1-chloro-7-methoxy-9H-β-carboline

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 1-chloro-7-methoxy-9H-β-carboline
• 英文别名: 1-chloro-7-methoxy-9H-pyrido[3,4-b]indole
• 化学式: C₁₂H₉ClN₂O
• 分子量: 232.669
• InChiKey: RMYYCGVKTZWCBB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  37.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-苯基吡咯烷 、 1-chloro-7-methoxy-9H-β-carboline 以 neat (no solvent) 为溶剂， 反应 24.0h， 以80%的产率得到1-(2-phenylpyrrolidin-1-yl)-7-methoxy-9H-β-carboline
  参考文献：
  名称：

  Development of Kinase-Selective, Harmine-Based DYRK1A Inhibitors that Induce Pancreatic Human β-Cell Proliferation

  摘要：

  DYRK1A has been implicated as an important drug target in various therapeutic areas, including neurological disorders and oncology. DYRK1A has more recently been shown to be involved in pathways regulating human beta-cell proliferation, thus making it a potential therapeutic target for both Type 1 and Type 2 diabetes. Our group, using a high-throughput phenotypic screen, identified harmine that is able to induce beta-cell proliferation both in vitro and in vivo. Since harmine has suboptimal kinase selectivity, we sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity, while retaining human beta-cell proliferation capability. We carried out the optimization of the 1-position of harmine and synthesized 15 harmine analogues. Six compounds showed excellent DYRK1A inhibition with IC50 in the range of 49.5-264 nM. Two compounds, 2-2 and 2-8, exhibited excellent human beta-cell proliferation at doses of 3-30 mu M, and compound 2-2 showed improved kinase selectivity as compared to harmine.

  DOI：

  10.1021/acs.jmedchem.8b00658
• 作为产物：
  描述：

  2-氧-3-哌啶羧酸乙酯 在 甲酸 、 2,3-二氯-5,6-二氰基-1,4-苯醌 、 sodium nitrite 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 盐酸 、 水 为溶剂， 反应 32.0h， 生成 1-chloro-7-methoxy-9H-β-carboline
  参考文献：
  名称：

  Development of Kinase-Selective, Harmine-Based DYRK1A Inhibitors that Induce Pancreatic Human β-Cell Proliferation

  摘要：

  DYRK1A has been implicated as an important drug target in various therapeutic areas, including neurological disorders and oncology. DYRK1A has more recently been shown to be involved in pathways regulating human beta-cell proliferation, thus making it a potential therapeutic target for both Type 1 and Type 2 diabetes. Our group, using a high-throughput phenotypic screen, identified harmine that is able to induce beta-cell proliferation both in vitro and in vivo. Since harmine has suboptimal kinase selectivity, we sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity, while retaining human beta-cell proliferation capability. We carried out the optimization of the 1-position of harmine and synthesized 15 harmine analogues. Six compounds showed excellent DYRK1A inhibition with IC50 in the range of 49.5-264 nM. Two compounds, 2-2 and 2-8, exhibited excellent human beta-cell proliferation at doses of 3-30 mu M, and compound 2-2 showed improved kinase selectivity as compared to harmine.

  DOI：

  10.1021/acs.jmedchem.8b00658

文献信息

• Structure-Based Design and Synthesis of Harmine Derivatives with Different Selectivity Profiles in Kinase versus Monoamine Oxidase Inhibition
  作者：Balázs Bálint、Csaba Wéber、Francisco Cruzalegui、Mike Burbridge、Andras Kotschy

  DOI：10.1002/cmdc.201600539

  日期：2017.6.21

  other hand, harmine is also a potent inhibitor of monoamine oxidase A (MAO-A). Using structure-based design, we synthesized a collection of harmine analogues with tunable selectivity toward these two enzymes. Modifications at the 7-position typically decreased affinity for DYRK1A, whereas substitution at the 9-position had a similar effect on MAO-A inhibition but DYRK1A inhibition was maintained. The resulting

  双特异性酪氨酸磷酸化调节激酶1A（DYRK1A）是一种新兴的生物学靶标，涉及多种治疗领域，例如神经系统疾病（尤其是唐氏综合症），代谢和肿瘤学。Harmine是一种在激酶中选择性抑制DYRK1A的天然产物，可以用作工具化合物，以更好地了解DYRK1A抑制作用引起的生物学过程。另一方面，harmine还是单胺氧化酶A（MAO-A）的有效抑制剂。使用基于结构的设计，我们合成了对这两种酶具有可调选择性的harmine类似物集合。在7位的修饰通常会降低对DYRK1A的亲和力，而在9位的取代对MAO-A的抑制作用相似，但仍保持DYRK1A的抑制作用。
• WO2019183245A5
  申请人：——

  公开号：WO2019183245A5

  公开（公告）日：2022-03-25
• KINASE INHIBITOR COMPOUNDS AND COMPOSITIONS AND METHODS OF USE
  申请人：Icahn School of Medicine at Mount Sinai

  公开号：US20210094950A1

  公开（公告）日：2021-04-01

  Described herein are compounds having the following structure: formula (I) or a stereoisomer, pharmaceutically acceptable salt, oxide, or solvate thereof. Also disclosed are compositions containing the compounds, methods of inhibiting activity of DYRK1 A in a cell, methods of increasing cell proliferation in a population of pancreatic beta cells, methods of treating a subject for a condition associated with insufficient insulin secretion, and methods of treating a subject for a neurological disorder.
• Development of Kinase-Selective, Harmine-Based DYRK1A Inhibitors that Induce Pancreatic Human β-Cell Proliferation
  作者：Kunal Kumar、Peng Wang、Roberto Sanchez、Ethan A Swartz、Andrew F. Stewart、Robert J. DeVita

  DOI：10.1021/acs.jmedchem.8b00658

  日期：2018.9.13

  DYRK1A has been implicated as an important drug target in various therapeutic areas, including neurological disorders and oncology. DYRK1A has more recently been shown to be involved in pathways regulating human beta-cell proliferation, thus making it a potential therapeutic target for both Type 1 and Type 2 diabetes. Our group, using a high-throughput phenotypic screen, identified harmine that is able to induce beta-cell proliferation both in vitro and in vivo. Since harmine has suboptimal kinase selectivity, we sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity, while retaining human beta-cell proliferation capability. We carried out the optimization of the 1-position of harmine and synthesized 15 harmine analogues. Six compounds showed excellent DYRK1A inhibition with IC50 in the range of 49.5-264 nM. Two compounds, 2-2 and 2-8, exhibited excellent human beta-cell proliferation at doses of 3-30 mu M, and compound 2-2 showed improved kinase selectivity as compared to harmine.