(2R)-2-[[9-异丙基-6-[[[4-(2-吡啶基)苯基]甲基]氨基]-9H-嘌呤-2-基]氨基]-1-丁醇 | 294646-77-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: (2R)-2-[[9-异丙基-6-[[[4-(2-吡啶基)苯基]甲基]氨基]-9H-嘌呤-2-基]氨基]-1-丁醇
• 英文名称: (R)-CR8
• 英文别名: (R)-2-(1-hydroxy-but-2-ylamino)-6-[4-(2-pyridyl)phenylmethylamino]-9-iso-propylpurine；(R)-2-(1-hydroxybut-2-ylamino)-6-[4-(2-pyridyl)phenylmethylamino]-9-iso-propylpurine；CR8；(2R)-2-({9-(1-methylethyl)-6-[(4-pyridin-2-ylbenzyl)amino]-9H-purin-2-yl}amino)butan-1-ol；(2R)-2-[[9-propan-2-yl-6-[(4-pyridin-2-ylphenyl)methylamino]purin-2-yl]amino]butan-1-ol
• CAS: 294646-77-8
• 化学式: C₂₄H₂₉N₇O
• 分子量: 431.541
• InChiKey: HOCBJBNQIQQQGT-LJQANCHMSA-N

物化性质

• 熔点：
  98-100℃
• 沸点：
  671.4±65.0 °C(Predicted)
• 密度：
  1.27±0.1 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：≥10mg/mL
• pKa：
  14.56±0.10 (Predicted,Most Acidic Temp: 25 °C)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  101
• 氢给体数：
  3
• 氢受体数：
  7

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(R)-CR8 (CR8) 是Roscovitine的第二代类似物，是一种有效的CDK1/2/5/7/9抑制剂。(R)-CR8 (CR8) 抑制 CDK1/cyclin B (IC50=0.09 μM)、CDK2/cyclin A (0.072 μM)、CDK2/cyclin E (0.041 μM)、CDK5/p25 (0.11 μM)、CDK7/cyclin H (1.1 μM)、CDK9/cyclin T (0.18 μM) 和 CK1δ/ε (0.4 μM)。(R)-CR8 (CR8) 诱导细胞凋亡并具有神经保护作用。(R)-CR8 作为一种分子胶降解剂来消耗细胞周期蛋白 K。

靶点	IC50 (μM)
Cdk1/cyclin B	0.09
cdk2/cyclin A	0.072
CDK2/cyclinE	0.041
Cdk5/p25	0.11
CDK7/cyclin H	1.1
CDK9/Cyclin T	0.18
CK1δ/ε	0.4

体外研究 (R)-CR8 (CR8) (0.1-100 μM; 48小时) 是一种强效的凋亡诱导剂，对于SH-SY5Y细胞系的半数抑制浓度（IC50）为0.49 μM。(R)-CR8 (0.25-10 μM) 剂量依赖性地诱导聚(ADP-核糖)聚合酶(PARP)切割。结合在CDK上的(R)-CR8 具有外露的吡啶基团，能诱导CDK12-cyclin K与CUL4连接蛋白DDB1形成复合物，绕过了需要底物受体的过程，并将cyclin K呈递用于泛素化和降解。

分析	细胞凋亡分析
细胞系	SH-SY5Y细胞系
浓度 (μM)	0.1, 1, 10, 100
孵化时间（小时）	24
结果	剂量依赖性地减少存活率

体内研究 (R)-CR8 (5 mg/Kg; 腹腔注射) 在组织学评估中显著减少了28天后的病灶大小。

动物模型	10至12周龄雄性Sprague-Dawley大鼠（310至330 g）
剂量 (mg/Kg)	5
给药方式	腹腔注射
结果	显著减少了病灶大小

反应信息

• 作为反应物：
  描述：

  2-(溴甲基)丙烯酸甲酯 、 (2R)-2-[[9-异丙基-6-[[[4-(2-吡啶基)苯基]甲基]氨基]-9H-嘌呤-2-基]氨基]-1-丁醇 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以78 %的产率得到methyl 2-[[[(1R)-1-(hydroxymethyl)propyl]-[7-isopropyl-4-[[4-(2-pyridyl)phenyl]methylamino]pyrrolo[2,3-d]pyrimidin-2-yl]amino]methyl]prop-2-enoate
  参考文献：
  名称：

