4-(5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indol-5-yl)butanenitrile

• 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: 4-(5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indol-5-yl)butanenitrile
• 英文别名: 4-(5H-[1,2,5]oxadiazolo[3',4':5,6]pyrazino[2,3-b]indol-5-yl)butanenitrile；4-(13-Oxa-8,10,12,14,16-pentazatetracyclo[7.7.0.02,7.011,15]hexadeca-1(16),2,4,6,9,11,14-heptaen-8-yl)butanenitrile；4-(13-oxa-8,10,12,14,16-pentazatetracyclo[7.7.0.02,7.011,15]hexadeca-1(16),2,4,6,9,11,14-heptaen-8-yl)butanenitrile
• 化学式: C₁₄H₁₀N₆O
• 分子量: 278.273
• InChiKey: HDKHTXFHMUEGTQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  93.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-(5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indol-5-yl)butanenitrile 在 三正丁基叠氮化锡 作用下， 以 甲苯 为溶剂， 反应 48.0h， 以57%的产率得到5-(3-(2H-tetrazol-5-yl)propyl)-5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole
  参考文献：
  名称：

  Discovery of Selective Small-Molecule Inhibitors for the β-Catenin/T-Cell Factor Protein–Protein Interaction through the Optimization of the Acyl Hydrazone Moiety

  摘要：

  Acyl hydrazone is an important functional group for the discovery of bioactive small molecules. This functional group is also recognized as a pan assay interference structure. In this study, a new small-molecule inhibitor for the beta-catenin/Tcf protein-protein interaction (PPI), ZINC02092166, was identified through AlphaScreen and FP assays. This compound contains an acyl hydrazone group and exhibits higher inhibitory activities in cell-based assays than biochemical assays. Inhibitor optimization resulted in chemically stable derivatives that disrupt the beta-catenin/Tcf PPI. The binding mode of new inhibitors was characterized by site-directed mutagenesis and structure-activity relationship studies. This series of inhibitors with a new scaffold exhibits dual selectivity for beta-catenin/Tcf over beta-catenin/cadherin and beta-catenin/APC PPIs. One derivative of this series suppresses canonical Wnt signaling, downregulates the expression of Wnt target genes, and inhibits the growth of cancer cells. This compound represents a solid starting point for the development of potent and selective beta-catenin/Tcf inhibitors.

  DOI：

  10.1021/acs.jmedchem.5b00223
• 作为产物：
  描述：

  靛红 在 sodium hydride 、 溶剂黄146 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.5h， 生成 4-(5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indol-5-yl)butanenitrile
  参考文献：
  名称：

  Discovery of Selective Small-Molecule Inhibitors for the β-Catenin/T-Cell Factor Protein–Protein Interaction through the Optimization of the Acyl Hydrazone Moiety

  摘要：

  Acyl hydrazone is an important functional group for the discovery of bioactive small molecules. This functional group is also recognized as a pan assay interference structure. In this study, a new small-molecule inhibitor for the beta-catenin/Tcf protein-protein interaction (PPI), ZINC02092166, was identified through AlphaScreen and FP assays. This compound contains an acyl hydrazone group and exhibits higher inhibitory activities in cell-based assays than biochemical assays. Inhibitor optimization resulted in chemically stable derivatives that disrupt the beta-catenin/Tcf PPI. The binding mode of new inhibitors was characterized by site-directed mutagenesis and structure-activity relationship studies. This series of inhibitors with a new scaffold exhibits dual selectivity for beta-catenin/Tcf over beta-catenin/cadherin and beta-catenin/APC PPIs. One derivative of this series suppresses canonical Wnt signaling, downregulates the expression of Wnt target genes, and inhibits the growth of cancer cells. This compound represents a solid starting point for the development of potent and selective beta-catenin/Tcf inhibitors.

