(8S,9S,10R,11S,13S,14S,17R)-17-(2-(benzo[d]thiazol-2-ylthio)acetyl)-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | 1168140-52-0

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: (8S,9S,10R,11S,13S,14S,17R)-17-(2-(benzo[d]thiazol-2-ylthio)acetyl)-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one
• 英文别名: (8S,9S,10R,11S,13S,14S,17R)-17-[2-(1,3-benzothiazol-2-ylsulfanyl)acetyl]-11,17-dihydroxy-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-3-one
• CAS: 1168140-52-0
• 化学式: C₂₈H₃₁NO₄S₂
• 分子量: 509.69
• InChiKey: DIGUPHFDYCGPRL-ALCUMQOQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  35
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  141
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  呋喃甲酰氯 、 (8S,9S,10R,11S,13S,14S,17R)-17-(2-(benzo[d]thiazol-2-ylthio)acetyl)-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one 在 4-二甲氨基吡啶 作用下， 以 二氯甲烷 为溶剂， 生成 (8S,9S,10R,11S,13S,14S,17R)-17-(2-(benzo[d]thiazol-2-ylthio)acetyl)-11-hydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-yclopenta[a]phenanthren-17-yl furan-2-carboxylate
  参考文献：
  名称：

  Steroidal C-21 mercapto derivatives as dissociated steroids: Discovery of an inhaled dissociated steroid

  摘要：

  A series of C-21 mercapto derivatives of hydrocortisone have been synthesized and evaluated in cell based transrepression and transactivation assays. The benzothiazole derivative, compound 6 not only showed a dissociated profile in vitro functional assays but also a pharmacological profile in a Brown-Norway rat therapeutic index model of asthma that dissociated side effects (thymolysis) while maintaining efficacy against pulmonary inflammation and lung function. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.08.108
• 作为产物：
  描述：

  泼尼松龙 在 potassium carbonate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 生成 (8S,9S,10R,11S,13S,14S,17R)-17-(2-(benzo[d]thiazol-2-ylthio)acetyl)-11,17-dihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one
  参考文献：
  名称：

  Steroidal C-21 mercapto derivatives as dissociated steroids: Discovery of an inhaled dissociated steroid

  摘要：

  A series of C-21 mercapto derivatives of hydrocortisone have been synthesized and evaluated in cell based transrepression and transactivation assays. The benzothiazole derivative, compound 6 not only showed a dissociated profile in vitro functional assays but also a pharmacological profile in a Brown-Norway rat therapeutic index model of asthma that dissociated side effects (thymolysis) while maintaining efficacy against pulmonary inflammation and lung function. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.08.108

文献信息

• Channel Expansion in the Ligand-Binding Domain of the Glucocorticoid Receptor Contributes to the Activity of Highly Potent Glucocorticoid Analogues
  作者：Wesley B. Seaton、Susan J. Burke、Alexander R. Fisch、William A. Schilletter、Mary Grace A. Beck、Gabrielle A. Cassagne、Innocence Harvey、Molly S. Fontenot、J. Jason Collier、Shawn R. Campagna

  DOI：10.3390/molecules29071546

  日期：——

  Glucocorticoids (GCs) act through the glucocorticoid receptor (GR) and are commonly used as anti-inflammatory and immunosuppressant medications. Chronic GC use has been linked with unwanted complications such as steroid-induced diabetes mellitus (SIDM), although the mechanisms for these effects are not completely understood. Modification of six GC parent molecules with 2-mercaptobenzothiazole resulted in consistently less promoter activity in transcriptional activation assays using a 3xGRE reporter construct while constantly reducing inflammatory pathway activity. The most selective candidate, DX1, demonstrated a significant reduction (87%) in transactivation compared to commercially available dexamethasone. DX1 also maintained 90% of the anti-inflammatory potential of dexamethasone while simultaneously displaying a reduced toxicity profile. Additionally, two novel and highly potent compounds, DX4 and PN4, were developed and shown to elicit similar mRNA expression at attomolar concentrations that dexamethasone exhibits at nanomolar dosages. To further explain these results, Molecular Dynamic (MD) simulations were performed to examine structural changes in the ligand-binding domain of the glucocorticoid receptor in response to docking with the top ligands. Differing interactions with the transcriptional activation function 2 (AF-2) region of the GR may be responsible for lower transactivation capacity in DX1. DX4 and PN4 lose contact with Arg611 due to a key interaction changing from a stronger hydrophilic to a weaker hydrophobic one, which leads to the formation of an unoccupied channel at the location of the deacylcortivazol (DAC)-expanded binding pocket. These findings provide insights into the structure–function relationships important for regulating anti-inflammatory activity, which has implications for clinical utility.