1-cyclopropyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]propan-2-one | 1383716-74-2

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 1-cyclopropyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]propan-2-one
• 英文别名: 1-cyclopropyl-3-(2-(methylthio)pyrimidin-4-yl)propan-2-one；1-cyclopropyl-3-(2-methylsulfanylpyrimidin-4-yl)propan-2-one
• CAS: 1383716-74-2
• 化学式: C₁₁H₁₄N₂OS
• 分子量: 222.311
• InChiKey: GTAWLTWRJFYRBT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  15
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  68.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-cyclopropyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]propan-2-one 在 间氯过氧苯甲酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 2.75h， 生成 (3Z)-1-cyclopropyl-4-(dimethylamino)-3-[2-(pyridin-4-ylamino)pyrimidin-4-yl]but-3-en-2-one
  参考文献：
  名称：

  [EN] BI-HETEROARYL COMPOUNDS AS VPS34 INHIBITORS
  [FR] COMPOSÉS BI-HÉTÉROARYLES EN TANT QU'INHIBITEURS DE VPS34

  摘要：

  本发明涉及治疗由Vps34高活性特征的疾病或紊乱的新方法，以及作为Vps34抑制剂的化合物；特别是公式I的化合物或其药用盐，以及治疗与Vps34抑制相关的疾病、紊乱或综合症的方法，特别是高增殖性疾病。本发明还包括包括公式I化合物及其药用盐的药物组合物。

  公开号：

  WO2012085815A1
• 作为产物：
  描述：

  环丙乙酸 在 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 8.0h， 生成 1-cyclopropyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]propan-2-one
  参考文献：
  名称：

  [EN] PYRAZOLE PYRIMIDINE DERIVATIVE AND USES THEREOF
  [FR] DÉRIVÉ DE PYRAZOLE PYRIMIDINE ET UTILISATIONS DE CELUI-CI

  摘要：

  本发明提供了抑制酪蛋白激酶I（CKI）和/或白细胞介素-1受体相关激酶1（IRAK1）的吡唑嘧啶衍生物，以及它们的制备方法、包含它们的组合物和在治疗恶性疾病和紊乱的方法中的用途，以及治疗炎症性疾病和紊乱的方法。

  公开号：

  WO2017021969A1

文献信息

• PIK3C3 Inhibition Promotes Sensitivity to Colon Cancer Therapy by Inhibiting Cancer Stem Cells
  作者：Balawant Kumar、Rizwan Ahmad、Swagat Sharma、Saiprasad Gowrikumar、Mark Primeaux、Sandeep Rana、Amarnath Natarajan、David Oupicky、Corey R. Hopkins、Punita Dhawan、Amar B. Singh

  DOI：10.3390/cancers13092168

  日期：——

  Background: Despite recent advances in therapies, resistance to chemotherapy remains a critical problem in the clinical management of colorectal cancer (CRC). Cancer stem cells (CSCs) play a central role in therapy resistance. Thus, elimination of CSCs is crucial for effective CRC therapy; however, such strategies are limited. Autophagy promotes resistance to cancer therapy; however, whether autophagy protects CSCs to promote resistance to CRC-therapy is not well understood. Moreover, specific and potent autophagy inhibitors are warranted as clinical trials with hydroxychloroquine have not been successful. Methods: Colon cancer cells and tumoroids were used. Fluorescent reporter-based analysis of autophagy flux, spheroid and side population (SP) culture, and qPCR were done. We synthesized 36-077, a potent inhibitor of PIK3C3/VPS34 kinase, to inhibit autophagy. Combination treatments were done using 5-fluorouracil (5-FU) and 36-077. Results: The 5-FU treatment induced autophagy only in a subset of the treated colon cancer. These autophagy-enriched cells also showed increased expression of CSC markers. Co-treatment with 36-077 significantly improved efficacy of the 5-FU treatment. Mechanistic studies revealed that combination therapy inhibited GSK-3β/Wnt/β-catenin signaling to inhibit CSC population. Conclusion: Autophagy promotes resistance to CRC-therapy by specifically promoting GSK-3β/Wnt/β-catenin signaling to promote CSC survival, and 36-077, a PIK3C3/VPS34 inhibitor, helps promote efficacy of CRC therapy.

