O8-Debutanoylthapsigargin | 105662-35-9

• 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: O8-Debutanoylthapsigargin
• 英文别名: 8-O-debutanoyl-thapsigargin；O-8-debutanoyl thapsigargin；8-O-debutanoylthapsigargin；8-debutanoylthapsigargin；Debutanoylthapsigargin；[(3S,3aR,4S,6S,6aR,7S,8S,9bS)-6-acetyloxy-3,3a,4-trihydroxy-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
• CAS: 105662-35-9
• 化学式: C₃₀H₄₄O₁₁
• 分子量: 580.673
• InChiKey: UBPDDZPGODTCDF-CQDUWLBUSA-N

物化性质

• 沸点：
  657.5±55.0 °C(Predicted)
• 密度：
  1.27±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  41
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  166
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  O8-Debutanoylthapsigargin 在 4-二甲氨基吡啶 、 溶剂黄146 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 反应 72.0h， 生成 (1S,2S,3bS,3b1R,5aS,8aS,10S,10aR)-10-acetoxy-3,5a,7,7,10-pentamethyl-2-{[(Z)-2-methylbut-2-enoyl]oxy}-5-oxo-1,2,3b,3b1,5,5a,8a,9,10,10a-decahydro-4,6,8-trioxabenzo[cd]-cyclopenta[h]azulene-1,3b1-diyl dioctanoate
  参考文献：
  名称：

  Water-Mediated Interactions Influence the Binding of Thapsigargin to Sarco/Endoplasmic Reticulum Calcium Adenosinetriphosphatase

  摘要：

  A crystal structure suggests four water molecules are present in the binding cavity of thapsigargin in sarco/endoplasmic reticulum calcium ATPase (SERCA). Computational chemistry indicates that three of these water molecules mediate an extensive hydrogen-bonding network between thapsigargin and the backbone of SERCA. The orientation of the thapsigargin molecule in SERCA is crucially dependent on these interactions. The hypothesis has been verified by measuring the affinity of newly synthesized model compounds, which are prevented from participating in such water-mediated interactions as hydrogen-bond donors.

  DOI：

  10.1021/jm4001083
• 作为产物：
  描述：

  (2aS,2a1R,5aS,7S,7aS,9S,10R,10aR,10bS)-9-((tert-butyldiphenylsilyl)oxy)-2a1,7-dihydroxy-2a,4,4,7,10-pentamethyldecahydro-1,3,5-trioxabenzo[cd]cyclopenta[h]azulen-2(2aH)-one 在 盐酸 、 4-二甲氨基吡啶 、 丁硫醇 、 zinc borohydride 、 四丁基氟化铵 、 氧气 、 二甲基二环氧乙烷 、 碳酸氢钠 、 potassium carbonate 、 戴斯-马丁氧化剂 、 对甲苯磺酸 、 臭氧 、 三乙胺 、 二异丙胺 、 N,N-二异丙基乙胺 、 magnesium bromide 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 214.0h， 生成 O8-Debutanoylthapsigargin
  参考文献：
  名称：

  五种毒胡萝卜素的总合成：表现出亚纳摩尔SERCA抑制作用的愈创木酚内酯天然产物。

  摘要：

  在这里，我们描述了五种愈创木酚内酯天然产物的总合成：thapsigargin，thapsivillosin C，thapsivillosin F，trilobolide和nortrilobolide。毒胡萝卜素的前药衍生物已显示出对前列腺肿瘤的选择性体内细胞毒性，并且对该现象的进一步研究的需要凸显了这些总合成的重要性。还描述了毒胡萝卜素C的第一个绝对立体化学分配。

  DOI：

  10.1002/chem.200700302

文献信息

• [EN] SYNTHESIS OF THAPSIGARGIN, NORTRILOBOLIDE, AND ANALOGS THEREOF<br/>[FR] SYNTHÈSE DE THAPSIGARGINE, NORTRILOBOLIDE ET LEURS ANALOGUES
  申请人：UNIV KINGSTON

  公开号：WO2018176133A1

  公开（公告）日：2018-10-04

  The present invention relates to the preparation of compounds of Formula I, including thapsigargin, nortrilobolide and 8-O-debutanoyl-thapsigargin from commercially available (R)-(-)-carvone via synthetic intermediate compound of formula 12 by pinacol coupling and in situ lactonization.

  本发明涉及通过对商业上可获得的(R)-(-)-香叶醇进行缩合反应和原位内酯化反应，从中间合成化合物12制备公式I的化合物，包括硫雄甾酮、北三叶甾酮和8-O-癸酰基硫雄甾酮。
• 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。
• [EN] METHOD OF MAKING PRODRUGS AND TARGETED THERAPEUTIC COMPOUNDS<br/>[FR] MÉTHODE DE PRÉPARATION DE PROMÉDICAMENTS ET DE COMPOSÉS THÉRAPEUTIQUES CIBLÉS
  申请人：GENSPERA INC

  公开号：WO2016081229A1

  公开（公告）日：2016-05-26

  Provided is a method for making the compound of Formula 1. Various compounds utilized in that method are also provided, as are methods of making those compounds. Also provided is a compound having the formula XO-CO-(CH2)nNH2, where n is an integer greater than 2. A method of making that compound is additionally provided. Further provided is a method of making a prodrug of a bioactive compound.

  提供了制备化合物1的方法。还提供了在该方法中使用的各种化合物，以及制备这些化合物的方法。还提供了一种具有公式XO-CO-(CH2)nNH2的化合物，其中n是大于2的整数。此外还提供了制备该化合物的方法。进一步提供了一种制备生物活性化合物的前药的方法。
• 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.
• Andersen, Annette; Cornett, Claus; Lauridsen, Annette, Acta Chemica Scandinavica, 1994, vol. 48, # 4, p. 340 - 346
  作者：Andersen, Annette、Cornett, Claus、Lauridsen, Annette、Olsen, Carl E.、Christensen, Soeren Broegger

  DOI：——

  日期：——