3-(pyridin-4-yl)naphtho[2,3-d]isoxazole-4,9-dione | 1383471-00-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 3-(pyridin-4-yl)naphtho[2,3-d]isoxazole-4,9-dione
• 英文别名: 3-Pyridin-4-ylbenzo[f][1,2]benzoxazole-4,9-dione
• CAS: 1383471-00-8
• 化学式: C₁₆H₈N₂O₃
• 分子量: 276.251
• InChiKey: IMPHIMFYNYZESA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  73.1
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-(pyridin-4-yl)naphtho[2,3-d]isoxazole-4,9-dione 、 碘甲烷 以 甲醇 为溶剂， 以36%的产率得到4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]isoxazol-3-yl)-1-methylpyridinium iodide
  参考文献：
  名称：

  Isoxazolo(aza)naphthoquinones: A new class of cytotoxic Hsp90 inhibitors

  摘要：

  A series of 3-aryl-naphtho[2,3-d]isoxazole-4,9-diones and some of their 6-aza analogues were Synthesized and found to inhibit the heat shock protein 90 (Hsp90). The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression in a series of human tumour cell lines. Representative compounds (7f, 10c) downregulated the Hsp90 client proteins EGFR, Akt, Cdk4, Raf-1, and survivin, and upregulated Hsp70. Most of the compounds, in particular the alkylated 3-pyridyl derivatives, exhibited potent antiproliferative activity, down to two-digit nanomolar range. Preliminary results indicated in vivo activity of 7f against human epithelial carcinoma A431 model growing as tumour xenograft in nude mice, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.03.036
• 作为产物：
  描述：

  4-吡啶甲醛肟 、 1,4-萘醌 在 sodium hypochlorite 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 生成 3-(pyridin-4-yl)naphtho[2,3-d]isoxazole-4,9-dione
  参考文献：
  名称：

  Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells

  摘要：

  热休克蛋白90（Hsp90）分子伴侣与参与癌症发生和癌症进展的广泛客体蛋白相互作用。然而，由于其高毒性、缺乏对癌细胞的选择性以及被负责多药耐药（MDR）的膜转运蛋白（如P-糖蛋白）排出，Hsp90抑制剂未能成为抗癌药物。认识到新化合物抑制P-糖蛋白功能和/或表达的潜力对于寻找有效的抗癌药物至关重要。合成了含有异噁唑醌酮核心的十一种Hsp90抑制剂，并在两种MDR模型中评估了这些抑制剂，这两种模型由敏感和相应的耐药癌细胞组成，这些癌细胞过表达P-糖蛋白（人非小细胞肺癌和结肠腺癌）。我们研究了Hsp90抑制剂对细胞生长抑制、P-糖蛋白活性和P-糖蛋白表达的影响。在细胞生长和P-糖蛋白抑制方面进行了构效关系分析。化合物5、7和9直接与P-糖蛋白相互作用并抑制其ATP酶活性。通过分子对接研究确定了它们潜在的P-糖蛋白结合位点。此外，这些化合物在MDR结肠癌细胞中下调了P-糖蛋白的表达，对癌细胞表现出良好的相对选择性，而化合物5以浓度依赖的方式逆转了对阿霉素和紫杉醇的耐药性。因此，化合物5、7和9可能是治疗P-糖蛋白过表达癌症的有希望的候选药物。

  DOI：

  10.3390/ijms20184575

文献信息

• Isoxazolo(aza)naphthoquinones: A new class of cytotoxic Hsp90 inhibitors
  作者：Alberto Bargiotti、Loana Musso、Sabrina Dallavalle、Lucio Merlini、Grazia Gallo、Andrea Ciacci、Giuseppe Giannini、Walter Cabri、Sergio Penco、Loredana Vesci、Massimo Castorina、Ferdinando Maria Milazzo、Maria Luisa Cervoni、Marcella Barbarino、Claudio Pisano、Chiara Giommarelli、Valentina Zuco、Michelandrea De Cesare、Franco Zunino

  DOI：10.1016/j.ejmech.2012.03.036

  日期：2012.7

  A series of 3-aryl-naphtho[2,3-d]isoxazole-4,9-diones and some of their 6-aza analogues were Synthesized and found to inhibit the heat shock protein 90 (Hsp90). The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression in a series of human tumour cell lines. Representative compounds (7f, 10c) downregulated the Hsp90 client proteins EGFR, Akt, Cdk4, Raf-1, and survivin, and upregulated Hsp70. Most of the compounds, in particular the alkylated 3-pyridyl derivatives, exhibited potent antiproliferative activity, down to two-digit nanomolar range. Preliminary results indicated in vivo activity of 7f against human epithelial carcinoma A431 model growing as tumour xenograft in nude mice, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors. (C) 2012 Elsevier Masson SAS. All rights reserved.
• Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells
  作者：Jelena Dinić、Ana Podolski-Renić、Mirna Jovanović、Loana Musso、Ivanka Tsakovska、Ilza Pajeva、Sabrina Dallavalle、Milica Pešić

  DOI：10.3390/ijms20184575

  日期：——

  Heat Shock Protein 90 (Hsp90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents due to their high toxicity, lack of selectivity against cancer cells and extrusion by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). Recognizing the potential of new compounds to inhibit P-gp function and/or expression is essential in the search for effective anticancer drugs. Eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in two MDR models comprised of sensitive and corresponding resistant cancer cells with P-gp overexpression (human non-small cell lung carcinoma and colorectal adenocarcinoma). We investigated the effect of Hsp90 inhibitors on cell growth inhibition, P-gp activity and P-gp expression. Structure–activity relationship analysis was performed in respect to cell growth and P-gp inhibition. Compounds 5, 7, and 9 directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was identified by molecular docking studies. In addition, these compounds downregulated P-gp expression in MDR colorectal carcinoma cells, showed good relative selectivity towards cancer cells, while compound 5 reversed resistance to doxorubicin and paclitaxel in concentration-dependent manner. Therefore, compounds 5, 7 and 9 could be promising candidates for treating cancers with P-gp overexpression.

  热休克蛋白90（Hsp90）分子伴侣与参与癌症发生和癌症进展的广泛客体蛋白相互作用。然而，由于其高毒性、缺乏对癌细胞的选择性以及被负责多药耐药（MDR）的膜转运蛋白（如P-糖蛋白）排出，Hsp90抑制剂未能成为抗癌药物。认识到新化合物抑制P-糖蛋白功能和/或表达的潜力对于寻找有效的抗癌药物至关重要。合成了含有异噁唑醌酮核心的十一种Hsp90抑制剂，并在两种MDR模型中评估了这些抑制剂，这两种模型由敏感和相应的耐药癌细胞组成，这些癌细胞过表达P-糖蛋白（人非小细胞肺癌和结肠腺癌）。我们研究了Hsp90抑制剂对细胞生长抑制、P-糖蛋白活性和P-糖蛋白表达的影响。在细胞生长和P-糖蛋白抑制方面进行了构效关系分析。化合物5、7和9直接与P-糖蛋白相互作用并抑制其ATP酶活性。通过分子对接研究确定了它们潜在的P-糖蛋白结合位点。此外，这些化合物在MDR结肠癌细胞中下调了P-糖蛋白的表达，对癌细胞表现出良好的相对选择性，而化合物5以浓度依赖的方式逆转了对阿霉素和紫杉醇的耐药性。因此，化合物5、7和9可能是治疗P-糖蛋白过表达癌症的有希望的候选药物。