  [EN] HETEROBIFUNCTIONAL COMPOUNDS AND THEIR USE IN TREATING DISEASE
  [FR] COMPOSÉS HÉTÉROBIFONCTIONNELS ET LEUR UTILISATION DANS LE TRAITEMENT DE MALADIES

  摘要：

  The invention provides heterobifunctional compounds comprising an effector protein binding moiety selected from GSPT1, Cyclin K, RBM23, RBM39, IKZF1, IKZF3, PLK1, CDK4 or CKlalpha which is linked to a moiety that binds to a target protein selected from KRAS, HER2, EGFR, androgen receptor protein, estrogen receptor protein, ALK, IDH1, FLT3, FGFR1, FGFR4, FGFR2, FGFR3, ERK1, ERK2, FGR, HER3 or HER4. Pharmaceutical compositions and their use in treating disease, such as cancer, are also disclosed.

  公开号：

  WO2023059609A1
• 作为产物：
  描述：

  4-(2-吡啶基)苯腈 在 氢化铝锂 、 sodium hydroxide 、 potassium carbonate 、 水 作用下， 以 四氢呋喃 、 水 、 乙醇 、 二甲基亚砜 为溶剂， 以67 %的产率得到(2R)-2-[[9-异丙基-6-[[[4-(2-吡啶基)苯基]甲基]氨基]-9H-嘌呤-2-基]氨基]-1-丁醇
  参考文献：
  名称：

  [EN] HETEROCYCLE SUBSTITUTED PURINE DERIVATIVES AS POTENT ANTIPROLIFERATIVE AGENTS
  [FR] DERIVES DE PURINE A SUBSTITUTION HETEROCYCLE UTILES EN TANT QUE PUISSANTS AGENTS ANTIPROLIFERATIFS

  摘要：

  The compounds of the present invention are 2,6,9-trisubstituted purine derivatives which are inhibitors of cyclin/cdk complexes. The compounds of the current invention also are potent inhibitors of human cellular proliferation. As such, the compounds of the present invention constitute pharmaceutical compositions with a pharmaceutically acceptable carrier. Such compounds are useful in treating a disorder mediated by elevated levels of cell proliferation in a mammal compared to a healthy mammal by administering to such mammal an effective amount of the compound. Examples of the compounds of the present invention are represented by the following chemical structures (I) and (II) with Y, V, A, R1, R2, R3, R4, R7, and n1 defined herein.

  公开号：

  WO2003022805A2

文献信息

• USE OF PURINE DERIVATIVES FOR THE MANUFACTURE OF A MEDICAMENT
  申请人：Meijer Laurent

  公开号：US20100311768A1

  公开（公告）日：2010-12-09

  The invention relates to the use of purine derivatives in the manufacture of a medicament for treating pathological conditions in which an imbalance between cell division and apoptosis is involved, and more particularly in which excessive apoptosis is responsible for the pathological condition. According to the invention, a purine derivative of formula I is used. The invention finds use in the pharmaceutical field.

  本发明涉及使用嘌呤衍生物制造药物，用于治疗细胞分裂和凋亡失衡所涉及的病理状况，尤其是过度凋亡导致病理状况的情况。根据本发明，使用式I的嘌呤衍生物。本发明在制药领域中得到应用。
• Differentiation of hepatocyte-like cells from stem cells
  申请人：Agency for Science, Technology and Research

  公开号：US10323228B2

  公开（公告）日：2019-06-18

  Disclosed are methods of differentiating stem cells in order to obtain hepatocyte-like cells, the method comprising the steps of a) subjecting definitive endoderm to at least one epigenetic modulator to obtain hepatoblasts and b) subjecting the hepatoblasts to at least one stem cell differentiation pathway inhibitor to obtain hepatocyte-like cells; wherein steps a) and b) do not comprise the use of a growth factor. In one preferred embodiment, the epigenetic modulator may be sodium butyrate and/or DMSO and the stem cell differentiation pathway inhibitor may be SB431542 and/or DMSO. Also disclosed are hepatocyte-like cells obtained from the method and uses of these cells such as drug screening.

