4-dehydrowithaferin A 27-tert-butyldimethylsilyl ether | 1214886-31-3

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: 4-dehydrowithaferin A 27-tert-butyldimethylsilyl ether
• 英文别名: 27-O-(tert-butyldimethylsilyl)-4-dehydroxy-4-oxowithaferin A；27-O-t-butyldimethylsilyl-4-dehydrowithaferin A；4-oxo-27-TBDMS Withaferin A；(1S,2R,7S,9R,11S,12S,15R,16S)-15-[(1S)-1-[(2R)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methyl-6-oxo-2,3-dihydropyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-ene-3,6-dione
• CAS: 1214886-31-3
• 化学式: C₃₄H₅₀O₆Si
• 分子量: 582.853
• InChiKey: RZWFBNOFUAHADD-VTYRCZOESA-N

物化性质

• 沸点：
  651.3±55.0 °C(Predicted)
• 密度：
  1.14±0.1 g/cm3(Predicted)
• 溶解度：
  DMF：5 mg/ml；二甲基亚砜：5 mg/ml； DMSO:PBS (pH 7.2) (1:1)：0.5mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  6.59
• 重原子数：
  41
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  82.2
• 氢给体数：
  0
• 氢受体数：
  6

制备方法与用途

27-TBDMS-4-脱氢叶黄素A是一种叶黄素A的衍生物，对肿瘤细胞具有强大的抗增殖作用，并能诱导其凋亡。这种化合物被证实为一种有效的抗癌剂。

反应信息

• 作为反应物：
  描述：

  4-dehydrowithaferin A 27-tert-butyldimethylsilyl ether 在 吡啶 、 盐酸 、 cerium(III) chloride heptahydrate 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 5.25h， 生成 4-acetyl-4-epi-withaferin A
  参考文献：
  名称：

  Structure–Activity Relationships for Withanolides as Inducers of the Cellular Heat-Shock Response

  摘要：

  To understand the relationship between the structure and the remarkably diverse bioactivities reported for withanolides, we obtained withaferin A (WA; 1) and 36 analogues (2-37) and compared their cytotoxicity to cytoprotective heat-shock-inducing activity (HSA). By analyzing structure activity relationships for the series, we found that the ring A enone is essential for both bioactivities. Acetylation of 27-OH of 4-epi-WA (28) to 33 enhanced both activities, whereas introduction of beta-OH to WA at C-12 (29) and C-15 (30) decreased both activities. Introduction of beta-OAc to 4,4,27-diacetyl-WA (16) at C-15 (37) decreased HSA without affecting cytotoxicity, but at C-12 (36), it had minimal effect. Importantly, acetylation of 27-OH, yielding 15 from 1, 16 from 14, and 35 from 34, enhanced HSA without increasing cytotoxicity. Our findings demonstrate that the withanolide scaffold can be modified to enhance HSA selectively, thereby assisting development of natural product-inspired drugs to combat protein aggregation-associated diseases by stimulating cellular defense mechanisms.

  DOI：

  10.1021/jm401279n
• 作为产物：
  描述：

  醉茄素 A 在 manganese(IV) oxide 作用下， 以 氯仿 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 4-dehydrowithaferin A 27-tert-butyldimethylsilyl ether
  参考文献：
  名称：

  Structure–Activity Relationships for Withanolides as Inducers of the Cellular Heat-Shock Response

  摘要：

  To understand the relationship between the structure and the remarkably diverse bioactivities reported for withanolides, we obtained withaferin A (WA; 1) and 36 analogues (2-37) and compared their cytotoxicity to cytoprotective heat-shock-inducing activity (HSA). By analyzing structure activity relationships for the series, we found that the ring A enone is essential for both bioactivities. Acetylation of 27-OH of 4-epi-WA (28) to 33 enhanced both activities, whereas introduction of beta-OH to WA at C-12 (29) and C-15 (30) decreased both activities. Introduction of beta-OAc to 4,4,27-diacetyl-WA (16) at C-15 (37) decreased HSA without affecting cytotoxicity, but at C-12 (36), it had minimal effect. Importantly, acetylation of 27-OH, yielding 15 from 1, 16 from 14, and 35 from 34, enhanced HSA without increasing cytotoxicity. Our findings demonstrate that the withanolide scaffold can be modified to enhance HSA selectively, thereby assisting development of natural product-inspired drugs to combat protein aggregation-associated diseases by stimulating cellular defense mechanisms.

