(S,Z)-N-((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)-4-hydroxypent-2-enamide | 1069120-28-0

• 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)-N-((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)-4-hydroxypent-2-enamide
• 英文别名: (S,Z)-N-((1R,4R)-4-((2E,4E)-5-((3R,5S)-7,7-dimethyl-1,6-dioxaspiro[2.5]octan-5-yl)-3-methylpenta-2,4-dienyl)cyclohexyl)-4-hydroxypent-2-enamide
• CAS: 1069120-28-0
• 化学式: C₂₅H₃₉NO₄
• 分子量: 417.589
• InChiKey: QYXYUXMKKSWUHV-NEOZBGOBSA-N

物化性质

• 沸点：
  614.6±55.0 °C(predicted)
• 密度：
  1.10±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.22
• 重原子数：
  30.0
• 可旋转键数：
  7.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  71.09
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (S,Z)-N-((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)-4-hydroxypent-2-enamide 在 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 反应 0.34h， 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,Z)-methyl 4-((tert-butyldimethylsilyl)oxy)pent-2-enoate 在 lithium hydroxide monohydrate 、 四丁基氟化铵 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙腈 为溶剂， 反应 45.0h， 生成 (S,Z)-N-((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)-4-hydroxypent-2-enamide
  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

• 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。
• ANTICANCER COMPOUNDS AND METHODS OF MAKING AND USING SAME
  申请人：Webb Thomas R.

  公开号：US20110178098A1

  公开（公告）日：2011-07-21

  In one aspect, the invention relates to compounds having anticancer activity; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders associated with uncontrolled cellular proliferation using the compounds and compositions. This abstract is intended to be used as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  本发明涉及具有抗癌活性的化合物；制备这些化合物的合成方法；包含这些化合物的药物组合物；以及使用这些化合物和组合物治疗与细胞不受控制增殖相关的疾病的方法。本摘要旨在用作扫描工具，用于在特定领域进行搜索，并不意味着对本发明的限制。
• ANTICANCER COMPOUNDS
  申请人：ST. JUDE CHILDREN'S RESEARCH HOSPITAL

  公开号：US20160009728A1

  公开（公告）日：2016-01-14

  In one aspect, the invention relates to compounds having anticancer activity; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders associated with uncontrolled cellular proliferation using the compounds and compositions. This abstract is intended to be used as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  本发明涉及具有抗癌活性的化合物；制备这些化合物的合成方法；包含这些化合物的制药组合物；以及使用这些化合物和组合物治疗与细胞不受控制增殖相关的疾病的方法。本摘要旨在作为在特定领域搜索的扫描工具使用，不旨在限制本发明。
• Synthetic mRNA Splicing Modulator Compounds with in Vivo Antitumor Activity
  作者：Chandraiah Lagisetti、Alan Pourpak、Tinopiwa Goronga、Qin Jiang、Xiaoli Cui、Judith Hyle、Jill M. Lahti、Stephan W. Morris、Thomas R. Webb

  DOI：10.1021/jm901215m

  日期：2009.11.26

  We report our progress on the development of new synthetic anticancer lead compounds that modulate the splicing of mRNA, We also report the synthesis and evaluation of new biologically active ester and carbamate analogues. Further, we describe initial animal studies demonstrating the antitumor efficacy of compound 5 in vivo. Additionally, we report the enantioselective and diastereospecific synthesis of a new 1,3-dioxane series of active analogues, We confirm that compound 5 inhibits the splicing of mRNA in cell-free nuclear extracts and in a cell-based dual-reporter mRNA splicing assay. In summary, we have developed totally synthetic novel spliceosome modulators as therapeutic lead compounds for a number or highly aggressive cancers. Future efforts will be directed toward the more complete optimization of these compounds as potential human therapeutics.
• US8969405B2
  申请人：——

  公开号：US8969405B2

  公开（公告）日：2015-03-03