3β-(N-acetyl L-cysteine methyl ester)-2αβ,3-dihydrogaliellalactone

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 3β-(N-acetyl L-cysteine methyl ester)-2αβ,3-dihydrogaliellalactone
• 英文别名: 3β-(N-acetyl L-cysteine methyl ester)-2aβ,3-dihydrogaliellalactone；GPA-512；methyl (2R)-2-acetamido-3-[[(4R,7R,9S,10R,11S)-11-hydroxy-9-methyl-2-oxo-3-oxatricyclo[5.3.1.04,11]undecan-10-yl]sulfanyl]propanoate
• 化学式: C₁₇H₂₅NO₆S
• 分子量: 371.455
• InChiKey: QXOOJZPKZHXIHX-VZRFOGRKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  127
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  L-半胱氨酸 、 galiellalactone 在 三乙胺 作用下， 以 甲醇 为溶剂， 反应 30.0h， 以91%的产率得到3β-(N-acetyl L-cysteine methyl ester)-2αβ,3-dihydrogaliellalactone
  参考文献：
  名称：

  Galiellalactone的四取代碳上的立体定向亲核取代。

  摘要：

  真菌代谢产物加利拉内酯（1）为乙酸盐4被发现与半胱氨酸衍生物发生取代反应。通过研究反应机理和所形成的中间体，并努力扩大加利拉内酯的化学多样性，开发了一种温和而通用的制备加利拉内酯的醚，硫醚和胺类似物的方法。该反应是在氧化的叔碳处的正式的立体保持亲核取代。进行的反应的NMR分析表明，它涉及初始的烯丙基取代以形成新的迈克尔受体，然后向该反应物中添加第二当量的亲核试剂，最后是逆迈克尔反应。这将恢复原始的galiellalactone系统，在C-2a和C-3之间具有双键，但在C-7b处具有新的取代基。由于加利拉内酯是一种有前途的STAT3抑制剂，

  DOI：

  10.1021/acs.joc.0c00152

文献信息

• [EN] TRICYCLIC PRODRUGS<br/>[FR] PROMÉDICAMENTS TRICYCLIQUES
  申请人：GLACTONE PHARMA DEV AB

  公开号：WO2015132396A1

  公开（公告）日：2015-09-11

  Prodrugs (I) and (Ia) of galiellactone, and derivatives thereof, are provided by reacting the parent compound, e.g. galiellactone, with a thiol. Such drugs may be administered orally to treat cancer and other proliferative diseases.

  通过将母体化合物（例如galiellactone）与硫醇反应，可制备galiellactone的前药（I）和（Ia）及其衍生物。这类药物可口服给药，用于治疗癌症和其他增生性疾病。
• Preclinical Characterization of 3β-(<i>N</i>-Acetyl <scp>l</scp>-cysteine methyl ester)-2aβ,3-dihydrogaliellalactone (GPA512), a Prodrug of a Direct STAT3 Inhibitor for the Treatment of Prostate Cancer
  作者：Zilma Escobar、Anders Bjartell、Giacomo Canesin、Susan Evans-Axelsson、Olov Sterner、Rebecka Hellsten、Martin H Johansson

  DOI：10.1021/acs.jmedchem.5b01814

  日期：2016.5.26

  The transcription factor STAT3 is a potential target for the treatment of castration-resistant prostate cancer. Galiellalactone (1), a direct inhibitor of STAT3, prevents the transcription of STAT3 regulated genes. In this study we characterized 6 (GPAS12, Johansson, M.; Sterner, O. Patent WO 2015/132396 A1, 2015), a prodrug of 1. In vitro studies showed that 6 is rapidly converted to 1 in plasma and is stable in a buffer solution. The pharmacokinetics of 6 following a single oral dose indicated that the prodrug was rapidly absorbed and converted to 1 with a t(max) of 15 min. Oral administration of 6 in mice increased the plasma exposure of the active parent compound 20-fold compared to when 1 was dosed orally. 6 treated mice bearing DU145 xenograft tumors had significantly reduced tumor growth compared to untreated mice. The favorable druglike properties and safety profile of 6 warrant further studies of 6 for the treatment of castration-resistant prostate cancer.
• TRICYCLIC PRODRUGS
  申请人：Glactone Pharma Development AB

  公开号：US20170015644A1

  公开（公告）日：2017-01-19

  Prodrugs (I) and (Ia) of galiellactone, and derivatives thereof, are provided by reacting the parent compound, e.g. galiellactone, with a thiol. Such drugs may be administered orally to treat cancer and other proliferative diseases.