(+/-)-(4aβ,8aβ,10aα)-3,4,4a,6,7,8,8a,9,10,10a-decahydro-8a-hydroxymethyl-1,1,4a-trimethylphenanthren-2(1H)-one

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 英文名称: (+/-)-(4aβ,8aβ,10aα)-3,4,4a,6,7,8,8a,9,10,10a-decahydro-8a-hydroxymethyl-1,1,4a-trimethylphenanthren-2(1H)-one
• 英文别名: (±)-(4aS,8aS)-8a-(hydroxymethyl)-1,1,4a-trimethyl-3,4,4a,6,7,8,8a,9,10,10a-decahydrophenanthren-2(1H)-one；(4aR,8aR,10aS)-8a-(hydroxymethyl)-1,1,4a-trimethyl-3,4,6,7,8,9,10,10a-octahydrophenanthren-2-one
• 化学式: C₁₈H₂₈O₂
• 分子量: 276.419
• InChiKey: UZXHDDWWXSUKEZ-XWIAVFTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (+/-)-(4aβ,8aβ,10aα)-3,4,4a,6,7,8,8a,9,10,10a-decahydro-8a-hydroxymethyl-1,1,4a-trimethylphenanthren-2(1H)-one 在 盐酸 、 4-甲基苯磺酸吡啶 作用下， 以 甲醇 、 苯 为溶剂， 反应 6.75h， 生成 [(4'aS,8'aS,10'aR)-1',1',4'a-trimethylspiro[1,3-dioxolane-2,2'-3,4,6,7,8,9,10,10a-octahydrophenanthrene]-8'a-yl]methanol
  参考文献：
  名称：

  在C-8a处具有乙炔基且在环A和C中具有氰基烯酮的新型三环化合物：高效抗炎剂和细胞保护剂。

  摘要：

  已经合成并在生物学上评估了在环A和C中具有氰基烯酮的新型C-8a官能化三环化合物。其中，在C-8a处具有乙炔基的化合物在体外和体内生物测定中显示出极高的抗炎和细胞保护活性。体外和体内效能均显着高于2-氰基3,12-二氧代油菜-1,9（11）-二烯-28-酸（CDDO），后者正被评估为抗癌药物我进行临床试验。

  DOI：

  10.1021/jm070141c
• 作为产物：
  描述：

  (±)-(4aS,8aS)-1,4a-dimethyl-2-oxo-2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthrene-8a-carboxylic acid 在 氨 、 lithium 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 2.0h， 生成 (+/-)-(4aβ,8aβ,10aα)-3,4,4a,6,7,8,8a,9,10,10a-decahydro-8a-hydroxymethyl-1,1,4a-trimethylphenanthren-2(1H)-one
  参考文献：
  名称：

  三环化合物的有效合成，(±)-(4aβ,8aβ,10aα)-1,2,3,4,4a,6,7,8,8a,9,10,10a-十二氢-1,1,4a -TRIMETHYL-2-OXOPHENANTHRENE-8a-羧酸，其甲酯，和 (±)-(4aβ,8aβ,10aα)-3,4,4a,6,7,8,8a,9,10,10a-十氢-8a-羟甲基-1,1,4a-TRIMETHYLPPHENANTHREN-2(1H)-ONE

  摘要：

  我们将注意力集中在 C-8a 位置的修饰上，因为一些具有生物活性的天然产物在同一位置具有功能（例如，抗肿瘤类 quassinoids4）。对于我们计划合成的 C-8a 官能化 TBE 化合物，简单的三环化合物 3-5 可能是非常理想的中间体。我们设想通过标准还原甲基化从已知的酸 65,6 制备 3-5。7 然而，尝试在不含质子供体的液氨中用 5-7 当量的锂还原甲基化酸 6，然后用重氮甲烷酯化得到 4 in 30% 的产率（7 次实验的平均值，产率波动）以及许多副产品。这些副产物对 4 的纯化造成了严重的困难。尝试使用一当量的叔丁醇得到与不使用质子供体相似的结果。尝试将甲基酯 7,6 用重氮甲烷还原甲基化，使用 10 当量锂在不含质子供体的液氨中得到所需化合物 3-5 以及几种副产物，包括烯酮 6 和 8 . 经过大量实验，我们发现加入一当量的水会显着改善这种还原性甲基化反应。因此，使用 7

