嗪并[1,2-A]嘧啶-1(6H)-甲酰胺
• 中文别名: 香紫苏醇.硬尾醇；(6S,9as)-n-苄基-6-(4-羟基苄基)-8-(萘-1-甲基)-4,7-二氧代八氢-1H-吡嗪o[1,2-a]嘧啶-1-羧酰胺；2,3-二氢-1,4-苯并恶嗪；(6R,9aR)-rel-六氢-6-((4-羟基苯基)甲基)-8-(1-萘基甲基)-4,7-二氧代-N-(苯基甲基)-2H-吡嗪并(1,2-a)嘧啶-1(6H)-甲酰胺
• 英文名称: ICG 001
• 英文别名: PRI-724；(6S,9aS)-N-benzyl-6-(4-hydroxybenzyl)-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxamide；(6S,9aS)-N-benzyl-6-[(4-hydroxyphenyl)methyl]-8-(naphthalen-1-ylmethyl)-4,7-dioxo-3,6,9,9a-tetrahydro-2H-pyrazino[1,2-a]pyrimidine-1-carboxamide
• CAS: 780757-88-2
• 化学式: C₃₃H₃₂N₄O₄
• 分子量: 548.641
• InChiKey: HQWTUOLCGKIECB-XZWHSSHBSA-N

物化性质

• 熔点：
  133-134℃
• 沸点：
  895.6±65.0 °C(Predicted)
• 密度：
  1.37
• 溶解度：
  DMSO:30.0(最大浓度 mg/mL);54.68(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  41
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  93.2
• 氢给体数：
  2
• 氢受体数：
  4

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

ICG-001 (OP-724, PRI-724, CBP-beta catenin inhibitor)拮抗Wnt/β-catenin/TCF介导的转录，并特异性结合到启动子结合蛋白（CBP)，IC50为3 μM，但不能结合到相关的转录共激活因子p300上。ICG-001 可诱导凋亡。

靶点

Target	Value
CBP (Cell-free assay)	3 μM

体外研究

ICG-001 作用于TOPFLASH 时，IC50为3 μM，而对含突变TCF位点的相关报告基因结构, FOPFLASH没有作用效果。使用25μM ICG-001处理SW480 细胞8小时后，降低Survivin和 Cyclin D1 RNA和蛋白的稳定水平，这两者都可通过β-catenin上调。ICG-001 作用于转化细胞而不是正常结肠细胞，选择性诱导凋亡，降低结肠癌细胞生长。 ICG-001作用于presenilin-1突变细胞，可表型营救正常神经生长因子(NGF)诱导的神经元分化和神经轴突生长，强调TCF/β-catenin 信号通路在神经轴突生长和神经元分化中的重要性。 最新研究显示 5μM ICG-001作用于MCF7细胞，抑制leptin诱导的EMT, 入侵和肿瘤干细胞球形成。

体内研究

ICG-001 水溶性类似物处理9周，降低42%结肠和小肠息肉的形成，和非甾体类抗炎试剂Sulindac效果类似，Sulindac是一贯治疗这种疾病模型的药物。在整个的处理期间观察不到明显的毒性。类似物按150 mg/kg 剂量静脉注射处理SW620裸鼠肿瘤衰退移植瘤模型，处理19天，显著降低肿瘤体积，没有死亡，体重也没有降低。 ICG-001 每天按5 mg/kg剂量处理小鼠，显著抑制beta-catenin信号，且降低 Bleomycin诱导的肺纤维化，同时保护上皮细胞。

反应信息

• 作为产物：
  描述：

  (S)-2-[3-(3-benzyl-ureido)-propionylamino]-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-N-naphthalen-1-ylmethyl-propionamide 在 甲酸 作用下， 反应 20.0h， 以57%的产率得到(6R,9AR)-REL-六氢-6-[(4-羟基苯基)甲基]-8-(1-萘基甲基)-4,7-二氧代-N-(苯基甲基)-2H-吡嗪并[1,2-A]嘧啶-1(6H)-甲酰胺
  参考文献：
  名称：

  SYNTHESIS AND ANALYSIS OF NOVEL COMPOUND CAPABLE OF INDUCING DIFFERENTIATION OF HUMAN MESENCHYMAL STEM CELL INTO HEPATOCYTE

  摘要：

  公开号：

  EP2698365B8

文献信息

• CBP/CATENIN ANTAGONISTS FOR ENHANCING ASYMMETRIC DIVISION OF SOMATIC STEM CELLS
  申请人：Kahn Michael

  公开号：US20150232468A1

  公开（公告）日：2015-08-20

  Provided are: composition and methods for: treating aging or an age-related condition, symptom or disease; stimulating hair growth, regrowth or pigmentation (or preventing hair loss); for increasing the expression of an adenosine receptor in dermal cells (in combination with hair growth); for treating a condition or disease of the skin or at least one symptom thereof, including cosmetic treatment (e.g., wrinkles, hyperpigmentation, redness, rosacea, dryness, cracking, loss of firmness, loss of elasticity, thinning, and loss of vibrance). The methods comprise administering a sufficient amount of the disclosed CBP/catenin (e.g., CBP/ B -catenin) antagonist compositions, and particularly wherein administration is in an amount and manner sufficient to provide for increasing the number of asymmetric renewing divisions relative to, or at the expense of symmetric divisions in relevant somatic stem cell population. In particular aspects, the CBP/catenin (e.g., CBP/ B -catenin) antagonist comprises an alkyl and/or fatty acid ester derivative thereof as disclosed herein.

