(3S,6S,10AS)-6-((叔丁氧基羰基)氨基)-5-氧杂十二烷基氢吡咯并[1,2-A]偶氮辛-3-羧酸 | 957134-90-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: (3S,6S,10AS)-6-((叔丁氧基羰基)氨基)-5-氧杂十二烷基氢吡咯并[1,2-A]偶氮辛-3-羧酸
• 英文名称: (3S,6S,10aS)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid
• 英文别名: (3S,6S,10aS)-6-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxo-2,3,6,7,8,9,10,10a-octahydro-1H-pyrrolo[1,2-a]azocine-3-carboxylic acid
• CAS: 957134-90-6
• 化学式: C₁₆H₂₆N₂O₅
• 分子量: 326.393
• InChiKey: JYNJSLVVNANPCL-SRVKXCTJSA-N

物化性质

• 沸点：
  535.9±39.0 °C(Predicted)
• 密度：
  1.22±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  95.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3S,6S,10AS)-6-((叔丁氧基羰基)氨基)-5-氧杂十二烷基氢吡咯并[1,2-A]偶氮辛-3-羧酸 在 三乙基硅烷 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 7.08h， 生成
  参考文献：
  名称：

  基于结构的 SD-36 作为 STAT3 蛋白的有效、选择性和有效的 PROTAC 降解剂的发现。

  摘要：

  信号转导和转录激活因子 3 (STAT3) 是一种转录因子，是癌症和其他人类疾病的有吸引力的治疗靶点。尽管进行了 20 年的持续研究努力，但针对 STAT3 的目标一直非常具有挑战性。我们在此报告了基于蛋白水解靶向嵌合体 (PROTAC) 概念的有效小分子 STAT3 降解剂的基于结构的发现。我们首先将 SI-109 设计为 STAT3 SH2 结构域的有效小分子抑制剂。使用 cereblon/cullin 4A E3 连接酶和 SI-109 的配体，我们获得了一系列有效的 PROTAC STAT3 降解剂，以 SD-36 为例。SD-36 在细胞中以低纳摩尔浓度诱导 STAT3 快速降解，并且不能降解其他 STAT 蛋白。SD-36 在具有高水平磷酸化 STAT3 的白血病和淋巴瘤细胞系中实现纳摩尔细胞生长抑制活性。单剂量的 SD-36 会导致异种移植肿瘤组织和正常小鼠组织中的 STAT3

  DOI：

  10.1021/acs.jmedchem.9b01530
• 作为产物：
  描述：

  C₁₈H₃₀N₂O₅ 在 水 、 lithium hydroxide 作用下， 生成 (3S,6S,10AS)-6-((叔丁氧基羰基)氨基)-5-氧杂十二烷基氢吡咯并[1,2-A]偶氮辛-3-羧酸
  参考文献：
  名称：

  [EN] STAT3 INHIBITORS AND THERAPEUTIC METHODS USING THE SAME
  [FR] INHIBITEURS DE STAT3 ET MÉTHODES THÉRAPEUTIQUES LES UTILISANT

  摘要：

  公开号：

  WO2010077589A3

文献信息

• [EN] STAT DEGRADERS AND USES THEREOF<br/>[FR] AGENTS DE DÉGRADATION DE STAT ET LEURS UTILISATIONS
  申请人：KYMERA THERAPEUTICS INC

  公开号：WO2021188696A1

  公开（公告）日：2021-09-23

  The present invention provides compounds, compositions thereof, and methods of using the same.

  本发明提供了化合物、其组合物以及使用相同的方法。
• [EN] SMALL MOLECULE DEGRADERS OF STAT3<br/>[FR] AGENTS DE DÉGRADATION, À PETITES MOLÉCULES, DE STAT3
  申请人：UNIV MICHIGAN REGENTS

  公开号：WO2020198435A1

  公开（公告）日：2020-10-01

  The present disclosure provides compounds represented by Formula I or Formula VIII: wherein R1a, R1b, M, A, E, QA, and QB are as defined in the specification, and the salts and solvates thereof. Compounds of Formula I are degraders of STAT3 or dedraders of STAT3 and STAT1. Compounds of Formula VIII are inhibitors of STAT3. STAT3 degraders and inhibitors are useful for the treatment of cancer and other diseases.

