2-[2-(2-nitro-fluoren-9-ylidenemethyl)-phenoxy]-ethylamine | 1425944-22-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: 2-[2-(2-nitro-fluoren-9-ylidenemethyl)-phenoxy]-ethylamine
• 英文别名: 2-(2-((2-nitro-9H-fluoren-9-ylidene)methyl)phenoxy)ethan-1-amine；CYD-2-11；Ylidene)methyl)phenoxy)ethan-1-amine；2-[2-[(2-nitrofluoren-9-ylidene)methyl]phenoxy]ethanamine
• CAS: 1425944-22-4
• 化学式: C₂₂H₁₈N₂O₃
• 分子量: 358.397
• InChiKey: BJIFXXDQMBHYKG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  81.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-[2-(2-nitro-fluoren-9-ylidenemethyl)-phenoxy]-ethylamine 在 氯化铵 、 锌 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 4.0h， 以63%的产率得到9-(2-(2-aminoethoxy)benzylidene)-9H-fluoren-2-amine
  参考文献：
  名称：

  Structure-activity relationship studies on Bax activator SMBA1 for the treatment of ER-positive and triple-negative breast cancer

  摘要：

  In an effort to develop novel Bax activators for breast cancer treatment, a series of diverse analogues have been designed and synthesized based on lead compound SMBA1 through several strategies, including introducing various alkylamino side chains to have a deeper access to S184 pocket, replacing carbon atoms with nitrogen, and reducing the nitro group of 9H-fluorene scaffold. Compounds 14 (CYD-2-11) and 49 (CYD-4-61) have been identified to exhibit significantly improved antiproliferative activity compared to SMBA1, with IC50 values of 3.22 mu M and 0.07 mu M against triple-negative breast cancer MDA-MB-231 and 3.81 mu M and 0.06 mu M against ER-positive breast cancer MCF-7 cell lines, respectively. Mechanism of action studies of compound 49 indicated that it can activate Bax protein to induce cytochrome c release and regulate apoptotic biomarkers, leading to cancer cell apoptosis. Further in vivo efficacy studies of compounds 14 and 49 in nude mice bearing MDA-MB-231 tumor xenografts demonstrated that these drug candidates can significantly suppress tumor growth, indicating their therapeutic potential for the treatment of breast cancer. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.06.004
• 作为产物：
  描述：

  2-硝基芴 在 偶氮二甲酸二异丙酯 、 potassium fluoride on basic alumina 、 三苯基膦 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 12.0h， 生成 2-[2-(2-nitro-fluoren-9-ylidenemethyl)-phenoxy]-ethylamine
  参考文献：
  名称：

  Modulation of Bax and mTOR for Cancer Therapeutics

  摘要：

  摘要 对促凋亡 Bcl2 家族成员 Bax 的丝氨酸 (S)184 磷酸化位点进行药理操作作为一种抗癌策略是有道理的。在此，我们报告了对 Bax 激动剂 SMBA1 的改进，以生成 CYD-2-11，它具有适合临床先导化合物的特征。CYD-2-11 以 Bax C 端 S184 附近的结构袋为靶点，通过诱导构象变化使线粒体膜中的 Bax 同源异构体形成，从而直接激活其促凋亡活性。在小细胞肺癌和非小细胞肺癌的小鼠模型中，包括源自患者的异种移植和基因工程突变型 KRAS 驱动的肺癌模型，CYD-2-11 可抑制恶性肿瘤的生长，而不会对正常组织产生明显的毒性。在接受 mTOR 抑制剂 RAD001 治疗的肺癌患者中，我们观察到肺癌细胞和组织中的 S184 Bax 磷酸化增强，从而使 Bax 的促凋亡功能失活，导致雷帕洛耐药。在小鼠肺癌模型中，CYD-2-11和RAD001的联合治疗显示出很强的协同活性，并在体外和体内克服了雷帕洛耐药性。综上所述，我们的研究结果为Bax激活和mTOR抑制的药理结合提供了临床前证据，是改善肺癌治疗的合理策略。癌症研究》；77（11）；3001-12。©2017 AACR。

  DOI：

  10.1158/0008-5472.can-16-2356

文献信息

• [EN] BAX AGONIST, COMPOSITIONS, AND METHODS RELATED THERETO<br/>[FR] AGONISTE DE BAX, COMPOSITIONS ET PROCÉDÉS ASSOCIÉS
  申请人：UNIV EMORY

  公开号：WO2013028543A1

  公开（公告）日：2013-02-28

  The disclosure relates to BAX activators and therapeutic uses relates thereto. In certain embodiments, the disclosure relates to methods of treating or preventing cancer, such as lung cancer, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound disclosed herein or pharmaceutically acceptable salt to a subject in need thereof.

