thapsigargin | 391610-86-9

• 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: thapsigargin
• 英文别名: 8-O-(12-tert-butoxycarbonylaminododecanoyl)-8-O-debutanoylthapsigargin；Boc-8ADT；(3S,3AR,4S,6S,6AR,7S,8S,9BS)-6-(Acetyloxy)-3,3A-dihydroxy-3,6,9-trimethyl-8-{[(2Z)-2-methylbut-2-enoyl]oxy}-7-(octanoyloxy)-2-oxo-2,3,3A,4,5,6,6A,7,8,9B-decahydroazuleno[4,5-B]furan-4-YL 12-[(tert-butoxycarbonyl)amino]dodecanoate；[(3S,3aR,4S,6S,6aR,7S,8S,9bS)-6-acetyloxy-3,3a-dihydroxy-3,6,9-trimethyl-8-[(Z)-2-methylbut-2-enoyl]oxy-7-octanoyloxy-2-oxo-4,5,6a,7,8,9b-hexahydroazuleno[4,5-b]furan-4-yl] 12-[(2-methylpropan-2-yl)oxycarbonylamino]dodecanoate
• CAS: 391610-86-9
• 化学式: C₄₇H₇₅NO₁₄
• 分子量: 878.111
• InChiKey: IBTNJSDBPZIGKM-GGGDSPQJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.7
• 重原子数：
  62
• 可旋转键数：
  29
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  210
• 氢给体数：
  3
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  thapsigargin 在 三氟乙酸 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 1.5h， 以90%的产率得到8-O-(12-aminododecanoyl)-8-O-debutanoylthapsigargin
  参考文献：
  名称：

  通过固相合成制备酶活化毒胡萝卜素前药。

  摘要：

  由于实体瘤中的细胞分裂速度不如骨髓中的细胞或免疫系统细胞，因此有丝分裂抑制剂在用于治疗前列腺癌和乳腺癌等疾病时通常会引起严重的副作用。克服这个问题的一种方法是尝试开发基于一般细胞毒素的药物，如加利车霉素和毒胡萝卜素，它们在细胞周期的所有阶段杀死细胞。然而，只有在可能有效靶向恶性组织时才能使用此类毒素。在毒胡萝卜素的情况下，通过将药物与仅在肿瘤附近裂解的肽结合以释放细胞毒性药物或具有保留活性的类似物来实现对肿瘤相关细胞的选择性。

  DOI：

  10.3390/molecules23061463
• 作为产物：
  描述：

  12-氨基十二酸 在 4-二甲氨基吡啶 、 sodium hydroxide 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 、 叔丁醇 为溶剂， 反应 6.0h， 生成 thapsigargin
  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

文献信息

• [EN] METHODS OF MAKING CANCER COMPOSITIONS<br/>[FR] PROCÉDÉS DE FABRICATION DE COMPOSITIONS DESTINÉES AU TRAITEMENT DU CANCER
  申请人：GENSPERA INC

  公开号：WO2014145035A8

  公开（公告）日：2016-04-14
• Design, Synthesis, and Pharmacological Evaluation of Thapsigargin Analogues for Targeting Apoptosis to Prostatic Cancer Cells
  作者：Carsten M. Jakobsen、Samuel R. Denmeade、John T. Isaacs、Alyssa Gady、Carl E. Olsen、Søren Brøgger Christensen

  DOI：10.1021/jm010985a

  日期：2001.12.1

  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.
• Preparation of Enzyme-Activated Thapsigargin Prodrugs by Solid-Phase Synthesis
  作者：Tomas Zimmermann、Søren Christensen、Henrik Franzyk

  DOI：10.3390/molecules23061463

  日期：——

  that is only cleaved in the vicinity of tumors to release the cytotoxic drug or an analog with retained activity. Solid-phase synthesis protocols were developed for preparation of three already validated prodrugs of thapsigargin: one prodrug cleavable by human kallikrein 2, one prodrug cleavable by prostate-specific antigen, and one prodrug cleavable by prostate-specific membrane antigen.

  由于实体瘤中的细胞分裂速度不如骨髓中的细胞或免疫系统细胞，因此有丝分裂抑制剂在用于治疗前列腺癌和乳腺癌等疾病时通常会引起严重的副作用。克服这个问题的一种方法是尝试开发基于一般细胞毒素的药物，如加利车霉素和毒胡萝卜素，它们在细胞周期的所有阶段杀死细胞。然而，只有在可能有效靶向恶性组织时才能使用此类毒素。在毒胡萝卜素的情况下，通过将药物与仅在肿瘤附近裂解的肽结合以释放细胞毒性药物或具有保留活性的类似物来实现对肿瘤相关细胞的选择性。