  本发明公开了分化干细胞以获得肝细胞样细胞的方法，该方法包括以下步骤：a)将确定的内胚层置于至少一种表观遗传调节剂中以获得肝母细胞；b)将肝母细胞置于至少一种干细胞分化途径抑制剂中以获得肝细胞样细胞；其中步骤a)和b)不包括使用生长因子。在一个优选的实施方案中，表观遗传调节剂可以是丁酸钠和/或二甲基亚砜，干细胞分化途径抑制剂可以是SB431542和/或二甲基亚砜。还公开了从该方法中获得的肝细胞样细胞以及这些细胞的用途，如药物筛选。
• Compounds for reducing c-Myc in c-Myc overexpressing cancers background
  申请人：The Trustees of Columbia University in the City of New York

  公开号：US10882863B2

  公开（公告）日：2021-01-05

  The invention relates to new compounds that reduce c-Myc expression and useful for cancer treatment, particularly hematological cancers such as aggressive B- and T-cell lymphomas. The new compounds may be combined with adjunct c-Myc inhibor agents such as a PI3K inhibitor, CK-1 inhibitor, Akt-inhibitor, proteasome inhibitor and/or mTor inhibitor. The c-Myc reducing agent may be provided as a lead-in treatment to reduce or initiate reduction of c-Myc prior to administration of the adjunct cancer therapeutic agent. Treatment with a c-Myc reducing agent modulates the disease state of the c-Myc overexpressing cancer making it less malignant and more susceptible to adjunctive cancer therapies.

  本发明涉及可降低 c-Myc 表达并可用于癌症治疗的新化合物，特别是血液肿瘤，如侵袭性 B 细胞和 T 细胞淋巴瘤。新化合物可与辅助性 c-Myc 抑制剂如 PI3K 抑制剂、CK-1 抑制剂、Akt-抑制剂、蛋白酶体抑制剂和/或 mTor 抑制剂结合使用。c-Myc还原剂可作为先导疗法，在使用辅助癌症治疗剂之前减少或开始减少c-Myc。使用c-Myc还原剂治疗可调节c-Myc过表达癌症的疾病状态，使其恶性程度降低，更容易接受辅助癌症疗法。
• Practical Synthesis of Roscovitine and CR8
  作者：Nassima Oumata、Yoan Ferandin、Laurent Meijer、Hervé Galons

  DOI：10.1021/op800284k

  日期：2009.5.15

  Roscovitine and CR8 are potent inhibitors of cyclin-dependent kinases. A scalable synthesis of both inhibitors is described. In the case of CR8, the biarylmethylamine moiety was obtained as a stable and high-purity salt.
• Roscovitine-Derived, Dual-Specificity Inhibitors of Cyclin-Dependent Kinases and Casein Kinases 1
  作者：Nassima Oumata、Karima Bettayeb、Yoan Ferandin、Luc Demange、Angela Lopez-Giral、Marie-Lorène Goddard、Vassilios Myrianthopoulos、Emmanuel Mikros、Marc Flajolet、Paul Greengard、Laurent Meijer、Hervé Galons

  DOI：10.1021/jm800109e

  日期：2008.9.11

  Cyclin-dependent kinases (CDKs) and casein kinases 1 (CK 1) are involved in the two key molecular features of Alzheimer's disease, production of amyloid-beta peptides (extracellular plaques) and hyper-phosphorylation of Tau (intracellular neurofibrillary tangles). A series of 2,6,9-trisubstituted purines, structurally related to the CDK inhibitor roscovitine, have been synthesized. They mainly differ by the substituent on the C-6 position. These compounds were screened for kinase inhibitory activities and antiproliferative effects. Several biaryl derivatives displayed potent inhibition of both CDKs and CK1. In particular, derivative 13a was a potent inhibitor of CDK1/cyclin B (IC50: 220 nM), CDK5/p25 (IC50: 80 nM), and CK1 (IC50: 14 nM). Modeling of these molecules into the ATP-binding pocket of CK1 delta provided a rationale for the increased selectivity toward this kinase. 13a was able to prevent the CK1-dependent production of anyloid-beta in a cell model. CDK/CK1 dual-specificity inhibitors may have important applications in Alzheimer's disease and cancers.