  DOI：

  10.1080/00304940509354983

文献信息

• Tricyclic-bis-enone derivatives and methods of use thereof
  申请人：——

  公开号：US20030232786A1

  公开（公告）日：2003-12-18

  Novel tricyclic-bis-enone derivatives (TBEs) as well as the process for the preparation of such TBEs are provided. Also provided are methods for prevention and/or treatment of cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotropic lateral sclerosis, rheumatoid arthritis, inflammatory bowel disease, and all other diseases whose pathogenesis is believed to involve excessive production of either nitric oxide (NO) or prostaglandins or the overexpression of iNOS or COX-2 genes or gene products. Further, methods for the synthesis of the TBE compounds of the invention utilize cheap commercially available reagents and are highly cost effective and amenable to scale-up. Additional high efficiency synthetic methods that utilize novel intermediates as well as the synthesis of these intermediates are also provided. Furthermore, the invention also provides methods for designing novel and water-soluble TBEs.

  提供了新型三环双烯酮衍生物（TBEs）以及制备此类TBEs的方法。还提供了用于预防和/或治疗癌症、阿尔茨海默病、帕金森病、多发性硬化症、肌萎缩侧索硬化、类风湿性关节炎、炎症性肠病以及所有其他疾病的方法，这些疾病的发病机制被认为涉及过量产生一氧化氮（NO）或前列腺素或iNOS或COX-2基因或基因产物的过度表达。此外，本发明的TBE化合物的合成方法利用廉价的商业可获得试剂，具有高成本效益且易于扩展。还提供了利用新型中间体的高效合成方法以及这些中间体的合成。此外，本发明还提供了设计新型水溶性TBEs的方法。
• [EN] A NOVEL METHOD FOR SYNTHESIZING TBE-31<br/>[FR] NOUVEAU PROCÉDÉ DE SYNTHÈSE DU TBE-31
  申请人：UNIV NEW YORK STATE RES FOUND

  公开号：WO2014151181A1

  公开（公告）日：2014-09-25

  A process for the synthesis of (±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile ("TBE-31"), which is useful for the treatment of various diseases and disorder in mammals. (±)-8a-(Hydroxymethyl)-1,4a-dimethyl-2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthren-2-ol; (±)-8a-(Hydroxymethyl)-1,4a-dimethyl-4,4a,6,7,8,8a,9,10-octahydrophenanthren-2(3H)-one; (±)-(2R,4aS,8aS)-8a-(Hydroxymethyl)-1,4a-dimethyl-2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthren-2-ol; (±)-(2S,4aS,8aS)-8a-(Hydroxymethyl)-1,4a-dimethyl-2,3,4,4a,6,7,8,8a,9,10-decahydrophenanthren-2-ol; and (±)-(4aS,8aS)-8a-(Hydroxymethyl)-1,4a-dimethyl-4,4a,6,7,8,8a,9,10-octahydrophenanthren-2(3H)-one (4).

  一种合成（±）-（4bS,8aR,10aS）-10a-乙炔基-4b,8,8-三甲基-3,7-二酮-3,4b,7,8,8a,9,10,10a-辛氢苯并-2,6-二腈（“TBE-31”）的方法，该方法对哺乳动物的各种疾病和紊乱具有治疗作用。 （±）-8a-（羟甲基）-1,4a-二甲基-2,3,4,4a,6,7,8,8a,9,10-十氢苯并-2-醇；（±）-8a-（羟甲基）-1,4a-二甲基-4,4a,6,7,8,8a,9,10-辛氢苯并-2（3H）-酮；（±）-（2R,4aS,8aS）-8a-（羟甲基）-1,4a-二甲基-2,3,4,4a,6,7,8,8a,9,10-十氢苯并-2-醇；（±）-（2S,4aS,8aS）-8a-（羟甲基）-1,4a-二甲基-2,3,4,4a,6,7,8,8a,9,10-十氢苯并-2-醇；以及（±）-（4aS,8aS）-8a-（羟甲基）-1,4a-二甲基-4,4a,6,7,8,8a,9,10-辛氢苯并-2（3H）-酮（4）。
• SYNTHESIS AND BIOLOGICAL ACTIVITIES OF NEW TRICYCLIC-BIS-ENONES (TBES)
  申请人：Honda Tadashi