  DOI：

  10.1021/acs.jmedchem.5b00223

文献信息

• [EN] METHODS AND COMPOSITIONS OF SUBSTITUTED 5H-[1,2,5]OXADIAZOLO[3',4':5,6] PYRAZIONO[2,3-B]INDOLE ANALOGS AS INHIBITORS OF BETA-CATENIN/T-CELL FACTOR PROTEIN-PROTEIN INTERACTIONS<br/>[FR] PROCÉDÉS ET COMPOSITIONS D'ANALOGUES SUBSTITUÉS DE 5H-[1,2,5]OXADIAZOLO[3',4':5,6] PYRAZIONO[2,3-B]INDOLE UTILISÉS COMME INHIBITEURS DES INTERACTIONS PROTÉINE-PROTÉINE BÊTA-CATÉNINE/FACTEURS TCF
  申请人：UNIV UTAH RES FOUND

  公开号：WO2016187050A1

  公开（公告）日：2016-11-24

  In one aspect, the invention relates to substituted 5H-[1,2,5]oxadiazolo [3',4':5,6]pyrazino[2,3-b]indole analogues, derivatives thereof, and related compound; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders, e.g., various tumors and cancers, associated with a β-catenin/T-cell factor interaction dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  在一个方面，该发明涉及替代的5H-[1,2,5]噁二唑[3',4':5,6]吡唑并[2,3-b]吲哚类似物，其衍生物以及相关化合物；制备这些化合物的合成方法；包含这些化合物的药物组合物；以及使用这些化合物和组合物治疗与β-连环蛋白/T细胞因子相互作用功能障碍相关的疾病的方法，例如各种肿瘤和癌症。本摘要旨在作为在特定领域搜索的扫描工具，并不旨在限制本发明。
• Methods and compositions of substituted 5H-[1,2,5] oxadiazolo [3′,4′:5,6] pyrazino[2,3-B] indole analogs as inhibitors of β-catenin/T-cell factor protein-protein interactions
  申请人：University of Utah Research Foundation

  公开号：US10273246B2

  公开（公告）日：2019-04-30

  In one aspect, the invention relates to substituted 5H-[1,2,5]oxadiazolo [3′,4′:5,6]pyrazino[2,3-b]indole analogs, derivatives thereof, and related compound; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and A methods of treating disorders, e.g., various tumors and cancers, associated with a β-catenin/T-cell factor interaction dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  在一个方面，本发明涉及取代的5H-[1,2,5]噁二唑并[3′,4′:5,6]吡嗪并[2,3-b]吲哚类似物、其衍生物和相关化合物；制造这些化合物的合成方法；包含这些化合物的药物组合物；以及使用这些化合物和组合物治疗与β-catenin/细胞因子相互作用功能障碍相关的疾病，例如各种肿瘤和癌症的方法。本摘要旨在作为一种扫描工具，用于特定技术领域的检索，并非对本发明的限制。
• METHODS AND COMPOSITIONS OF SUBSTITUTED 5H-[1,2,5] OXADIAZOLO [3',4':5,6] PYRAZINO[2,3-B] INDOLE ANALOGS AS INHIBITORS OF BETA-CATENIN/T-CELL FACTOR PROTEIN-PROTEIN INTERACTIONS
  申请人：University of Utah Research Foundation

  公开号：US20180134729A1

  公开（公告）日：2018-05-17

  In one aspect, the invention relates to substituted 5H-[1,2,5]oxadiazolo [3′,4′:5,6]pyrazino[2,3-b]indole analogues, derivatives thereof, and related compound; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and A methods of treating disorders, e.g., various tumors and cancers, associated with a β-catenin/T-cell factor interaction dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
• Discovery of Selective Small-Molecule Inhibitors for the β-Catenin/T-Cell Factor Protein–Protein Interaction through the Optimization of the Acyl Hydrazone Moiety
  作者：J. Leon Catrow、Yongqiang Zhang、Min Zhang、Haitao Ji

  DOI：10.1021/acs.jmedchem.5b00223

  日期：2015.6.11

  Acyl hydrazone is an important functional group for the discovery of bioactive small molecules. This functional group is also recognized as a pan assay interference structure. In this study, a new small-molecule inhibitor for the beta-catenin/Tcf protein-protein interaction (PPI), ZINC02092166, was identified through AlphaScreen and FP assays. This compound contains an acyl hydrazone group and exhibits higher inhibitory activities in cell-based assays than biochemical assays. Inhibitor optimization resulted in chemically stable derivatives that disrupt the beta-catenin/Tcf PPI. The binding mode of new inhibitors was characterized by site-directed mutagenesis and structure-activity relationship studies. This series of inhibitors with a new scaffold exhibits dual selectivity for beta-catenin/Tcf over beta-catenin/cadherin and beta-catenin/APC PPIs. One derivative of this series suppresses canonical Wnt signaling, downregulates the expression of Wnt target genes, and inhibits the growth of cancer cells. This compound represents a solid starting point for the development of potent and selective beta-catenin/Tcf inhibitors.