(+/-)-(4aβ,8aβ,10aα)-3,4,4a,6,7,8,8a,9,10,10a-decahydro-1,1,4a,8a-tetramethylphenanthren-2(3H)-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-1,1,4a,8a-tetramethylphenanthren-2(3H)-one
• 英文别名: (+/-)-(4aβ,8aβ,10aα)-3,4,4a,6,7,8,8a,9,10,10a-decahydro-1,1,4a,8a-tetramethylphenanthren-2(1H)-one；(+/-)-(4aS,8aR,10aR)-1,1,4a,8a-tetramethyl-3,4,4a,6,7,8,8a,9,10,10a-decahydrophenanthren-2(1H)-one；(4aS,8aR,10aR)-1,1,4a,8a-tetramethyl-3,4,6,7,8,9,10,10a-octahydrophenanthren-2-one
• 化学式: C₁₈H₂₈O
• 分子量: 260.42
• InChiKey: NFPOCLBTJGPNIS-VHSSKADRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  19
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  17.1
• 氢给体数：
  0
• 氢受体数：
  1

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-1,1,4a,8a-tetramethylphenanthren-2(3H)-one 在 chromium(VI) oxide 、 叔丁基过氧化氢 、 4-甲基苯磺酸吡啶 作用下， 以 二氯甲烷 、 苯 为溶剂， 反应 8.58h， 生成 (+/-)-(4a'S,8a'S,10a'R)-1',1',4a',8a'-tetramethyl-4',4a',7',8',8a',9',10',10a'-octahydro-1'H-spiro[[1,3]dioxolane-2,2'-phenanthren]-6'(3'H)-one
  参考文献：
  名称：

  Tricyclic Compounds Containing Nonenolizable Cyano Enones. A Novel Class of Highly Potent Anti-Inflammatory and Cytoprotective Agents

  摘要：

  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.

  DOI：

  10.1021/jm101445p
• 作为产物：
  描述：

  (-)-(4aR,8S,8aS,10aS)-(4aα,8α,8aα,10aβ)-3,4,4a,6,7,8,8a,9,10,10a-decahydro-8-hydroxy-1,1,4a,8a-tetramethylphenanthrene-2(1H)-one 在 三正丁基氢锡 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 22.0h， 生成 (+/-)-(4aβ,8aβ,10aα)-3,4,4a,6,7,8,8a,9,10,10a-decahydro-1,1,4a,8a-tetramethylphenanthren-2(3H)-one
  参考文献：
  名称：

  Tricyclic Compounds Containing Nonenolizable Cyano Enones. A Novel Class of Highly Potent Anti-Inflammatory and Cytoprotective Agents

  摘要：

  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.

  DOI：

  10.1021/jm101445p

文献信息

• Efficient synthesis of (−)- and (+)-tricyclic compounds with enone functionalities in rings A and C. A novel class of orally active anti-inflammatory and cancer chemopreventive agents
  作者：Tadashi Honda、Frank G. Favaloro, Jr.、Tomasz Janosik、Yukiko Honda、Nanjoo Suh、Michael B. Sporn、Gordon W. Gribble

  DOI：10.1039/b307491a

  日期：——

  desired to synthesize optically active TBE compounds for a comparison of the biological potency of both enantiomers. We now describe the synthesis of both enantiomers of (4a[small beta],8a[small beta],10a[small alpha])-1,2,4a,6,8a,9,10,10a-octahydro-1,1,4a,8a-tetramethyl-2,6-dioxophenanthren e-3-carbonitrile (2) and 3 from commercially available simple compounds. Interestingly, (+)-3 having the same

  根据合成的三萜类化合物2-氰基-3,12-二氧代油酸酯-1,9（11）的结构设计了在环A和环C具有烯酮官能团的新型三环化合物[三环-双-烯酮（TBE）化合物]。 ）-二烯-28-油酸（CDDO）（1），它是预防和/或治疗癌症和炎症性疾病的有前途的候选药物，其发病机理可能涉及一氧化氮（NO）和/或前列腺素的过量生产。一系列外消旋形式的TBE化合物显示出对小鼠巨噬细胞中干扰素-γ（IFN-γ）诱导的NO产生的高抑制活性。这些化合物之一，（+/-）-（4a [小β，8a [小β，10a [小α]）-1,2,4a，6,8a，9,10,10a-八氢-1 ，1,4a，8a-tetramethyl-2,6-dioxophenanthren e-3,7-dicarbonitrile（（+/-）-3），在一项初步研究中，使用硫代乙醇酸酯和IFN-γ诱导的小鼠腹膜炎症，口服活性为15 mg kg（-1）（单次
• 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。
• Design and Synthesis of Tricyclic Compounds with Enone Functionalities in Rings A and C:  A Novel Class of Highly Active Inhibitors of Nitric Oxide Production in Mouse Macrophages
  作者：Frank G. Favaloro,、Tadashi Honda、Yukiko Honda、Gordon W. Gribble、Nanjoo Suh、Renee Risingsong、Michael B. Sporn

  DOI：10.1021/jm025565f

  日期：2002.10.1

  Novel tricyclic compounds with enone functionalities in rings A and C, which were designed on the basis of the structure of a synthetic triterpenoid, 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid, have been synthesized. Among them, 10 shows high inhibitory activity (IC50 = 1 nM level) against production of nitric oxide induced by interferon-gamma in mouse macrophages and is orally active at 15 mg/kg (once) in a preliminary in vivo study using mouse peritoneal inflammation induced by thioglycollate and interferon-gamma.
• EP1465615A4
  申请人：——

  公开号：EP1465615A4

  公开（公告）日：2006-09-06
• TRICYCLIC-BIS-ENONE DERIVATIVES AND METHODS OF USE THEREOF
  申请人：Trustees of Dartmouth College

  公开号：EP1465615B1

  公开（公告）日：2012-08-01