NSC130813

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: NSC130813
• 英文别名: 4-((6-chloro-2-methoxyacridin-9-yl)amino)-2-((4-methylpiperazin-1-yl)methyl)phenol；NCI 130813；4-[(6-chloro-2-methoxyacridin-9-yl)amino]-2-[(4-methylpiperazin-1-yl)methyl]phenol
• 化学式: C₂₆H₂₇ClN₄O₂
• 分子量: 462.979
• InChiKey: SUSDGTMJKOGWSZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  60.9
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  N-[4-Hydroxy-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-acetamide 在 盐酸 作用下， 以 水 为溶剂， 生成 NSC130813
  参考文献：
  名称：

  ERCC1-XPF蛋白-蛋白质相互作用的小分子抑制剂的计算机辅助药物设计。

  摘要：

  DNA切除修复蛋白ERCC-1和DNA修复核酸内切酶XPF（ERCC1-XPF）的异二聚体是核苷酸切除修复（NER）途径必不可少的5´-3´结构特异性核酸内切酶，并且它也参与其他DNA修复途径。在癌细胞中，ERCC1-XPF在修复化学疗法（包括铂基和交联剂）引起的DNA损伤中起着核心作用，因此其抑制作用是增强这些疗法效果的有前途的策略。在这项研究中，我们合理地修饰了F06（ERCC1-XPF相互作用的小分子抑制剂）的结构（Jordheim等，2013），以改善其与靶标的结合。我们采用了多步计算方法来研究F06的潜在修饰位点，合理设计和排列类似物库，并确定化学合成和体外测试的候选对象。我们的顶级化合物B5对ERCC1-XPF核酸内切酶活性的抑制作用显示出改善的半最大抑制浓度（IC50）值为0.49 µM，为进一步的测试和优化奠定了基础。同样，此处报道的计算方法可用于开发靶向ERCC1-XPF复合物的DNA修复抑制剂。

  DOI：

  10.1111/cbdd.13660

文献信息

• Enhancing the activity of platinum-based drugs by improved inhibitors of ERCC1–XPF-mediated DNA repair
  作者：Gloria Ciniero、Ahmed H. Elmenoufy、Francesco Gentile、Michael Weinfeld、Marco A. Deriu、Frederick G. West、Jack A. Tuszynski、Charles Dumontet、Emeline Cros-Perrial、Lars Petter Jordheim

  DOI：10.1007/s00280-020-04213-x

  日期：2021.2

  in cancer cells. Inhibitors of the interaction between ERCC1 and XPF can be used to sensitize cancer cells to such drugs. Methods We tested recently synthesized new generation inhibitors of this interaction and evaluated their capacity to sensitize cancer cells to the genotoxic activity of agents in synergy studies, as well as their capacity to inhibit the protein–protein interaction in cancer cells

  目的 ERCC1-XPF 5'-3' DNA 核酸内切酶复合物参与核苷酸切除修复途径和 DNA 链间交联修复途径，这是调节癌细胞中化学治疗烷化剂活性的两个关键机制。ERCC1 和 XPF 之间相互作用的抑制剂可用于使癌细胞对此类药物敏感。 方法 我们测试了最近合成的这种相互作用的新一代抑制剂，并评估了它们在协同研究中使癌细胞对药物的基因毒性活性敏感的能力，以及它们使用邻近连接试验抑制癌细胞中蛋白质-蛋白质相互作用的能力。 结果 化合物B9在结肠癌细胞和肺癌细胞中与顺铂和丝裂霉素C协同显示出最佳活性。此外，如邻近连接试验所示，B9消除了癌细胞中 ERCC1 和 XPF 之间的相互作用。不同化合物的结果与我们之前获得的计算机预测值相关。 结论 由于新合成化合物的结合亲和力提高，我们的结果证实了靶向 ERCC1 和 XPF 之间的蛋白质 - 蛋白质相互作用以使癌细胞对烷化剂敏感的方法的可行性。
• Compounds as modulators of a mutant CFTR protein and their use for treating diseases associated with CFTR protein malfunction
  申请人：Instytut Biochemii I Biofizyki Polskiej Akademii Nauk

  公开号：EP2816035A2

  公开（公告）日：2014-12-24

  The present invention relates to novel protein modulators capable of altering function of the mutant CFTR protein and their use for treating diseases associated with CFTR protein malfunction. The invention provides compositions, pharmaceutical preparations and methods of correcting the cellular alteration of a mutant CFTR protein wherein the CFTR mutation is a mutation ΔF508-CFTR, or another mutation of class II.

