flumethasone-21-mesylate | 2414-34-8

• 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: flumethasone-21-mesylate
• 英文别名: 2-[(1R,2S,8S,10S,11S,13R,14R,15S,17S)-1,8-difluoro-14,17-dihydroxy-2,13,15-trimethyl-5-oxotetracyclo[8.7.0.0²'⁷.0^11,15]heptadeca-3,6-dien-14-yl]-2-oxoethyl methanesulfonate；[2-[(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] methanesulfonate
• CAS: 2414-34-8
• 化学式: C₂₃H₃₀F₂O₇S
• 分子量: 488.55
• InChiKey: ZTPBFKQYAIAATO-BSMQTTSKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  126
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  flumethasone-21-mesylate 在 sodium azide 作用下， 以 丙酮 为溶剂， 反应 18.0h， 生成
  参考文献：
  名称：

  开发用于治疗炎症性疾病的抗体药物缀合物的新型糖皮质激素

  摘要：

  糖皮质激素（GC）广泛用于治疗多种自身免疫性疾病和炎症性疾病；然而，GC 的全身递送会产生基本上影响每个器官系统的副作用，这反映出糖皮质激素受体 (GR) 的表达几乎无处不在。使用抗体-糖皮质激素缀合物 (GC-ADC) 将 GC 靶向递送至患病组织，为克服这些副作用提供了一种治疗替代方案。在此，我们描述了新型 GC，其比地塞米松和布地奈德表现出更强的效力，对 GR 的选择性比其他核受体高 100 倍，并且在药理学测定（hERG、AMES）中没有体外安全责任，并且证明了显着降低脂多糖（LPS）攻击小鼠体内肿瘤坏死因子-α（TNF-α）的释放。通过组织蛋白酶可裂解接头进行位点特异性缀合的 GC-ADC 在血浆中高度稳定，并在抗原阳性细胞中特异性释放 GC，这表明这些新型 GC 可以作为 ADC 有效负载来治疗自身免疫和炎症性疾病。

  DOI：

  10.1021/acs.jmedchem.1c00541
• 作为产物：
  描述：

  甲基磺酰氯 、 氟米松 在 吡啶 作用下， 反应 2.0h， 生成 flumethasone-21-mesylate
  参考文献：
  名称：

  具有抗炎和抗菌活性的新型阳离子脂质的合成及其构效关系

  摘要：

  已知某些具有膜活性的阳离子类固醇也具有抗炎和抗微生物的特性。这种组合的功能对于与组织损伤增高相关的感染的潜在疗法特别相关，例如，囊性纤维化气道疾病，一种以慢性细菌感染和持续炎症为特征的疾病。在这项研究中，使用倍氯米松，布地奈德和氟美松酮合成了六种新型阳离子糖皮质激素。产物被单取代或二取代，分别含有一个或两个甾族基团。对生物活性的体外评估表明，对于所有合成化合物而言，双重抗炎和抗微生物特性具有有限的细胞毒性。布地奈德衍生的化合物在其各自的单取代和双取代类别中均显示出最高程度的糖皮质激素和抗菌性能。结构活性分析表明，活性通常与母体糖皮质激素的效力有关。综上所述，这些数据表明可以用合适的起始类固醇合成这些类型的双作用阳离子脂质，以根据需要调节活性。

  DOI：

  10.1016/j.bmcl.2015.04.104

文献信息

• Steroidal C-21 mercapto derivatives as dissociated steroids: Discovery of an inhaled dissociated steroid
  作者：Purakkattle Biju、Kevin McCormick、Robert Aslanian、Michael Berlin、Daniel Solomon、Richard Chapman、Robbie McLeod、Daniel Prelusky、Stephen Eckel、George Kelly、Michelle Natiello、Aileen House、Xiomara Fernandez、Rema Bitar、Jonathan Phillips、John Anthes

  DOI：10.1016/j.bmcl.2011.08.108

  日期：2011.11

  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.
• 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.