8-O-(3-[4-{N_α-tert-butoxycarbonyl-L-leucinoylamino}phenyl]propanoyl)-8-O-debutanoylthapsigargin | 216371-68-5

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: 8-O-(3-[4-{N_α-tert-butoxycarbonyl-L-leucinoylamino}phenyl]propanoyl)-8-O-debutanoylthapsigargin
• 英文别名: [(3S,3aR,4S,6S,6aR,7S,8S,9bS)-6-acetyloxy-3,3a-dihydroxy-3,6,9-trimethyl-8-[(Z)-2-methylbut-2-enoyl]oxy-4-[3-[4-[[(2S)-4-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoyl]amino]phenyl]propanoyloxy]-2-oxo-4,5,6a,7,8,9b-hexahydroazuleno[4,5-b]furan-7-yl] octanoate
• CAS: 216371-68-5
• 化学式: C₅₀H₇₂N₂O₁₅
• 分子量: 941.126
• InChiKey: KQRLGEXHJSJYNQ-FVBHKTRSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  67
• 可旋转键数：
  25
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.66
• 拓扑面积：
  239
• 氢给体数：
  4
• 氢受体数：
  15

反应信息

• 作为反应物：
  描述：

  8-O-(3-[4-{N_α-tert-butoxycarbonyl-L-leucinoylamino}phenyl]propanoyl)-8-O-debutanoylthapsigargin 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以100%的产率得到[(3S,3aR,4S,6S,6aR,7S,8S,9bS)-6-acetyloxy-4-[3-[4-[[(2S)-2-amino-4-methylpentanoyl]amino]phenyl]propanoyloxy]-3,3a-dihydroxy-3,6,9-trimethyl-8-[(Z)-2-methylbut-2-enoyl]oxy-2-oxo-4,5,6a,7,8,9b-hexahydroazuleno[4,5-b]furan-7-yl] octanoate
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of Thapsigargin Analogues for Targeting Apoptosis to Prostatic Cancer Cells

  摘要：

  A series of thapsigargin (TG) analogues, containing an amino acid applicable for conjugation to a peptide specifically cleaved by prostate-specific antigen (PSA), has been prepared to develop the drug-moiety of prodrugs for treatment of prostatic cancer. The analogues were synthesized by converting TG into O-8-debutanoylthapsigargin (DBTG) and esterifying O-8 of DBTG with various amino acid linkers. The compounds were evaluated for their ability to elevate the cytosolic Ca2+ concentration ([Ca2+](i)) in TSU-Pr1 cells, their ability to inhibit the rabbit skeletal muscle SERCA pump, and their ability to induce apoptosis in TSU-Pr1 human prostatic cancer cells. The activity of analogues, in which DBTG were esterified with w-amino acids [HOOC-(CH2)(n),NH2, n = 5-7, 10, 11], increased with the linker length. Analogues with 3-[4-(L-leucinoylamino)phenyl]propanoyl, 6-(L-leucinoylamino)hexanoyl, and 12-(L-serinoylamino)dodecanoyl were considerably less active than TG, and analogues with 12-(L-alaninoylamino)dodecanoyl and 12-(L-phenylalaninoylamino)dodecanoyl were almost as active as TG. The 12-(L-leucinoylamino)dodecanoyl gave an analogue equipotent with TG, making this compound promising as the drug-moiety of a PSA sensitive prodrug of TG.

  DOI：

  10.1021/jm010985a
• 作为产物：
  描述：

  3-(4-[N_α-tert-butoxycarbonyl-L-leucinoylamino]phenyl)propanoic acid methyl ester 在 4-二甲氨基吡啶 、 sodium hydroxide 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 8.67h， 生成 8-O-(3-[4-{N_α-tert-butoxycarbonyl-L-leucinoylamino}phenyl]propanoyl)-8-O-debutanoylthapsigargin
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of Thapsigargin Analogues for Targeting Apoptosis to Prostatic Cancer Cells

  摘要：

  A series of thapsigargin (TG) analogues, containing an amino acid applicable for conjugation to a peptide specifically cleaved by prostate-specific antigen (PSA), has been prepared to develop the drug-moiety of prodrugs for treatment of prostatic cancer. The analogues were synthesized by converting TG into O-8-debutanoylthapsigargin (DBTG) and esterifying O-8 of DBTG with various amino acid linkers. The compounds were evaluated for their ability to elevate the cytosolic Ca2+ concentration ([Ca2+](i)) in TSU-Pr1 cells, their ability to inhibit the rabbit skeletal muscle SERCA pump, and their ability to induce apoptosis in TSU-Pr1 human prostatic cancer cells. The activity of analogues, in which DBTG were esterified with w-amino acids [HOOC-(CH2)(n),NH2, n = 5-7, 10, 11], increased with the linker length. Analogues with 3-[4-(L-leucinoylamino)phenyl]propanoyl, 6-(L-leucinoylamino)hexanoyl, and 12-(L-serinoylamino)dodecanoyl were considerably less active than TG, and analogues with 12-(L-alaninoylamino)dodecanoyl and 12-(L-phenylalaninoylamino)dodecanoyl were almost as active as TG. The 12-(L-leucinoylamino)dodecanoyl gave an analogue equipotent with TG, making this compound promising as the drug-moiety of a PSA sensitive prodrug of TG.

  DOI：

  10.1021/jm010985a