(3S,4E)-3-hydroxy-1-((4R)-4-isopropyl-2-thioxothiazolidin-3-yl)-7-tritylsulfanyl-hept-4-en-1-one | 663918-95-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: (3S,4E)-3-hydroxy-1-((4R)-4-isopropyl-2-thioxothiazolidin-3-yl)-7-tritylsulfanyl-hept-4-en-1-one
• 英文别名: (S,E)-3-hydroxy-1-((R)-4-isopropyl-2-thioxothiazolidin-3-yl)-7-(tritylthio)hept-4-en-1-one；3S-hydroxy-1-(4R-isopropyl-2-thioxothiazolidin-3-yl)-7-tritylsulfanylhept-4E-en-1-one；(E,3S)-3-hydroxy-1-[(4R)-4-propan-2-yl-2-sulfanylidene-1,3-thiazolidin-3-yl]-7-tritylsulfanylhept-4-en-1-one
• CAS: 663918-95-4
• 化学式: C₃₂H₃₅NO₂S₃
• 分子量: 561.833
• InChiKey: AJTPUSQJWPQHSY-WGWPJPJGSA-N

物化性质

• 沸点：
  674.2±65.0 °C(Predicted)
• 密度：
  1.25±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.6
• 重原子数：
  38
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  123
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3S,4E)-3-hydroxy-1-((4R)-4-isopropyl-2-thioxothiazolidin-3-yl)-7-tritylsulfanyl-hept-4-en-1-one 在 4-二甲氨基吡啶 、 N-羟基-7-氮杂苯并三氮唑 、 三异丙基硅烷 、 2,4,6-三氯苯甲酰氯 、 二乙胺 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 43.33h， 生成 largazole
  参考文献：
  名称：

  Largazole and Analogues with Modified Metal-Binding Motifs Targeting Histone Deacetylases: Synthesis and Biological Evaluation

  摘要：

  The histone deacetylase inhibitor largazole 1 was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using tert-butyl as thiol protecting group proved problematic, and synthesis was accomplished by switching to the trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn2+ were synthesized, and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of alpha-tubulin.

  DOI：

  10.1021/jm200432a
• 作为产物：
  描述：

  (E)-5-(tritylthio)pent-2-en-1-ol 在 manganese(IV) oxide 、 四氯化钛 作用下， 以 二氯甲烷 为溶剂， 反应 10.5h， 生成 (3S,4E)-3-hydroxy-1-((4R)-4-isopropyl-2-thioxothiazolidin-3-yl)-7-tritylsulfanyl-hept-4-en-1-one
  参考文献：
  名称：

  [EN] AN IMPROVED PROCESS FOR THE PREPARATION OF (1S, 4S, 7Z, 10S, 16E, 21R)- 7-ETHYLIDENE-4,21-BIS(1-METHYLETHYL)-2-OXA-12,13-DITHIA-5, 8, 20, 23- TETRAAZABICYCLO[8.7.6]TRICOS-16-ENE-3, 6, 9, 19, 22-PENTONE
  [FR] PROCÉDÉ AMÉLIORÉ POUR LA PRÉPARATION DE (1S, 4S, 7Z, 10S, 16E, 21R)- 7-ÉTHYLIDÈNE-4,21-BIS(1-MÉTHYLÉTHYL)-2-OXA-12,13-DITHIA-5, 8, 20, 23- TÉTRAAZABICYCLO[8.7.6]TRICOS-16-ÈNE-3, 6, 9, 19, 22-PENTONE

  摘要：

  本发明涉及一种改进的制备过程，用于制备式I的(1S,4S,7Z,10S,16E,21R)-7-乙烯基-4,21-双(1-甲基乙基)-2-氧-12,13-二硫-5,8,20,23-四氮杂环[8.7.6]三十一烯-16-烯-3,6,9,19,22-五酮。

  公开号：

  WO2017068596A1

文献信息

• Depsipeptides and Their Therapeutic Use
  申请人：Shuttleworth Stephen Joseph

  公开号：US20110112090A1

  公开（公告）日：2011-05-12

  A Compound of structure (IX) or (X) or a pharmaceutically acceptable salt thereof, wherein: X is —C(═O)N(R 10 )— or —CH(OPr 3 )—; R 7 , R 9 and R 10 are the same or different and represent hydrogen or an amino acid side chain moiety from either a natural or an unnatural amino acid; Pr 1 and Pr 2 are the same or different and represent hydrogen or a thiol protecting group; Pr 3 is hydrogen or an alcohol protecting group; R 1 , R 2 , R 5 and R 6 are the same or different and represent hydrogen or an amino acid side chain moiety from either a natural or an unnatural amino acid, or R 1 and R 2 and/or R 5 and R 6 , taken together with the carbon atom to which they are attached, form a spirocyclic moiety, with the proviso that: each of R 1 and R 2 is not hydrogen, or each of R 5 and R 6 is not hydrogen.