  本发明涉及能够改变突变型CFTR蛋白功能的新型蛋白调节剂及其用于治疗与CFTR蛋白功能失常有关的疾病。本发明提供了纠正突变型CFTR蛋白细胞改变的组合物、药物制剂和方法，其中CFTR突变是ΔF508-CFTR突变或II类的另一种突变。
• Methods for increasing platelet count by inhibiting biliverdin IXβ reductase
  申请人：The Research Foundation for The State University of New York

  公开号：US10543286B2

  公开（公告）日：2020-01-28

  The present disclosure provides methods of treating a human having a disease or disorder that would benefit from increasing platelet counts. The method involves inhibiting the enzyme activity of biliverdin IXβ reductase (BLVRB) activity or inhibiting the expression of BLVRB gene.

  本公开提供了治疗人类疾病或失调的方法，这种疾病或失调将受益于血小板计数的增加。该方法包括抑制胆绿素 IXβ 还原酶（BLVRB）的酶活性或抑制 BLVRB 基因的表达。
• [EN] TARGETING DNA REPAIR IN TUMOR CELLS VIA INHIBITION OF ERCC1-XPF<br/>[FR] CIBLAGE DE LA RÉPARATION DE L'ADN DANS DES CELLULES TUMORALES PAR INHIBITION D'ERCC1-XPF
  申请人：UNIV ALBERTA

  公开号：WO2020248075A9

  公开（公告）日：2021-10-21
• Targeting DNA Repair in Tumor Cells via Inhibition of ERCC1–XPF
  作者：Ahmed H. Elmenoufy、Francesco Gentile、David Jay、Feridoun Karimi-Busheri、Xiaoyan Yang、Olivier M. Soueidan、Claudia Weilbeer、Rajam S. Mani、Khaled H. Barakat、Jack A. Tuszynski、Michael Weinfeld、Frederick G. West

  DOI：10.1021/acs.jmedchem.9b00326

  日期：2019.9.12

  The ERCC1-XPF heterodimer is a 5'-3' structure-specific endonuclease, which plays an essential role in several DNA repair pathways in mammalian cells. ERCC1-XPF is primarily involved in the repair of chemically induced helix distorting and bulky DNA lesions, such as cyclobutane pyrimidine dimers (CPDs), and DNA interstrand cross-links. Inhibition of ERCC1-XPF has been shown to potentiate cytotoxicity of platinum-based drugs and cyclophosphamide in cancer cells. In this study, the previously described ERCC1-XPF inhibitor 4-((6-chloro-2-methoxyacridin-9-yl)amino)-2-((4-methylpiperazin-1-yl)methyl)phenol (compound 1) was used as a reference compound. Following the outcome of docking-based virtual screening (VS), we synthesized seven novel derivatives of 1 that were identified in silico as being likely to have high binding affinity for the ERCC1-XPF heterodimerization interface by interacting with the XPF double helix hairpin helix (HhH2) domain. Two of the new compounds, 4-((6-chloro-2-methoxyacridin-9-yl)amino)-2-((4-cyclohexylpiperazin-1-yl)methyl)-phenol (compound 3) and 4-((6-chloro-2-methoxyacridin-9-yl)amino)-24(4-(2-(dimethylamino)ethyl) piperazin-1-yl) methyl) phenol (compound 4), were shown to be potent inhibitors of ERCC1-XPF activity in vitro. Compound 4 showed significant inhibition of the removal of CPDs in UV-irradiated cells and the capacity to sensitize colorectal cancer cells to UV radiation and cyclophosphamide.