methyl 8-[(4-fluorophenyl)amino]-8-oxooctanoate | 1332599-32-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: methyl 8-[(4-fluorophenyl)amino]-8-oxooctanoate
• 英文别名: methyl 8-(4-fluoroanilino)-8-oxooctanoate
• CAS: 1332599-32-2
• 化学式: C₁₅H₂₀FNO₃
• 分子量: 281.327
• InChiKey: PXWVIJNSQFVJBW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  20
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  55.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 8-[(4-fluorophenyl)amino]-8-oxooctanoate 在 lithium aluminium tetrahydride 、 盐酸羟胺 、 sodium acetate 、 silica gel 、 pyridinium chlorochromate 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 16.0h， 生成 (4-fluorophenyl)-8-(N-hydroxyimino)octanamide
  参考文献：
  名称：

  Synthesis and biological evaluation of aziridin-1-yl oxime-based vorinostat analogs as anticancer agents

  摘要：

  The suberoyl anilide hydroxamic acid (vorinostat) analogs with the aziridin-1-yl oxime moiety as a possible metal chelating functionality have been synthesized. Their biological activity and stability under physiological conditions have been evaluated. Although some of the synthesized compounds demonstrated high antiproliferative activity against human HT1080 fibrosarcoma (HT1080, IC50 0.3-7.7 mu M) comparable to vorinostat (HT1080, IC50 2.4 mu M), they showed only weak histone deacetylase inhibition activity in HeLa cell line extracts.

  DOI：

  10.1007/s10593-015-1752-z
• 作为产物：
  描述：

  辛二酸 在 乙酸酐 、 potassium carbonate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 methyl 8-[(4-fluorophenyl)amino]-8-oxooctanoate
  参考文献：
  名称：

  Synthesis and biological evaluation of aziridin-1-yl oxime-based vorinostat analogs as anticancer agents

  摘要：

  The suberoyl anilide hydroxamic acid (vorinostat) analogs with the aziridin-1-yl oxime moiety as a possible metal chelating functionality have been synthesized. Their biological activity and stability under physiological conditions have been evaluated. Although some of the synthesized compounds demonstrated high antiproliferative activity against human HT1080 fibrosarcoma (HT1080, IC50 0.3-7.7 mu M) comparable to vorinostat (HT1080, IC50 2.4 mu M), they showed only weak histone deacetylase inhibition activity in HeLa cell line extracts.

  DOI：

  10.1007/s10593-015-1752-z

文献信息

• Precursor-Directed Biosynthesis of Aminofulvenes: New Chalanilines from Endophytic Fungus Chalara sp.
  作者：Mahsa Khoshbakht、Jason Srey、Donovon A. Adpressa、Annika Jagels、Sandra Loesgen

  DOI：10.3390/molecules26154418

  日期：——

  The plant endophyte Chalara sp. is able to biotransform the epigenetic modifier vorinostat to form unique, aniline-containing polyketides named chalanilines. Here, we sought to expand the chemical diversity of chalaniline A-type molecules by changing the aniline moiety in the precursor vorinostat. In total, twenty-three different vorinostat analogs were prepared via two-step synthesis, and nineteen were incorporated by the fungus into polyketides. The highest yielding substrates were selected for large-scale precursor-directed biosynthesis and five novel compounds, including two fluorinated chalanilines, were isolated, purified, and structurally characterized. Structure elucidation relied on 1D and 2D NMR techniques and was supported by low- and high-resolution mass spectrometry. All compounds were tested for their bioactivity but were not active in antimicrobial or cell viability assays. Aminofulvene-containing natural products are rare, and this high-yielding, precursor-directed process allows for the diversification of this class of compounds.

  植物内生真菌 Chalara sp. 能够将表观遗传修饰剂 vorinostat 生物转化为形成独特的含苯胺的聚酮类化合物，被命名为 chalanilines。在这里，我们试图通过改变前体 vorinostat 中的苯胺基团来扩展 chalaniline A 类分子的化学多样性。总共，通过两步合成制备了二十三种不同的 vorinostat 类似物，其中十九种被真菌转化为聚酮类化合物。选择产量最高的底物进行大规模前体导向生物合成，分离、纯化并结构表征了五种新化合物，包括两种氟代 chalanilines。结构阐明依赖于一维和二维核磁共振技术，并得到低分辨率和高分辨率质谱的支持。所有化合物均进行了生物活性测试，但在抗微生物或细胞存活率测定中均不活跃。含氨基富烯的天然产物很少见，而这种高产率的前体导向过程允许对这类化合物进行多样化。
• Synthesis and biological effects of small molecule enhancers for improved recombinant protein production in plant cell cultures
  作者：Bárbara A. Rebelo、Rita B. Santos、Osvaldo S. Ascenso、Ana Cláudia Nogueira、Diana Lousa、Rita Abranches、M. Rita Ventura

  DOI：10.1016/j.bioorg.2019.103452

  日期：2020.1

  various cellular events such as transcription. Novel HDAC inhibitors were designed and synthesised to promote higher levels of recombinant protein production in tobacco cell cultures. The effect of these chemical enhancers on the epigenetic profiles in plant cells has been evaluated by molecular docking, in vitro and in vivo studies. The addition of these novel enhancers led to an increase in histone

