(S,Z)-4-((tert-butyldimethylsilyl)oxy)pent-2-enoic acid | 878673-32-6

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (S,Z)-4-((tert-butyldimethylsilyl)oxy)pent-2-enoic acid
• 英文别名: (S,Z)-4-(tert-butyldimethylsilyloxy)pent-2-enoic acid；(2Z,4S)-4-(t-butyldimethylsilyloxy)pent-2-enoic acid；(S,Z)-4-(dimethyl-t-butylsilyloxy)pent-2-enoic acid；(S,Z)-4-((TBS)oxy)pent-2-enoic acid；(S,Z)-4-(TBSO)pent-2-enoic acid；(Z,4S)-4-[tert-butyl(dimethyl)silyl]oxypent-2-enoic acid
• CAS: 878673-32-6
• 化学式: C₁₁H₂₂O₃Si
• 分子量: 230.379
• InChiKey: BQYJTPADGKWSNB-FUOZMLNRSA-N

物化性质

• 沸点：
  299.4±23.0 °C(Predicted)
• 密度：
  0.956±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.04
• 重原子数：
  15
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S,Z)-4-((tert-butyldimethylsilyl)oxy)pent-2-enoic acid 在 四丁基氟化铵 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 1,2-二氯乙烷 、 乙腈 为溶剂， 反应 5.34h， 生成 (S,Z)-5-(((1s,4s)-4-((2E,4E)-5-((3R,5S)-7,7-dimethyl-1,6-dioxaspiro[2.5]octan-5-yl)-3-methylpenta-2,4-dien-1-yl)cyclohexyl)-amino)-5-oxopent-3-en-2-yl methylcarbamate
  参考文献：
  名称：

  Optimization of Antitumor Modulators of Pre-mRNA Splicing

  摘要：

  The spliceosome regulates pre-mRNA splicing, which is a critical process in normal mammalian cells. Recently, recurrent mutations in numerous spliceosomal proteins have been associated with a number of cancers. Previously, natural product antitumor agents have been shown to interact with one of the proteins that is subject to recurrent mutations (SF3B1). We report the optimization of a class of tumor-selective spliceosome modulators that demonstrate significant in vivo antitumor activity. This optimization culminated in the discovery of sudemycin D6, which shows potent cytotoxic activity in the melanoma line SK-MEL-2 (IC50 = 39 nM) and other tumor cell lines, including JeKo-1 (IC50 = 22 nM), He La (IC50 = SO nM), and SK-N-AS (IC50 = 81 nM). We also report improved processes for the synthesis of these compounds. Our work supports the idea that sudemycin D6 is worthy of further investigation as a novel preclinical anticancer agent with application in the treatment of numerous human cancers.

  DOI：

  10.1021/jm401370h
• 作为产物：
  描述：

  (s)-(-)-2-(叔丁基二甲基甲硅烷基氧基)丙酸乙酯 在 lithium hydroxide monohydrate 、 potassium tert-butylate 、 二异丁基氢化铝 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 水 为溶剂， 反应 45.17h， 生成 (S,Z)-4-((tert-butyldimethylsilyl)oxy)pent-2-enoic acid
  参考文献：
  名称：

  Optimization of Antitumor Modulators of Pre-mRNA Splicing

  摘要：

  The spliceosome regulates pre-mRNA splicing, which is a critical process in normal mammalian cells. Recently, recurrent mutations in numerous spliceosomal proteins have been associated with a number of cancers. Previously, natural product antitumor agents have been shown to interact with one of the proteins that is subject to recurrent mutations (SF3B1). We report the optimization of a class of tumor-selective spliceosome modulators that demonstrate significant in vivo antitumor activity. This optimization culminated in the discovery of sudemycin D6, which shows potent cytotoxic activity in the melanoma line SK-MEL-2 (IC50 = 39 nM) and other tumor cell lines, including JeKo-1 (IC50 = 22 nM), He La (IC50 = SO nM), and SK-N-AS (IC50 = 81 nM). We also report improved processes for the synthesis of these compounds. Our work supports the idea that sudemycin D6 is worthy of further investigation as a novel preclinical anticancer agent with application in the treatment of numerous human cancers.

