3-(7-methoxy-1-methyl-β-carbolin-9-yl)propylamine | 1342260-98-3

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: 3-(7-methoxy-1-methyl-β-carbolin-9-yl)propylamine
• 英文别名: 3-(7-Methoxy-1-methylpyrido[3,4-b]indol-9-yl)propan-1-amine
• CAS: 1342260-98-3
• 化学式: C₁₆H₁₉N₃O
• 分子量: 269.346
• InChiKey: AWPWSWALRFFFFR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  53.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-(7-methoxy-1-methyl-β-carbolin-9-yl)propylamine 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 4.5h， 生成 N-methyl-3-(7-methoxy-1-methyl-β-carbolin-9-yl)propylamine
  参考文献：
  名称：

  Synthesis and Biological Validation of a Harmine-Based, Central Nervous System (CNS)-Avoidant, Selective, Human β-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor

  摘要：

  Recently, our group identified that harmine is able to induce beta-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from a lack of selectivity, both against other kinases and CNS off-targets, we therefore sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity for off-targets while retaining human beta-cell proliferation activity. We carried out optimization of the 9-N-position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human beta-cell proliferation capability. An optimized DYRK1A inhibitor, 2-2c, was identified as a novel, efficacious in vivo lead candidate. 2-2c also demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for beta-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that 2-2c is a much improved in vivo lead candidate as compared to harmine for the treatment of diabetes.

  DOI：

  10.1021/acs.jmedchem.9b01379
• 作为产物：
  描述：

  N-(3-(7-methoxy-1-methyl-β-carbolin-9-yl)propyl) tert-butyl carbamate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成 3-(7-methoxy-1-methyl-β-carbolin-9-yl)propylamine
  参考文献：
  名称：

  基于 Harmine 的靶向组蛋白去乙酰化酶 (HDAC) 和 DNA 的双重抑制剂作为癌症治疗的有前景的策略

  摘要：

  在不同类型的癌症中观察到组蛋白去乙酰化酶 (HDACs) 的过度表达，但组蛋白去乙酰化酶抑制剂 (HDACIs) 作为针对实体瘤的单一疗法并未显示出显着疗效。近期研究表明，将 HDACI 与 DNA 损伤剂联合使用可提高 DNA 损伤水平，从而获得更好的实体瘤治疗效果。Harmine 已被证明通过嵌入 DNA 导致 DNA 损伤。因此，我们设计了一系列多靶点靶向HDAC和DNA的基于harmine的抑制剂，最具潜力的化合物27可以与DNA结合并造成DNA损伤。此外， 27通过 p53 信号通路引起细胞凋亡，并对 HCT-116 细胞表现出显着的抗增殖作用（IC 50 = 1.41 微米）。作为 DNA 损伤剂，27在正常细胞中表现出低毒性。化合物27被证明是一种靶向HDAC（HDAC1 IC 50  = 0.022 μM和HDAC6 IC 50 = 0.45 μM）和DNA的双重抑制剂 ，具有治疗实体瘤的潜力。

  DOI：

  10.1016/j.bioorg.2022.105604

文献信息

• WO2019183245A5
  申请人：——

  公开号：WO2019183245A5

  公开（公告）日：2022-03-25
• Structure–activity relationship study of beta-carboline derivatives as haspin kinase inhibitors
  作者：Gregory D. Cuny、Natalia P. Ulyanova、Debasis Patnaik、Ji-Feng Liu、Xiangjie Lin、Ken Auerbach、Soumya S. Ray、Jun Xian、Marcie A. Glicksman、Ross L. Stein、Jonathan M.G. Higgins

  DOI：10.1016/j.bmcl.2012.01.028

  日期：2012.3

  Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure-activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented. (C) 2012 Elsevier Ltd. All rights reserved.
• Beta-Carbolines as Inhibitors of Haspin and DYRK Kinases
  申请人：Higgins Jonathan

  公开号：US20130231360A1

  公开（公告）日：2013-09-05

  The present disclosure is directed to compounds of Formula (I) which are inhibitors of Haspin kinase and DYRK kinases. The compounds of the present disclosure, and compositions thereof, are useful in the treatment of disease related to Haspin kinase and DYRK kinase expression and/or activity.
• 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.
• Synthesis and Biological Validation of a Harmine-Based, Central Nervous System (CNS)-Avoidant, Selective, Human β-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor
  作者：Kunal Kumar、Peng Wang、Jessica Wilson、Viktor Zlatanic、Cecilia Berrouet、Susmita Khamrui、Cody Secor、Ethan A. Swartz、Michael Lazarus、Roberto Sanchez、Andrew F. Stewart、Adolfo Garcia-Ocana、Robert J. DeVita

  DOI：10.1021/acs.jmedchem.9b01379

  日期：2020.3.26

  Recently, our group identified that harmine is able to induce beta-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from a lack of selectivity, both against other kinases and CNS off-targets, we therefore sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity for off-targets while retaining human beta-cell proliferation activity. We carried out optimization of the 9-N-position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human beta-cell proliferation capability. An optimized DYRK1A inhibitor, 2-2c, was identified as a novel, efficacious in vivo lead candidate. 2-2c also demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for beta-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that 2-2c is a much improved in vivo lead candidate as compared to harmine for the treatment of diabetes.