  本公开提供由公式I或公式VIII表示的化合物：其中R1a、R1b、M、A、E、QA和QB如规范中定义，并其盐和溶剂合物。公式I的化合物是STAT3的降解物或STAT3和STAT1的去除物。公式VIII的化合物是STAT3的抑制剂。STAT3的降解物和抑制剂对于癌症和其他疾病的治疗是有用的。
• Structure-Based Design, Synthesis, Evaluation, and Crystallographic Studies of Conformationally Constrained Smac Mimetics as Inhibitors of the X-linked Inhibitor of Apoptosis Protein (XIAP)
  作者：Haiying Sun、Jeanne A. Stuckey、Zaneta Nikolovska-Coleska、Dongguang Qin、Jennifer L. Meagher、Su Qiu、Jianfeng Lu、Chao-Yie Yang、Naoyuki G. Saito、Shaomeng Wang

  DOI：10.1021/jm8006849

  日期：2008.11.27

  Small molecules designed to mimic the binding of Smac protein to X-linked inhibitor of apoptosis protein (XIAP) are being pursued as a promising new class of anticancer drugs. Herein, we report the design, synthesis, and comprehensive structure-activity relationship studies of a series of conformationally constrained bicyclic Smac mimetics. Our studies led to the discovery of a number of highly potent and cell-permeable Smac mimetics and yielded important new insights into their structure-activity relationship for their binding to XIAP and for their activity in inhibition of cancer cell growth. Determination of the crystal structure of one potent Smac mimetic, compound 21, in complex with XIAP BIR3 provides the structural basis for its high-affinity binding to XIAP and for the design of highly potent Smac mimetics.
• Design, Synthesis, and Characterization of a Potent, Nonpeptide, Cell-Permeable, Bivalent Smac Mimetic That Concurrently Targets Both the BIR2 and BIR3 Domains in XIAP
  作者：Haiying Sun、Zaneta Nikolovska-Coleska、Jianfeng Lu、Jennifer L. Meagher、Chao-Yie Yang、Su Qiu、York Tomita、Yumi Ueda、Sheng Jiang、Krzysztof Krajewski、Peter P. Roller、Jeanne A. Stuckey、Shaomeng Wang

  DOI：10.1021/ja074725f

  日期：2007.12.1

  XIAP is a central apoptosis regulator that inhibits apoptosis by binding to and inhibiting the effectors caspase-3/-7 and an initiator caspase-9 through its BIR2 and BIR3 domains, respectively. Smac protein in its dimeric form effectively antagonizes XIAP by concurrently, targeting both its BIR2 and BIR3 domains. We report the design, synthesis, and characterization of a nonpeptide, cell-permeable, bivalent small-molecule (SM-164) which mimics Smac protein for targeting XIAP. Our study shows that SM-164 binds to XIAP containing both BIR domains with an IC50 value of 1.39 nM, being 300 and 7000 times more potent than its monovalent counterparts and the natural Smac AVPI peptide, respectively. SM-164 concurrently interacts with both BIR domains in XIAP and functions as an ultrapotent antagonist of XIAP in both cell-free functional and cell-based assays. SM-164 targets cellular XIAP and effectively induces apoptosis at concentrations as low as 1 nM in the HL-60 leukemia cell line. The potency of bivalent SM-164 in binding, functional, and cellular assays is 2-3 orders of magnitude higher than its corresponding monovalent Smac mimetics.
• INTERMEDIATES FOR THE PREPARATION OF BIVALENT SMAC MIMETICS
  申请人：THE REGENTS OF THE UNIVERSITY OF MICHIGAN

  公开号：EP2019671B1

  公开（公告）日：2014-09-24