3-amino-7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxooxotetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-8-methyl-2H-chromen-2-one | 915118-12-6

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: 3-amino-7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxooxotetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-8-methyl-2H-chromen-2-one
• 英文别名: 3-amino-7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-8-methyl-2H-chromen-2-one；3-amino-7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxotetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yloxy)-8-methyl-2H-chromen-2-one
• CAS: 915118-12-6
• 化学式: C₁₉H₂₁NO₈
• 分子量: 391.378
• InChiKey: MEDQPYVJZZZFGY-KLZNWCGWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.12
• 重原子数：
  28.0
• 可旋转键数：
  3.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  119.45
• 氢给体数：
  1.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  3-amino-7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxooxotetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-8-methyl-2H-chromen-2-one 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 42.0h， 生成 (E)-N¹,N⁶-bis(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)hex-3-enediamide
  参考文献：
  名称：

  抑制Hsp90蛋白折叠机制的香豆素A1类似物的合成和评估。

  摘要：

  香豆素抗生素不仅是DNA促旋酶的有效抑制剂，而且是迄今为止报道的最有效的90 kDa热休克蛋白（Hsp90）C端抑制剂。与N端ATP结合位点相反，对Hsp90 C端的了解很少。此外，这类天然产物与Hsp90之间存在非常有限的构效关系。在这封信中，介绍了二聚香豆素类似物的合成及其在乳腺癌细胞系中的抑制作用。

  DOI：

  10.1021/ol061918j
• 作为产物：
  描述：

  benzyl 7-hydroxy-8-methyl-2-oxo-2H-chromen-3-yl carbamate 在 palladium on activated charcoal 三氟化硼乙醚 、 氢气 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 20.0h， 生成 3-amino-7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxooxotetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-8-methyl-2H-chromen-2-one
  参考文献：
  名称：

  抑制Hsp90蛋白折叠机制的香豆素A1类似物的合成和评估。

  摘要：

  香豆素抗生素不仅是DNA促旋酶的有效抑制剂，而且是迄今为止报道的最有效的90 kDa热休克蛋白（Hsp90）C端抑制剂。与N端ATP结合位点相反，对Hsp90 C端的了解很少。此外，这类天然产物与Hsp90之间存在非常有限的构效关系。在这封信中，介绍了二聚香豆素类似物的合成及其在乳腺癌细胞系中的抑制作用。

  DOI：

  10.1021/ol061918j

文献信息

• Novobiocin:  Redesigning a DNA Gyrase Inhibitor for Selective Inhibition of Hsp90
  作者：Joseph A. Burlison、Len Neckers、Andrew B. Smith、Anthony Maxwell、Brian S. J. Blagg

  DOI：10.1021/ja065793p

  日期：2006.12.1

  binding site, a library of novobiocin analogues was prepared and initial structure-activity relationships revealed. These data suggested that the 4-hydroxy moiety of the coumarin ring and the 3'-carbamate of the noviose appendage were detrimental to Hsp90 inhibitory activity. In an effort to confirm these findings, 4-deshydroxy novobiocin (DHN1) and 3'-descarbamoyl-4-deshydroxynovobiocin (DHN2) were prepared

  Novobiocin 是香豆霉素抗生素家族的成员，是一种成熟的 DNA 促旋酶抑制剂。最近的研究表明，新生霉素在 Hsp90 的 C 末端与以前未被识别的 ATP 结合位点结合，并在大约 700 microM 处诱导 Hsp90 依赖性客户蛋白的降解。为了开发更有效的 C 末端结合位点抑制剂，制备了新生霉素类似物库并揭示了初始结构-活性关系。这些数据表明香豆素环的 4-羟基部分和新糖附属物的 3'-氨基甲酸酯对 Hsp90 抑制活性有害。为了证实这些发现，制备了 4-去羟基新生霉素 (DHN1) 和 3'-去氨基甲酰基-4-去羟基新生霉素 (DHN2)，并针对 Hsp90 进行了评估。这两种化合物都比天然产物更有效，而且 DHN2 被证明比 DHN1 更活跃。为了确定这些部分是否对 DNA 促旋酶抑制很重要，测试了这些化合物抑制 DNA 促旋酶的能力，并发现它们显示出促旋酶活性的显着降低。因此，我们已经建立了第一组明确区分
• Development of Novobiocin Analogues That Manifest Anti-proliferative Activity against Several Cancer Cell Lines
  作者：Joseph A. Burlison、Christopher Avila、George Vielhauer、Donna J. Lubbers、Jeffrey Holzbeierlein、Brian S. J. Blagg

  DOI：10.1021/jo702191a

  日期：2008.3.1

  Recent studies have shown that the DNA gyrase inhibitor, novobiocin, binds to a previously unrecognized ATP-binding site located at the C-terminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at similar to 700 mu M. As a result of these studies, several analogues of the coumarin family of antibiotics have been reported and shown to exhibit increased Hsp90 inhibitory activity; however, the monomeric species lacked the ability to manifest anti-proliferative activity against cancer cell lines at concentrations tested. In an effort to develop more efficacious compounds that produce growth inhibitory activity against cancer cell lines, structure-activity relationships; were investigated surrounding the prenylated benzamide side chain of the natural product. Results obtained from these studies have produced the first novobiocin analogues that manifest anti-proliferative activity against several cancer cell lines.
• Targeting the Heat Shock Protein 90 Dimer with Dimeric Inhibitors
  作者：Bhaskar Reddy Kusuma、Laura B. Peterson、Huiping Zhao、George Vielhauer、Jeffrey Holzbeierlein、Brian S. J. Blagg

  DOI：10.1021/jm200553w

  日期：2011.9.22

  The design, synthesis, and biological evaluation of conformationally constrained coumermycin Al analogues are reported. Compounds were evaluated against both breast cancer (SKBr3 and MCF7) and prostate cancer (PC3 mm2, A549, and HT29) cell lines. Non-noviosylated coumermycin Al analogues that manifest potent antiproliferative activity resulting from Hsp90 inhibition are provided, wherein replacement of the stereochemically complex noviose sugar with readily available piperidine rings resulted in similar to 100 fold increase in antiproliferative activities as compared to coumermycin Al, producing small molecule Hsp90 inhibitors that exhibit nanomolar activities.
• Diverging Novobiocin Anti-Cancer Activity from Neuroprotective Activity through Modification of the Amide Tail
  作者：Suman Ghosh、Yang Liu、Gaurav Garg、Mercy Anyika、Nolan T. McPherson、Jiacheng Ma、Rick T. Dobrowsky、Brian S. J. Blagg

  DOI：10.1021/acsmedchemlett.6b00224

  日期：2016.8.11

  Novobiocin is a natural product that binds the Hsp90 C-terminus and manifests Hsp90 inhibitory activity. Structural investigations on novobiocin led to the development of both anti-cancer and neuroprotective agents. The varied pharmacological activity manifested by these novobiocin analogs prompted the investigation of structure function studies to identify these contradictory effects, which revealed that modifications to the amide side chain produce either anticancer or neuroprotective activity. Compounds that exhibit neuroprotective activity contain a short alkyl or cycloalkyl amide side chain. In contrast, anti-cancer agents contain five or more carbons, disrupt interactions between Hsp90 alpha and Aha1, and induce the degradation of Hsp90-dependent client proteins.