Fluorosalinosporamide | 889457-14-1

• 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: Fluorosalinosporamide
• 英文别名: (1R,4R,5S)-1-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-4-(2-fluoroethyl)-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione
• CAS: 889457-14-1
• 化学式: C₁₅H₂₀FNO₄
• 分子量: 297.327
• InChiKey: BBRUKBOXDSBEQC-SHTIJGAHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  NPI-2070 在 silver fluoride 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 以15%的产率得到(1R,4R,5S)-1-((S)-((S)-cyclohex-2-en-1-yl)(hydroxy)methyl)-4-(2-hydroxyethyl)-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione
  参考文献：
  名称：

  Leaving Groups Prolong the Duration of 20S Proteasome Inhibition and Enhance the Potency of Salinosporamides

  摘要：

  Salinosporamide A (1 (NPI-0052)) is a potent, monochlorinated 20S proteasome inhibitor in clinical trials for the treatment of cancer. To elucidate the role of the chlorine leaving group (LG), we synthesized analogues with a range of LG potentials and determined their IC50 values for inhibition of chymotrypsin-like (CT-L) trypsin-like (T-L), and caspase-like (C-L) activities of 20S proteasomes. Proteasome activity was also determined before and after attempted removal of the inhibitors by dialysis. Analogues bearing substituents with good LG potential exhibited the greatest potency and prolonged duration of proteasome inhibition, with no recovery after 24 h of dialysis. In contrast, activity was restored after : 12 h in the case of non-LG analogues. Intermediate results were observed for fluorosalinosporamide, with poor LG potential. Kinetic studies indicate that 1 acts as a classical slow, tight inhibitor of the CT-L, T-L, and C-L activities and that inhibition occurs via a two-step mechanism involving reversible recognition followed by rate-limiting formation of a covalent enzyme-inhibitor complex.

  DOI：

  10.1021/jm800548b

文献信息

• Leaving Groups Prolong the Duration of 20S Proteasome Inhibition and Enhance the Potency of Salinosporamides
  作者：Rama Rao Manam、Katherine A. McArthur、Ta-Hsiang Chao、Jeffrey Weiss、Janid A. Ali、Vito J. Palombella、Michael Groll、G. Kenneth Lloyd、Michael A. Palladino、Saskia T. C. Neuteboom、Venkat R. Macherla、Barbara C. M. Potts

  DOI：10.1021/jm800548b

  日期：2008.11.13

  Salinosporamide A (1 (NPI-0052)) is a potent, monochlorinated 20S proteasome inhibitor in clinical trials for the treatment of cancer. To elucidate the role of the chlorine leaving group (LG), we synthesized analogues with a range of LG potentials and determined their IC50 values for inhibition of chymotrypsin-like (CT-L) trypsin-like (T-L), and caspase-like (C-L) activities of 20S proteasomes. Proteasome activity was also determined before and after attempted removal of the inhibitors by dialysis. Analogues bearing substituents with good LG potential exhibited the greatest potency and prolonged duration of proteasome inhibition, with no recovery after 24 h of dialysis. In contrast, activity was restored after : 12 h in the case of non-LG analogues. Intermediate results were observed for fluorosalinosporamide, with poor LG potential. Kinetic studies indicate that 1 acts as a classical slow, tight inhibitor of the CT-L, T-L, and C-L activities and that inhibition occurs via a two-step mechanism involving reversible recognition followed by rate-limiting formation of a covalent enzyme-inhibitor complex.