  DOI：

  10.1021/jm401279n

文献信息

• Expanding the Chemical Space of Withaferin A by Incorporating Silicon To Improve Its Clinical Potential on Human Ovarian Carcinoma Cells
  作者：Nayra R. Perestelo、Gabriel G. Llanos、Carolina P. Reyes、Angel Amesty、Kartheek Sooda、Saeed Afshinjavid、Ignacio A. Jiménez、Farideh Javid、Isabel L. Bazzocchi

  DOI：10.1021/acs.jmedchem.9b00146

  日期：2019.5.9

  Ovarian cancer represents the seventh most commonly diagnosed cancer worldwide. Herein, we report on the development of a withaferin A (WA)-silyl ether library with 30 analogues reported for the first time. Cytotoxicity assays on human epithelial ovarian carcinoma cisplatin-sensitive and -resistant cell lines identified eight analogues displaying nanomolar potency (IC50 ranging from 1 to 32 nM), higher

  卵巢癌是全球第七大最常被诊断出的癌症。在此，我们报道了withaferin A（WA）-甲硅烷基醚文库的开发，该文库首次报道了30种类似物。对人上皮性卵巢癌顺铂敏感和耐药细胞系的细胞毒性试验鉴定出八种类似物，它们显示出纳摩尔效价（IC50为1至32 nM），高于先导化合物和参考药物。这种细胞毒性效力还与在非肿瘤细胞系上的良好选择性指数相结合。两种有效类似物的细胞周期分析显示，细胞凋亡通过细胞凋亡而没有表明细胞周期停滞在G0 / G1期。构效关系与计算机吸收，分布，代谢，排泄研究表明，WA框架中C-4处的硅和羰基基团的结合增强了效能，选择性和药物相似性。这些发现揭示了类似物22、23和25是复发性卵巢癌患者中临床翻译的潜在候选者。
• Withaferin A-related steroids from Withania aristata exhibit potent antiproliferative activity by inducing apoptosis in human tumor cells
  作者：Gabriel G. LLanos、Liliana M. Araujo、Ignacio A. Jiménez、Laila M. Moujir、Isabel L. Bazzocchi

  DOI：10.1016/j.ejmech.2012.05.032

  日期：2012.8

  Six new withanolides (1-6) along with eleven known ones (7-17) were isolated from the leaves of Withania aristata. Their structures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques. Semisynthesis of the minority metabolites 7 and 15 from compounds 6 and 9, respectively, as starting material, was performed. The isolated compounds as well as three derivatives (7a, 9a and 9b) of withaferin A were evaluated for cytotoxicity against HeLa (carcinoma of the cervix), A549 (lung carcinoma) and MCF-7 (breast adenocarcinoma) human cancer cell lines, and against normal Vero cells (African green monkey kidney). Five compounds from this series (8, 9a, 9b, 11 and 13) exhibited potent antiproliferative effects on the tumor cells, even higher than the well known anticancer agent, withaferin A (9). Phosphatidylserine externalization, chromatin condensation, and caspase-3 activation clearly indicated apoptosis as a mechanism of action. The structure-activity relationship revealed valuable information on the pharmacophore for withanolide-type compounds. (C) 2012 Elsevier Masson SAS. All rights reserved.
• [EN] WITHAFERIN A ANALOGS AND USES THEREOF<br/>[FR] ANALOGUES DE LA WITHAFÉRINE A ET LEURS UTILISATIONS
  申请人：WHITEHEAD BIOMEDICAL INST

  公开号：WO2010030395A3

  公开（公告）日：2010-07-01
• Structure–Activity Relationships for Withanolides as Inducers of the Cellular Heat-Shock Response
  作者：E. M. Kithsiri Wijeratne、Ya-Ming Xu、Ruth Scherz-Shouval、Marilyn T. Marron、Danilo D. Rocha、Manping X. Liu、Leticia V. Costa-Lotufo、Sandro Santagata、Susan Lindquist、Luke Whitesell、A. A. Leslie Gunatilaka

  DOI：10.1021/jm401279n

  日期：2014.4.10

  To understand the relationship between the structure and the remarkably diverse bioactivities reported for withanolides, we obtained withaferin A (WA; 1) and 36 analogues (2-37) and compared their cytotoxicity to cytoprotective heat-shock-inducing activity (HSA). By analyzing structure activity relationships for the series, we found that the ring A enone is essential for both bioactivities. Acetylation of 27-OH of 4-epi-WA (28) to 33 enhanced both activities, whereas introduction of beta-OH to WA at C-12 (29) and C-15 (30) decreased both activities. Introduction of beta-OAc to 4,4,27-diacetyl-WA (16) at C-15 (37) decreased HSA without affecting cytotoxicity, but at C-12 (36), it had minimal effect. Importantly, acetylation of 27-OH, yielding 15 from 1, 16 from 14, and 35 from 34, enhanced HSA without increasing cytotoxicity. Our findings demonstrate that the withanolide scaffold can be modified to enhance HSA selectively, thereby assisting development of natural product-inspired drugs to combat protein aggregation-associated diseases by stimulating cellular defense mechanisms.