tert-butyl 4-fluoro-1-methyl-2-oxo-6-(((trifluoromethyl)sulfonyl)oxy)spiro[indoline-3,4′-piperidine]-1′-carboxylate

• 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: tert-butyl 4-fluoro-1-methyl-2-oxo-6-(((trifluoromethyl)sulfonyl)oxy)spiro[indoline-3,4′-piperidine]-1′-carboxylate
• 英文别名: 1'-(tert-butyloxycarbonyl)-4-fluoro-1-methyl-2-oxospiro[indolin-3,4'-piperidin]-6-yl trifluoromethanesulfonate；Tert-butyl 4-fluoro-1-methyl-2-oxo-6-(trifluoromethylsulfonyloxy)spiro[indole-3,4'-piperidine]-1'-carboxylate；tert-butyl 4-fluoro-1-methyl-2-oxo-6-(trifluoromethylsulfonyloxy)spiro[indole-3,4'-piperidine]-1'-carboxylate
• 化学式: C₁₉H₂₂F₄N₂O₆S
• 分子量: 482.453
• InChiKey: XSCPUVMAPBGIRD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  102
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-fluoro-1-methyl-2-oxo-6-(((trifluoromethyl)sulfonyl)oxy)spiro[indoline-3,4′-piperidine]-1′-carboxylate 在 palladium diacetate 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 三氟乙酸 作用下， 以 氯仿 、 甲苯 为溶剂， 反应 23.0h， 生成
  参考文献：
  名称：

  Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer

  摘要：

  Tankyrases (TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase family. Inhibition of their enzymatic activities attenuates the Wnt/beta-catenin signaling, which plays an important role in cancer pathogenesis. We previously reported the discovery of RK-287107, a spiroindoline-based, highly selective, potent tankyrase inhibitor. Herein we describe the optimization process of RK-287107 leading to RK-582, which exhibits a markedly improved robust tumor growth inhibition in a COLO-320DM mouse xenograft model when orally administered. In addition to the dose-dependent elevation and attenuation of the levels of biomarkers AXIN2 and beta-catenin, respectively, results of the TCF reporter and cell proliferation studies on COLO-320DM are discussed.

  DOI：

  10.1021/acs.jmedchem.0c00045
• 作为产物：
  描述：

  2,6-二氟-4-甲氧基苯基乙腈 在 双氧水 、 三溴化硼 、 lithium hydride 、 sodium hydride 、 三乙胺 、 sodium hydroxide 作用下， 以 二氯甲烷 、 氯仿 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 生成 tert-butyl 4-fluoro-1-methyl-2-oxo-6-(((trifluoromethyl)sulfonyl)oxy)spiro[indoline-3,4′-piperidine]-1′-carboxylate
  参考文献：
  名称：

  EP3733206

  摘要：

  公开号：

文献信息

• ANTICANCER AGENT
  申请人：Japanese Foundation For Cancer Research

  公开号：EP3733206A1

  公开（公告）日：2020-11-04

  To provide an anticancer agent for preventing and/or treating cancer, comprising a tankyrase inhibitor containing a tankyrase inhibitory compound and a microtubule inhibitor containing a microtubule inhibitory compound as active ingredients.

  提供一种用于预防和/或治疗癌症的抗癌剂，其有效成分包括一种含有抑制毒力蛋白酶化合物的毒力蛋白酶抑制剂和一种含有抑制微管化合物的微管抑制剂。
• EP3733206
  申请人：——

  公开号：——

  公开（公告）日：——
• Design and Discovery of an Orally Efficacious Spiroindolinone-Based Tankyrase Inhibitor for the Treatment of Colon Cancer
  作者：Fumiyuki Shirai、Anna Mizutani、Yoko Yashiroda、Takeshi Tsumura、Yuko Kano、Yukiko Muramatsu、Tsubasa Chikada、Hitomi Yuki、Hideaki Niwa、Shin Sato、Kenichi Washizuka、Yasuko Koda、Yui Mazaki、Myung-Kyu Jang、Haruka Yoshida、Akiko Nagamori、Masayuki Okue、Takashi Watanabe、Kouichi Kitamura、Eiki Shitara、Teruki Honma、Takashi Umehara、Mikako Shirouzu、Takehiro Fukami、Hiroyuki Seimiya、Minoru Yoshida、Hiroo Koyama

  DOI：10.1021/acs.jmedchem.0c00045

  日期：2020.4.23

  Tankyrases (TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase family. Inhibition of their enzymatic activities attenuates the Wnt/beta-catenin signaling, which plays an important role in cancer pathogenesis. We previously reported the discovery of RK-287107, a spiroindoline-based, highly selective, potent tankyrase inhibitor. Herein we describe the optimization process of RK-287107 leading to RK-582, which exhibits a markedly improved robust tumor growth inhibition in a COLO-320DM mouse xenograft model when orally administered. In addition to the dose-dependent elevation and attenuation of the levels of biomarkers AXIN2 and beta-catenin, respectively, results of the TCF reporter and cell proliferation studies on COLO-320DM are discussed.