  背景：尽管近年来治疗方面取得了进展，但化疗耐药仍然是结直肠癌（CRC）临床管理中的重要问题。癌症干细胞（CSCs）在治疗耐药中起着核心作用。因此，清除CSCs对于有效的CRC治疗至关重要；然而，这样的策略受到限制。自噬促进了对癌症治疗的耐药性；然而，自噬是否保护CSCs以促进对CRC治疗的耐药性尚不明确。此外，由于羟氯喹的临床试验并不成功，因此需要特异性和有效的自噬抑制剂。方法：使用结肠癌细胞和肿瘤体。进行自噬通量的荧光报告基础分析，球体和侧向群体（SP）培养，以及qPCR。我们合成了36-077，一种有效的PIK3C3/VPS34激酶抑制剂，用于抑制自噬。使用5-氟尿嘧啶（5-FU）和36-077进行联合治疗。结果：5-FU治疗仅在部分受治疗的结肠癌细胞中诱导自噬。这些富含自噬的细胞还显示出CSC标记物的表达增加。与36-077联合治疗显著提高了5-FU治疗的疗效。机制研究显示，联合治疗抑制了GSK-3β/Wnt/β-连环蛋白信号通路以抑制CSC种群。结论：自噬通过特异性促进GSK-3β/Wnt/β-连环蛋白信号通路，从而促进CSC存活，从而促进CRC治疗的耐药性，而PIK3C3/VPS34抑制剂36-077有助于促进CRC治疗的疗效。
• BI-HETEROARYL COMPOUNDS AS VPS34 INHIBITORS
  申请人：Taracido Ivan Cornella

  公开号：US20140155402A1

  公开（公告）日：2014-06-05

  The present invention includes novel methods of treating a disease or disorder characterized by hyperactivity of Vps34, and compound as Vps34 inhibitors; particularly compounds of Formula I: or a pharmaceutically acceptable salt thereof, as well as methods of treating a disease, disorder, or syndrome associated with Vps34 inhibition, particularly hyperproliferative diseases. The present invention also includes pharmaceutical compositions including compounds of formula I and pharmaceutically acceptable salts thereof.

  本发明包括治疗由Vps34高活性所特征的疾病或障碍的新方法，以及作为Vps34抑制剂的化合物；特别是公式I的化合物：或其药学上可接受的盐，以及治疗与Vps34抑制相关的疾病、障碍或综合症的方法，特别是增殖过度性疾病的方法。本发明还包括包括公式I的化合物和其药学上可接受的盐的药物组合物。
• Bi-heteroaryl compounds as Vps34 inhibitors
  申请人：Taracido Ivan Cornella

  公开号：US08685993B2

  公开（公告）日：2014-04-01

  The present invention includes novel methods of treating a disease or disorder characterized by hyperactivity of Vps34, and compound as Vps34 inhibitors; particularly compounds of Formula I or a pharmaceutically acceptable salt thereof, as well as methods of treating a disease, disorder, or syndrome associated with Vps34 inhibition, particularly hyperproliferative diseases. The present invention also includes pharmaceutical compositions including compounds of formula I and pharmaceutically acceptable salts thereof.

  本发明包括治疗由Vps34过度活化引起的疾病或障碍的新方法，以及作为Vps34抑制剂的化合物；特别是公式I的化合物或其药学上可接受的盐，以及治疗与Vps34抑制相关的疾病、障碍或综合征的方法，特别是增殖过度性疾病。本发明还包括包括公式I的化合物及其药学上可接受的盐的制药组合物。
• Pyrazole pyrimidine derivative and uses thereof
  申请人：Yissum Research Development Company of the Hebrew University of Jerusalem LTD

  公开号：US10376511B2

  公开（公告）日：2019-08-13

  The present invention provides pyrazole pyrimidine derivatives which inhibit Casein kinase I (CKI) and/or Interleukin-1 receptor-associated kinase 1 (IRAKI) and methods of their manufacture, compositions comprising them and uses thereof in methods of treating malignant disease and disorders and methods for treating inflammatory diseases and disorders.

  本发明提供了抑制酪蛋白激酶 I（CKI）和/或白细胞介素-1 受体相关激酶 1（IRAKI）的吡唑嘧啶衍生物及其制造方法、包含它们的组合物以及它们在治疗恶性疾病和紊乱以及治疗炎症性疾病和紊乱的方法中的用途。
• Potent, Selective, and Orally Bioavailable Inhibitors of VPS34 Provide Chemical Tools to Modulate Autophagy <i>in Vivo</i>
  作者：Ayako Honda、Edmund Harrington、Ivan Cornella-Taracido、Pascal Furet、Mark S. Knapp、Meir Glick、Ellen Triantafellow、William E. Dowdle、Dmitri Wiedershain、Wieslawa Maniara、Christine Moore、Peter M. Finan、Lawrence G. Hamann、Brant Firestone、Leon O. Murphy、Erin P. Keaney

  DOI：10.1021/acsmedchemlett.5b00335

  日期：2016.1.14

  Autophagy is a dynamic process that regulates lysosomal-dependent degradation of cellular components. Until recently the study of autophagy has been hampered by the lack of reliable pharmacological tools, but selective inhibitors are now available to modulate the PI 3-kinase VPS34, which is required for autophagy. Here we describe the discovery of potent and selective VPS34 inhibitors, their pharmacokinetic (PK) properties, and ability to inhibit autophagy in cellular and mouse models.