  组蛋白脱乙酰酶参与染色质重塑，因此在基因表达的表观遗传调控中发挥着至关重要的作用。 HDAC 抑制剂改变组蛋白和非组蛋白的乙酰化状态，以调节转录等各种细胞事件。设计和合成了新型 HDAC 抑制剂，以促进烟草细胞培养物中重组蛋白产量的更高水平。这些化学增强剂对植物细胞表观遗传谱的影响已通过分子对接、体外和体内研究进行了评估。这些新型增强子的添加导致组蛋白 H3 乙酰化水平增加，从而促进细胞培养物中重组蛋白积累水平的增加。这些结果可以为这些增强剂的应用铺平道路，以改善基于植物细胞的系统中高价值产品的生产。
• Modified Cap Group Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitor Derivatives Reveal Improved Selective Antileukemic Activity
  作者：Chanaz Salmi-Smail、Aurélie Fabre、Franck Dequiedt、Audrey Restouin、Rémy Castellano、Slaveia Garbit、Philippe Roche、Xavier Morelli、Jean Michel Brunel、Yves Collette

  DOI：10.1021/jm901358y

  日期：2010.4.22

  A series of SAHA cap derivatives was designed and prepared in good-to-excellent yields that varied from 49% to 95%. These derivatives were evaluated for their antiproliferative activity in several human cancer cell lines. Antiproliferative activity was observed for concentrations varying from 0.12 to > 100 mu M, and a molecular modeling approach of selected SAHA derivatives, based on available structural information of human HDAC8 in complex with SAHA, was performed. Strikingly, two compounds displayed up to 10-fold improved antileukemic activity with respect to SAHA; however, these compounds displayed antiproliferative activity similar to SAHA when assayed against solid tumor-derived cell lines. A 10-fold improvement in the leukemic vs peripheral blood mononuclear cell therapeutic ratio, with no evident in vivo toxicity toward blood cells, was also observed. The herein-described compounds and method of synthesis will provide invaluable tools to investigate the molecular mechanism responsible for the reported selectively improved antileukemic activity.
• Reappraising the Structures and Distribution of Metabolites from Black Aspergilli Containing Uncommon 2-Benzyl-4<i>H</i>-pyran-4-one and 2-Benzylpyridin-4(1<i>H</i>)-one Systems
  作者：Jon C. Henrikson、Trevor K. Ellis、Jarrod B. King、Robert H. Cichewicz

  DOI：10.1021/np200454z

  日期：2011.9.23

  To date, natural products containing 2-benzyl-4H-pyran-4-one and 2-benzylpyridin-4(1H)-one substructures have been encountered in relatively few fungi outside of the black aspergilli clade. While exploring the occurrence of these compounds among Aspergillus spp., it was determined that the structures of the unusual furopyrrols tensidols A and B (5 and 6) and JBIR-86 and JBIR-87 (9 and 10) were incorrect and should be reassigned as 2-benzyl-4H-pyran-4-ones (7, 8, lie, and 12, respectively). The origin of the unique N-phenyl groups in the 2-benzylpyridin-4(1H)-ones nygerones A and B (1 and 2) were also examined, and it was established that N-phenylamides added to the culture medium were suitable substrates for generating these metabolites; however, this phenomenon remained limited to a single fungus in our collection (Aspergillus niger ATCC 1015). A variety of 2-benzyl-4H-pyran-4-ones and 2-benzylpyridin-4(1H)-ones were detected among the black aspergilli, but only pestalamide B (13) was found in all 11 of the tested strains. These metabolites, as well as a group of synthetic analogues, demonstrated weak antifungal activity against several Candida strains, Aspergillus flavus, and Aspergillus fumigatus.
• In Vivo PET Imaging of Histone Deacetylases by ¹⁸F-Suberoylanilide Hydroxamic Acid (¹⁸F-SAHA)
  作者：J. Adam Hendricks、Edmund J. Keliher、Brett Marinelli、Thomas Reiner、Ralph Weissleder、Ralph Mazitschek

  DOI：10.1021/jm200620f

  日期：2011.8.11

  Histone deacetylases (HDACs) are a group of enzymes that modulate gene expression and cell state by deacetylation of both histone and non-histone proteins. A variety of HDAC inhibitors (HDACi) have already undergone clinical testing in cancer. Real-time in vivo imaging of HDACs and their inhibition would be invaluable; however, the development of appropriate imaging agents has remained a major challenge. Here, we describe the development and evaluation of F-18-suberoylanilide hydroxamic acid (F-18-SAHA 1a), a close analogue of the most clinically relevant HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). We demonstrate that 1a has near identical biochemical activity profiles to that of SAHA and report findings from pharmacokinetic studies. Using a murine ovarian. cancer model, we likewise show that HDAC inhibitor target binding efficacy can be quantitated within 24 h of administration. 1a thus represents the first F-18-positron emission tomography (PET) HDAC imaging agent, which also exhibits low nanomolar potency and is pharmacologically analogous to a clinically relevant HDAC inhibitor.