  一种结构化合物（IX）或（X）或其药学上可接受的盐，其中：X为—C(═O)N(R10)—或—CH(OPr3)—；R7、R9和R10相同或不同，代表氢或来自天然或非天然氨基酸的氨基酸侧链基团；Pr1和Pr2相同或不同，代表氢或巯基保护基团；Pr3为氢或醇保护基团；R1、R2、R5和R6相同或不同，代表氢或来自天然或非天然氨基酸的氨基酸侧链基团，或R1和R2和/或R5和R6，与它们连接的碳原子一起形成螺环基团，条件是：R1和R2中的每一个都不是氢，或R5和R6中的每一个都不是氢。
• Synthesis and biological evaluation of largazole analogues with modified surface recognition cap groups
  作者：Pravin Bhansali、Christin L. Hanigan、Lalith Perera、Robert A. Casero、L.M. Viranga Tillekeratne

  DOI：10.1016/j.ejmech.2014.09.009

  日期：2014.10

  tolerance of structural changes at C7 position of largazole, these data show the negative effect of conformational change accompanying change of configuration at this position. Similarly, analogue 16a with d-1-naphthylmethyl side chain at C2 too had negligible inhibition of HDAC activity, failed to induce global histone 3 (H3) acetylation in the HCT116 colorectal cancer cell line and demonstrated minimal

  合成了几种具有修饰的表面识别帽基团的拉格唑类似物，并测定了它们的 HDAC 抑制活性。C7-差向异构体12对 HDAC 活性的抑制作用可忽略不计，未能在 HCT116 结肠直肠癌细胞系中诱导全局组蛋白 3 (H3) 乙酰化，并且对生长的影响很小。尽管以前的研究表明拉格唑 C7 位置的结构变化有一定程度的耐受性，但这些数据显示了伴随该位置构型变化的构象变化的负面影响。类似地，模拟16a与dC2 上的 -1-萘基甲基侧链对 HDAC 活性的抑制也可以忽略不计，未能在 HCT116 结肠直肠癌细胞系中诱导全局组蛋白 3 (H3) 乙酰化，并且对生长的影响很小。相比之下，l -烯丙基类似物16b和l -1-萘甲基类似物16c是有效的 HDAC 抑制剂，显示出对整体 H3 乙酰化的强烈诱导和对细胞生长的显着影响。数据表明，只要保留 C2 处的立体化学，即使是大的取代基在该位置也是可以容忍的。对于庞大的取代基，C2
• Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue
  作者：Jehad Almaliti、Ayad A. Al-Hamashi、Ahmed T. Negmeldin、Christin L. Hanigan、Lalith Perera、Mary Kay H. Pflum、Robert A. Casero、L. M. Viranga Tillekeratne

  DOI：10.1021/acs.jmedchem.6b01271

  日期：2016.12.8

  hybridization from sp3 to sp2 at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge 7 represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination

  合成了许多海洋生物组蛋白脱乙酰基酶抑制剂拉格唑的类似物，这些类似物在二肽肽环中引入了主要的结构变化。用联吡啶基团取代拉格唑的噻唑-噻唑啉片段可得到具有强大的细胞生长抑制活性和与拉格唑相似的活性特征的类似物7，表明伴随C-7处sp3到sp2杂交的伴随构象变化是可以很好地耐受的。与largazole相比，类似物7对I类的选择性更高，与对II类HDAC6的选择性相比，对I类HDAC蛋白的选择性至少高464倍，而对largazole观察到的选择性高22倍。据我们所知，7代表了不包含噻唑啉环的有效且具有高细胞毒性的拉格唑类似物的第一个例子。
• HDAC Inhibitors as Anti-Cancer Agents
  申请人：The University of Toledo

  公开号：US20150329560A1

  公开（公告）日：2015-11-19

  Largazole analogues, methods of making the same, and methods of using the same, are described.

  Largazole类似物，其制备方法和使用方法被描述。
• The First Biologically Active Synthetic Analogues of FK228, the Depsipeptide Histone Deacetylase Inhibitor
  作者：Alexander Yurek-George、Alexander Richard Liam Cecil、Alex Hon Kit Mo、Shijun Wen、Helen Rogers、Fay Habens、Satoko Maeda、Minoru Yoshida、Graham Packham、A. Ganesan

  DOI：10.1021/jm0703800

  日期：2007.11.1

  spiruchostatin bicyclic depsipeptide natural products are among the most potent histone deacetylase (HDAC) inhibitors known. Although FK228 is in advanced clinical trials, the complexity of the natural products has precluded mechanistic studies and the discovery of structure-activity relationships. By total synthesis, we have prepared the first depsipeptide analogues. Our results prove that the dehydrobutyrine

  FK228和螺旋藻抑素双环二肽天然产物是已知最有效的组蛋白脱乙酰基酶（HDAC）抑制剂。尽管FK228处于高级临床试验中，但是天然产物的复杂性阻碍了机理研究和结构-活性关系的发现。通过全合成，我们制备了第一种二肽肽类似物。我们的结果证明FK228中的脱氢丁酸残基不是必需的，并且其他残基可以被取代而不会丧失HDAC抑制活性。大环支架的构象限制很重要，因为线性肽是无活性的。只要保护锌结合的硫醇以确保良好的细胞利用率，就可以除去由半胱氨酸侧链形成的分子内二硫键。像天然产品一样