  提供的是：用于治疗衰老或与年龄相关的病症、症状或疾病的组合物和方法；刺激头发生长、再生或色素沉着（或预防脱发）；增加皮肤细胞中腺苷酸受体的表达（与头发生长相结合）；用于治疗皮肤病或其中至少一种症状的条件或疾病，包括美容治疗（例如皱纹、色素沉着、发红、酒渣鼻、干燥、龟裂、松弛、弹性下降、变薄和失去活力）。该方法包括给予足够量的揭示的CBP/β-连环素（例如CBP/B-连环素）拮抗剂组合物，特别是在足够的量和方式下给予，以提高与相关体细胞干细胞群体对称分裂相对或代价的非对称更新分裂数量。在特定方面，CBP/β-连环素（例如CBP/B-连环素）拮抗剂包括其烷基和/或脂肪酸酯衍生物，如本文所述。
• REVERSE-TURN MIMETICS AND METHOD RELATING THERETO
  申请人：Moon Sung Hwan

  公开号：US20100029630A1

  公开（公告）日：2010-02-04

  Conformationally constrained compounds that mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins are disclosed. Such reverse-turn mimetic structures have utility over a wide range of fields, including use as diagnostic and therapeutic agents. Libraries containing the reverse-turn mimetic structures of this invention are also disclosed as well as methods for screening the same to identify biologically active members. The invention also relates to the use of such compounds for inhibiting or treating disorders modulated by Wnt-signaling pathway, such as cancer, especially colorectal cancer, restenosis associated with angioplasty, polycystic kidney disease, aberrant angiogenesis disease, rheumatoid arthritis disease, tuberous sclerosis complex, Alzheimer's disease, excess hair growth or loss, or ulcerative colitis.

  本文揭示了具有构象约束的化合物，其模拟生物活性肽和蛋白质的反转区域的二级结构。这种反转区域模拟结构在广泛的领域中具有实用性，包括用作诊断和治疗剂。本发明还揭示了包含这种反转区域模拟结构的文库，以及筛选这些文库以识别具有生物活性成员的方法。本发明还涉及使用这些化合物来抑制或治疗由Wnt信号通路调节的疾病，例如癌症，特别是结肠直肠癌，与血管成形术相关的再狭窄，多囊肾病，异常血管生成疾病，类风湿性关节炎疾病，结节性硬化症，阿尔茨海默病，过度生长或脱发，或溃疡性结肠炎。
• Reverse-turn mimetics and method relating thereto
  申请人：Moon Hwan Sung

  公开号：US20070021425A1

  公开（公告）日：2007-01-25

  Conformationally constrained compounds that mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins are disclosed. Such reverse-turn mimetic structures have utility over a wide range of fields, including use as diagnostic and therapeutic agents. Libraries containing the reverse-turn mimetic structures of this invention are also disclosed as well as methods for screening the same to identify biologically active members. The invention also relates to the use of such compounds for inhibiting or treating disorders modulated by Wnt-signaling pathway, such as cancer, especially colorectal cancer, restenosis associated with angioplasty, polycystic kidney disease, aberrant angiogenesis disease, rheumatoid arthritis disease, tuberous sclerosis complex, Alzheimer's disease, excess hair growth or loss, or ulcerative colitis.

  本发明揭示了能够模拟生物活性肽和蛋白质的反转区域的二级结构的构象限制化合物。这种反转区域拟态结构在广泛的领域中具有实用性，包括用作诊断和治疗剂。本发明还揭示了包含这种反转区域拟态结构的库，以及筛选这些库以识别生物活性成员的方法。本发明还涉及使用这些化合物来抑制或治疗由Wnt信号通路调节的疾病，例如癌症，特别是结直肠癌，与血管成形术相关的再狭窄，多囊肾病，异常血管生成疾病，类风湿性关节炎疾病，结节性硬化症，阿尔茨海默病，过度生发或脱发，或溃疡性结肠炎。
• COMPOSITION FOR INDUCTION OR INHIBITION OF STEM CELL DIFFERENTIATION
  申请人：Oh Se Woong

  公开号：US20090215783A1

  公开（公告）日：2009-08-27

  The present invention relates to composition and methods for inducing or inhibiting differentiation of stem cells. The invention also relates to applications in the treatment of medical conditions, e.g., osteoporosis, bone fracture, bone injuries, myocardiac infarction, cardiomyopathy, degenerative muscle diseases, myopathy, and urinary incontinence.

  本发明涉及诱导或抑制干细胞分化的组合物和方法。本发明还涉及在治疗医疗状况方面的应用，例如骨质疏松症、骨折、骨伤、心肌梗塞、心肌病、退行性肌肉疾病、肌病和尿失禁。
• WNT PATHWAY STIMULATION IN REPROGRAMMING SOMATIC CELLS
  申请人：Whitehead Institute for Biomedical Research

  公开号：EP3078738A1

  公开（公告）日：2016-10-12

  The invention provides compositions and methods of use in reprogramming somatic cells. Compositions and methods of the invention are of use, e.g., for generating or modulating (e.g., enhancing) generation of induced pluripotent stem cells by reprogramming somatic cells. The reprogrammed somatic cells are useful for a number of purposes, including treating or preventing a medical condition in an individual. The invention further provides methods for identifying an agent that reprograms somatic cells to a pluripotent state and/or enhances the speed and/or efficiency of reprogramming. Certain of the compositions and methods relate to modulating the Wnt pathway.

  本发明提供了用于体细胞重编程的组合物和方法。本发明的组合物和方法具有用途，例如，通过对体细胞进行重编程，生成或调节（例如，增强）诱导多能干细胞的生成。重编程的体细胞可用于多种目的，包括治疗或预防个体的医疗状况。本发明进一步提供了确定将体细胞重编程为多能状态和/或提高重编程速度和/或效率的制剂的方法。某些组合物和方法与调节 Wnt 通路有关。