  公开号：US20080261985A1

  公开（公告）日：2008-10-23

  This invention describes novel tricyclic-bis-enone derivatives (TBEs), such as TBE-31, TBE-34, TBE-45 and water-soluble TBEs. The methods of preparing these compounds are also disclosed. The inventors demonstrate the ability of these new TBEs to inhibit proliferation of human myeloma cells, inhibit the induction of iNOS in cells stimulated with interferon-γ, induce heme oxygenase-1 (HO-1), induce CD11b expression—a leukemia differentiation marker, inhibit proliferation of leukemia cells, induce apoptosis in human lung cancer, and induce apoptosis in other cancerous cells. The TBEs of this invention are expected to be useful agents for the treatment and prevention of many diseases, including cancer, neurological disorders, inflammation, and pathologies involving oxidative stress.

  这项发明描述了新的三环双烯酮衍生物（TBEs），如TBE-31、TBE-34、TBE-45和水溶性TBEs。还公开了制备这些化合物的方法。发明人展示了这些新TBEs抑制人骨髓瘤细胞增殖的能力，抑制干扰素-γ刺激下细胞中iNOS的诱导，诱导血红素氧合酶-1（HO-1），诱导CD11b表达-一种白血病分化标志物，抑制白血病细胞增殖，诱导人肺癌细胞凋亡，并诱导其他癌细胞凋亡。这项发明的TBEs预计将成为治疗和预防许多疾病的有用药物，包括癌症、神经系统疾病、炎症和涉及氧化应激的病理学。
• Tricyclic Compounds Containing Nonenolizable Cyano Enones. A Novel Class of Highly Potent Anti-Inflammatory and Cytoprotective Agents
  作者：Tadashi Honda、Hidenori Yoshizawa、Chitra Sundararajan、Emilie David、Marc J. Lajoie、Frank G. Favaloro、Tomasz Janosik、Xiaobo Su、Yukiko Honda、Bill D. Roebuck、Gordon W. Gribble

  DOI：10.1021/jm101445p

  日期：2011.3.24

  Forty-four novel tricycles containing nonenolizable cyano enones (TCEs) were designed and synthesized on the basis of a semisynthetic pentacyclic triterpenoid, bardoxolone methyl, which is currently being developed in phase II clinical trials for the treatment of severe chronic kidney disease in diabetic patients. Most of the TCEs having two different kinds of nonenolizable cyano enones in rings A and C are highly potent suppressors of induction of inducible nitric oxide synthase stimulated with interferon-gamma and are highly potent inducers of the cytoprotective enzymes heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1. Among these compounds, (+/-)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile ((+/-)-31) is the most potent in these bioassays in our pool of drug candidates including semisynthetic triterpenoids and synthetic tricycles. These facts strongly suggest that an essential factor for potency is not a triterpenoid skeleton but the cyano enone functionality. Notably, TCE 31 reduces hepatic tumorigenesis induced with aflatoxin in rats. Further preclinical studies and detailed mechanism studies on 31 are in progress.
• An Improved Synthesis of a Hydroxymethyl Tricyclic Ketone from Cyclohexanone, the Key Processes for the Synthesis of a Highly Potent Anti-inflammatory and Cytoprotective Agent
  作者：Tadashi Honda、Akira Saito、Suqing Zheng、Motohiro Takahashi、Wei Li、Iwao Ojima

  DOI：10.1055/s-0033-1339900

  日期：——

  An improved synthesis of hydroxymethyl tricyclic ketone, (+/-)-(4aS,8aS)-8a-(hydroxymethyl)-1,1,4a-trimethyl-3,4,4a,6,7,8,8a,9,10,10a-decahydrophenanthren-2(1H)-one, in five steps (34% yield) from cyclohexanone has been successfully established. Accordingly, 10 grams of a highly potent anti-inflammatory and cytoprotective agent, (+/-)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile (TBE-31), was obtained in 15 steps (9.2% overall yield) via the hydroxymethyl tricyclic ketone from 32 grams of cyclohexanone.