  DOI：

  10.1021/jm401370h

文献信息

• Design and synthesis of a phenyl C-glycoside derivative of Spliceostatin A and its biological evaluation toward prostate cancer treatment
  作者：Yusuke Yoshikawa、Airi Ishibashi、Kenichi Murai、Yasufumi Kaneda、Keisuke Nimura、Mitsuhiro Arisawa

  DOI：10.1016/j.tetlet.2019.151313

  日期：2019.12

  synthesized a novel phenyl C-glycoside analogue of Spliceostatin A, which is potent splicing inhibitor and has anti-cancer activities. We successfully synthesized its right phenyl C-glycoside sugar fragment in shorter steps compared to previous synthetic methods for Spliceostatin A and revealed an appropriate fragment combination with a Julia-coupling reaction. Regarding biological activity, the Ph-C-glycoside

  我们设计并合成了新型的Spliceostatin A苯基C-糖苷类似物，它是有效的剪接抑制剂，具有抗癌活性。与以前的Spliceostatin A合成方法相比，我们以较短的步骤成功合成了其正确的苯基C-糖苷糖片段，并揭示了具有朱莉娅偶联反应的适当片段组合。关于生物学活性，Spliceostatin A的Ph- C-糖苷类似物在三种前列腺癌细胞系中显示出抑制的细胞增殖，并抑制了AR-V7表达。
• Sudemycin K: A Synthetic Antitumor Splicing Inhibitor Variant with Improved Activity and Versatile Chemistry
  作者：Kamil Makowski、Luisa Vigevani、Fernando Albericio、Juan Valcárcel、Mercedes Álvarez

  DOI：10.1021/acschembio.6b00562

  日期：2017.1.20

  replaces the pharmacophore’s oxycarbonyl by an amide group, displays improved potency as an inhibitor of cancer cell proliferation, as a regulator of alternative splicing in cultured cells and as an inhibitor of in vitro spliceosome assembly. Sudemycin K displays higher stability, likely related to the replacement of the oxycarbonyl group, which can be a substrate of esterases, by an amide group. The activity

  前mRNA剪接过程与癌症之间存在重要联系，例如肿瘤中剪接因子的频繁突变以及靶向剪接机制组分的各种抗肿瘤药物家族的出现，尤其是SF3B1（剪接体的蛋白质亚基） U2小核糖核蛋白颗粒（snRNP）。Sudemycins是具有各种剪接抑制剂共有的药效基团的合成化合物。在这里，我们描述了新型sudemycin类似物的合成和功能表征，它们在功能上探究了该药效团内的关键化学基团。我们的结果证实了共轭二烯基的重要性，此外还揭示了在该分子区域中显着的空间柔性。Sudemycin K，体外剪接体组装。Sudemycin K显示出更高的稳定性，这可能与酰胺基取代了可能是酯酶底物的氧羰基有关。sudemycin K的活性和特殊反应性可以为合成和评估各种新型sudemycin衍生物铺平道路。
• Antitumor Compounds Based on a Natural Product Consensus Pharmacophore
  作者：Chandraiah Lagisetti、Alan Pourpak、Qin Jiang、Xiaoli Cui、Tinopiwa Goronga、Stephan W. Morris、Thomas R. Webb

  DOI：10.1021/jm8006195

  日期：2008.10.9

  We report the design and highly enantioselective synthesis of a potent analogue of the spliceosome inhibitor FR901464, based on a non-natural product scaffold. The design of this compound was facilitated by a pharmacophore hypothesis that assumed key interaction types that are common to FR901464 and an otherwise unrelated natural product (pladienolide). The synthesis allows for the preparation of numerous

  我们报告了基于非天然产物支架的剪接体抑制剂 FR901464 的有效类似物的设计和高度对映选择性合成。药效团假设促进了该化合物的设计，该假设假设了 FR901464 和其他不相关的天然产物（pladienolide）共有的关键相互作用类型。该合成允许制备许多新型类似物。我们展示了该化合物对几种肿瘤细胞系的体外活性结果。
• Internal activation of acrylate-type dienophiles in Diels-Alder reactions
  作者：Toshiyuki Kan、Yasufumi Ohfune

  DOI：10.1016/0040-4039(94)02379-p

  日期：1995.2

  Diels-Alder reactions of less reactive acrylate-type dienophiles with dienes were achieved by replacing its ester counterpart to a pentafluorophenyl group, which remarkably enhanced the reactivity of the dienophiles to give the corresponding cycloadducts in excellent yields with a high stereoselectivity.
• Internal activation of acrylate-type dienophiles for the Diels-Alder reaction. Stereoselective synthesis of conformationally constrained glutamate analogs
  作者：Yasufumi Ohfune、Toshiyuki Kan、Terumi Nakajima

  DOI：10.1016/s0040-4020(98)00219-1

  日期：1998.5

  The [4+2] cycloaddition reaction of the unreactive acrylate-type dienophiles such as 5a and 6a was accomplished by introducing an electronegative or electron-withdrawing group as the ester counterpart. Among them, the pentafluorophenyl (PFP) group was found to be an excellent ester counterpart in view of its rate acceleration and chemical stability under the reaction conditions. The C-13 NMR spectral data of the dienophiles with the PFP group suggested that the conjugated CC-double bond was strongly polarized. The internal activation was found to be effective for the related dienophile or other dienes, in particular, unstable to Lewis acid catalysts. A successful application of this method is demonstrated by the syntheses of conformationally restricted analogs of L-glutamate, 3 and 4. (C) 1998 Elsevier Science Ltd. All rights reserved.