  本公开涉及BAX激活剂及其治疗用途。在某些实施例中，本公开涉及治疗或预防癌症的方法，例如肺癌，包括向需要的受试者施用本公开的化合物或药学上可接受的盐所述的药物组合的治疗有效量。
• Structure-activity relationship studies on Bax activator SMBA1 for the treatment of ER-positive and triple-negative breast cancer
  作者：Gang Liu、Tao Yin、Hyejin Kim、Chunyong Ding、Zhuo Yu、Hong Wang、Haiying Chen、Ruping Yan、Eric A. Wold、Hao Zou、Xi Liu、Ye Ding、Qiang Shen、Jia Zhou

  DOI：10.1016/j.ejmech.2019.06.004

  日期：2019.9

  In an effort to develop novel Bax activators for breast cancer treatment, a series of diverse analogues have been designed and synthesized based on lead compound SMBA1 through several strategies, including introducing various alkylamino side chains to have a deeper access to S184 pocket, replacing carbon atoms with nitrogen, and reducing the nitro group of 9H-fluorene scaffold. Compounds 14 (CYD-2-11) and 49 (CYD-4-61) have been identified to exhibit significantly improved antiproliferative activity compared to SMBA1, with IC50 values of 3.22 mu M and 0.07 mu M against triple-negative breast cancer MDA-MB-231 and 3.81 mu M and 0.06 mu M against ER-positive breast cancer MCF-7 cell lines, respectively. Mechanism of action studies of compound 49 indicated that it can activate Bax protein to induce cytochrome c release and regulate apoptotic biomarkers, leading to cancer cell apoptosis. Further in vivo efficacy studies of compounds 14 and 49 in nude mice bearing MDA-MB-231 tumor xenografts demonstrated that these drug candidates can significantly suppress tumor growth, indicating their therapeutic potential for the treatment of breast cancer. (C) 2019 Elsevier Masson SAS. All rights reserved.
• Modulation of Bax and mTOR for Cancer Therapeutics
  作者：Rui Li、Chunyong Ding、Jun Zhang、Maohua Xie、Dongkyoo Park、Ye Ding、Guo Chen、Guojing Zhang、Melissa Gilbert-Ross、Wei Zhou、Adam I. Marcus、Shi-Yong Sun、Zhuo G. Chen、Gabriel L. Sica、Suresh S. Ramalingam、Andrew T. Magis、Haian Fu、Fadlo R. Khuri、Walter J. Curran、Taofeek K. Owonikoko、Dong M. Shin、Jia Zhou、Xingming Deng

  DOI：10.1158/0008-5472.can-16-2356

  日期：2017.6.1

  A rationale exists for pharmacologic manipulation of the serine (S)184 phosphorylation site of the proapoptotic Bcl2 family member Bax as an anticancer strategy. Here, we report the refinement of the Bax agonist SMBA1 to generate CYD-2-11, which has characteristics of a suitable clinical lead compound. CYD-2-11 targeted the structural pocket proximal to S184 in the C-terminal region of Bax, directly activating its proapoptotic activity by inducing a conformational change enabling formation of Bax homooligomers in mitochondrial membranes. In murine models of small-cell and non–small cell lung cancers, including patient-derived xenograft and the genetically engineered mutant KRAS-driven lung cancer models, CYD-2-11 suppressed malignant growth without evident significant toxicity to normal tissues. In lung cancer patients treated with mTOR inhibitor RAD001, we observed enhanced S184 Bax phosphorylation in lung cancer cells and tissues that inactivates the propaoptotic function of Bax, contributing to rapalog resistance. Combined treatment of CYD-2-11 and RAD001 in murine lung cancer models displayed strong synergistic activity and overcame rapalog resistance in vitro and in vivo. Taken together, our findings provide preclinical evidence for a pharmacologic combination of Bax activation and mTOR inhibition as a rational strategy to improve lung cancer treatment. Cancer Res; 77(11); 3001–12. ©2017 AACR.

  摘要 对促凋亡 Bcl2 家族成员 Bax 的丝氨酸 (S)184 磷酸化位点进行药理操作作为一种抗癌策略是有道理的。在此，我们报告了对 Bax 激动剂 SMBA1 的改进，以生成 CYD-2-11，它具有适合临床先导化合物的特征。CYD-2-11 以 Bax C 端 S184 附近的结构袋为靶点，通过诱导构象变化使线粒体膜中的 Bax 同源异构体形成，从而直接激活其促凋亡活性。在小细胞肺癌和非小细胞肺癌的小鼠模型中，包括源自患者的异种移植和基因工程突变型 KRAS 驱动的肺癌模型，CYD-2-11 可抑制恶性肿瘤的生长，而不会对正常组织产生明显的毒性。在接受 mTOR 抑制剂 RAD001 治疗的肺癌患者中，我们观察到肺癌细胞和组织中的 S184 Bax 磷酸化增强，从而使 Bax 的促凋亡功能失活，导致雷帕洛耐药。在小鼠肺癌模型中，CYD-2-11和RAD001的联合治疗显示出很强的协同活性，并在体外和体内克服了雷帕洛耐药性。综上所述，我们的研究结果为Bax激活和mTOR抑制的药理结合提供了临床前证据，是改善肺癌治疗的合理策略。癌症研究》；77（11）；3001-12。©2017 AACR。