(R)-methyl 2-(2-(((3S,4E)-3-hydroxy-7-(tritylthio)hept-4-enamido)methyl)thiazol-4-yl)-4-methyl-4,5-dihydrothiazole-4-carboxylate | 1092363-37-5

• 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: (R)-methyl 2-(2-(((3S,4E)-3-hydroxy-7-(tritylthio)hept-4-enamido)methyl)thiazol-4-yl)-4-methyl-4,5-dihydrothiazole-4-carboxylate
• 英文别名: (R)-methyl 2-(2-(((S,E)-3-hydroxy-7-(tritylthio)hept-4-enamido)methyl)thiazol-4-yl)-4-methyl-4,5-dihydrothiazole-4-carboxylate；methyl (4R)-2-[2-[[[(E,3S)-3-hydroxy-7-tritylsulfanylhept-4-enoyl]amino]methyl]-1,3-thiazol-4-yl]-4-methyl-5H-1,3-thiazole-4-carboxylate
• CAS: 1092363-37-5
• 化学式: C₃₆H₃₇N₃O₄S₃
• 分子量: 671.905
• InChiKey: CUDNPEBWFICCFW-VVIVEAFLSA-N

物化性质

• 密度：
  1.25±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  46
• 可旋转键数：
  15
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  180
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (R)-methyl 2-(2-(((3S,4E)-3-hydroxy-7-(tritylthio)hept-4-enamido)methyl)thiazol-4-yl)-4-methyl-4,5-dihydrothiazole-4-carboxylate 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 42.25h， 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：

  (2E)-5-[(triphenylmethyl)thio]-2-pentenal 在 4-二甲氨基吡啶 、 四氯化钛 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 4.08h， 生成 (R)-methyl 2-(2-(((3S,4E)-3-hydroxy-7-(tritylthio)hept-4-enamido)methyl)thiazol-4-yl)-4-methyl-4,5-dihydrothiazole-4-carboxylate
  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

文献信息

• 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
• Evaluation of class I HDAC isoform selectivity of largazole analogues
  作者：Bumki Kim、Heekwang Park、Lilibeth A. Salvador、Patrick E. Serrano、Jason C. Kwan、Sabrina L. Zeller、Qi-Yin Chen、Soyoung Ryu、Yanxia Liu、Seongrim Byeon、Hendrik Luesch、Jiyong Hong

  DOI：10.1016/j.bmcl.2014.07.006

  日期：2014.8

  Largazole is a potent class I selective histone deacetylase (HDAC) inhibitor. The majority of largazole analogues to date have modified the thiazole-thiazoline and the warhead moiety. In order to elucidate class I-specific structure-activity relationships, a series of analogues with modifications in the valine or the linker region were prepared and evaluated for their class I isoform selectivity. The inhibition profile showed that the C2 position of largazole has an optimal steric requirement for efficient HDAC inhibition and that substitution of the trans-alkene in the linker with an aromatic group results in complete loss of activity. This data will aid the design of class I isoform selective HDAC inhibitors.