N6-(2,4,5-trimethoxybenzoyl)adenine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: N6-(2,4,5-trimethoxybenzoyl)adenine
• 英文别名: 2,4,5-trimethoxy-N-(7H-purin-6-yl)benzamide
• 化学式: C₁₅H₁₅N₅O₄
• 分子量: 329.315
• InChiKey: PTCXNQUAMPSQNB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2,4,5-三甲氧基苯甲酸 、 腺嘌呤 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以23%的产率得到N6-(2,4,5-trimethoxybenzoyl)adenine
  参考文献：
  名称：

  N 6-苯甲酰腺嘌呤衍生物作为新型BRD4抑制剂的发现及其构效关系研究

  摘要：

  溴结构域和末端外结构域（BET）蛋白是表观遗传阅读器，可与组蛋白中的乙酰化赖氨酸结合。其中，BRD4是用于多种疾病（包括癌症和炎性疾病）的治疗剂的候选靶分子。作为我们对沙利度胺进行结构开发的持续研究的一部分，该研究基于“多模板”方法获得了广泛的生物改性剂，在这项工作中，我们着重于BRD4抑制活性，并发现N 6-苯甲酰腺嘌呤衍生物显示出这种活性。活动。结构与活性之间的关系研究导致了N 6-（2,4,5-三甲氧基苯甲酰基）腺嘌呤（29），其表现出强大的BRD4 bromodomain1抑制活性，IC 50值为0.427μM 。ñ6-苄基腺嘌呤似乎是开发BRD4抑制剂的新化学支架。

  DOI：

  10.1016/j.bmc.2015.01.022

文献信息

• Discovery and structure–activity relationship studies of N6-benzoyladenine derivatives as novel BRD4 inhibitors
  作者：Tomomi Noguchi-Yachide、Taki Sakai、Yuichi Hashimoto、Takao Yamaguchi

  DOI：10.1016/j.bmc.2015.01.022

  日期：2015.3

  Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that bind to acetylated lysines in histones. Among them, BRD4 is a candidate target molecule of therapeutic agents for diverse diseases, including cancer and inflammatory disease. As a part of our continuing structural development studies of thalidomide to obtain a broad spectrum of biological modifiers based on the ‘multi-template’

  溴结构域和末端外结构域（BET）蛋白是表观遗传阅读器，可与组蛋白中的乙酰化赖氨酸结合。其中，BRD4是用于多种疾病（包括癌症和炎性疾病）的治疗剂的候选靶分子。作为我们对沙利度胺进行结构开发的持续研究的一部分，该研究基于“多模板”方法获得了广泛的生物改性剂，在这项工作中，我们着重于BRD4抑制活性，并发现N 6-苯甲酰腺嘌呤衍生物显示出这种活性。活动。结构与活性之间的关系研究导致了N 6-（2,4,5-三甲氧基苯甲酰基）腺嘌呤（29），其表现出强大的BRD4 bromodomain1抑制活性，IC 50值为0.427μM 。ñ6-苄基腺嘌呤似乎是开发BRD4抑制剂的新化学支架。
• [EN] HETERO-BIFUNCTIONAL DEGRADER COMPOUNDS AND THEIR USE AS MODULATORS OF TARGETED UBIQUINATION (VHL)<br/>[FR] COMPOSÉS DE DÉGRADATION HÉTÉRO-BIFONCTIONNELS ET LEUR UTILISATION EN TANT QUE MODULATEURS DE L'UBIQUINATION CIBLÉE (VHL)
  申请人：GENENTECH INC

  公开号：WO2019183523A1

  公开（公告）日：2019-09-26

  The present disclosure relates to bifunctional compounds, which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds that contain on one end a VHL ligand moiety, which binds to the VHL ubiquitin ligase (E3), and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. The target protein may be EGFR. Also disclosed are VHL ligands.

  本公开涉及双功能化合物，可用作靶向泛素化的调节剂。特别是，本公开是针对包含在一端具有VHL配体基团的化合物，该基团结合到VHL泛素连接酶(E3)，而在另一端具有结合目标蛋白的基团，从而实现目标蛋白/多肽的降解。目标蛋白可以是EGFR。还公开了VHL配体。
• (4-hydroxypyrrolidin-2-yl)-heterocyclic compounds and methods of use thereof
  申请人：Genentech, Inc.

  公开号：US11242344B2

  公开（公告）日：2022-02-08

  The present disclosure relates to bifunctional compounds, which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds which contain on one end a VHL ligand moiety, which binds to the VHL E3 ubiquitin ligase, and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. Also disclosed are VHL ligands.

  本公开涉及可用作靶向泛素化调节剂的双功能化合物。特别是，本公开涉及的化合物一端含有与 VHL E3 泛素连接酶结合的 VHL 配体分子，另一端含有与靶蛋白结合的分子，从而实现靶蛋白/多肽的降解。还公开了 VHL 配体。
• (4-HYDROXYPYRROLIDIN-2-YL)-HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF
  申请人：Genentech, Inc.

  公开号：US20210309660A1

  公开（公告）日：2021-10-07

  The present disclosure relates to bifunctional compounds, which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds which contain on one end a VHL ligand moiety, which binds to the VHL E3 ubiquitin ligase, and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. Also disclosed are VHL ligands.
• Structure–Activity Relationship Study of &lt;i&gt;N&lt;/i&gt;&lt;sup&gt;6&lt;/sup&gt;-Benzoyladenine-Type BRD4 Inhibitors and Their Effects on Cell Differentiation and TNF-α Production
  作者：Seika Amemiya、Takao Yamaguchi、Taki Sakai、Yuichi Hashimoto、Tomomi Noguchi-Yachide

  DOI：10.1248/cpb.c16-00410

  日期：——

  Bromodomains are epigenetic ‘readers’ of histone acetylation. The first potent bromodomain and extra-terminal domain (BET) inhibitors, (+)-JQ1 and I-BET762 (also known as GSK525762), were reported in 2010. Some BET inhibitors are already under clinical trial for the treatment of cancers, but so far, only a few chemical scaffolds are available. We have reported potent N6-benzoyladenine-based inhibitors of BRD4, a BET family member that serves as a key mediator of transcriptional elongation. Here we present an analysis of the structure–activity relationships of these inhibitors. Among the compounds examined, 20, 28 and 29 enhanced all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation and inhibited tumor necrosis factor (TNF)-α production by THP-1 cells.

  溴结构域是组蛋白乙酰化的表观遗传 "阅读器"。2010 年报道了第一种强效溴化多域和末端外域（BET）抑制剂--(+)-JQ1 和 I-BET762（又称 GSK525762）。一些 BET 抑制剂已用于治疗癌症的临床试验，但迄今为止，只有少数化学支架可用。我们已经报道了基于 N6-苯甲酰基腺嘌呤的 BRD4 强效抑制剂，BRD4 是一种 BET 家族成员，是转录伸长的关键介质。在此，我们对这些抑制剂的结构-活性关系进行了分析。在所研究的化合物中，20、28 和 29 增强了全反式维甲酸（ATRA）诱导的 HL-60 细胞分化，并抑制了 THP-1 细胞产生肿瘤坏死因子（TNF）-α。