27-O-(tert-butyldimethylsilyl)withaferin A | 1392820-18-6

• 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: 27-O-(tert-butyldimethylsilyl)withaferin A
• 英文别名: (1S,2R,6S,7R,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]-6-hydroxy-2,16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-3-one
• CAS: 1392820-18-6
• 化学式: C₃₄H₅₂O₆Si
• 分子量: 584.869
• InChiKey: XCXYVTYOGSYQQL-ZKIGBFCOSA-N

物化性质

• 沸点：
  667.4±55.0 °C(Predicted)
• 密度：
  1.15±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.38
• 重原子数：
  41
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  85.4
• 氢给体数：
  1
• 氢受体数：
  6

制备方法与用途

27-O-(叔丁基二甲基硅基)与aferin A(化合物9a)及anolide均为天然产物，且均是凋亡诱导剂。27-O-(叔丁基二甲基硅基)和aferin A对HeLa、A-549和MCF-7人癌细胞系以及正常Vero细胞表现出显著的抗增殖活性[1]。

反应信息

• 作为反应物：
  描述：

  27-O-(tert-butyldimethylsilyl)withaferin A 在 吡啶 、 咪唑 、 chromium(VI) oxide 、 4-二甲氨基吡啶 、 三乙胺 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 反应 28.08h， 生成 27-O-(trimethylsilyl)-4-dehydroxy-4-oxowithaferin A
  参考文献：
  名称：

  通过掺入硅来扩大Withaferin A的化学空间，以提高其在人卵巢癌细胞上的临床潜力。

  摘要：

  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。

  DOI：

  10.1021/acs.jmedchem.9b00146
• 作为产物：
  描述：

  叔丁基二甲基氯硅烷 、 醉茄素 A 在 咪唑 、 4-二甲氨基吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以94%的产率得到27-O-(tert-butyldimethylsilyl)withaferin A
  参考文献：
  名称：

  通过掺入硅来扩大Withaferin A的化学空间，以提高其在人卵巢癌细胞上的临床潜力。

  摘要：

  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。

  DOI：

  10.1021/acs.jmedchem.9b00146

文献信息

• Structure-based design, synthesis, and biological evaluation of withaferin A-analogues as potent apoptotic inducers
  作者：Gabriel G. Llanos、Liliana M. Araujo、Ignacio A. Jiménez、Laila M. Moujir、Jaime Rodríguez、Carlos Jiménez、Isabel L. Bazzocchi

  DOI：10.1016/j.ejmech.2017.09.004

  日期：2017.11

  investigation clearly indicated that compounds 3, 11, 12, and 18 induce apoptosis evidenced by chromatin condensation, phosphatidylserine externalization, and caspase-3 activation effects on HeLa cells. The potent capacity to induce apoptosis with concomitant cell loss in G2/M highlights the potential of 27-benzyl analogue (18) as an apoptotic inducer drug candidate.

  凋亡诱导剂是发现和开发抗癌剂的一种有吸引力的方法。在此，我们通过的分子微调睡茄素的63种化合物（基于A-文库发展报告2 - 64），它们中的53报道首次。他们对HeLa，A-549和MCF-7人肿瘤细胞系的抗增殖评估确定了十五种类似物，它们的活性（IC 50值范围为0.3–4.8μM）比铅（IC 50）高。值处于滞后或对数生长期的数值（1.3-10.1μM）。SAR分析表明，酰化作用增强了细胞毒性，表明疏水性部分可能通过增加亲和力和/或细胞膜通透性而有助于细胞活性。进一步调查清楚地表明，化合物3，11，12，和18诱导染色质缩合，磷脂酰丝氨酸外翻，并且在HeLa细胞胱天蛋白酶-3激活的细胞凋亡效果证明。在G2 / M中诱导细胞凋亡并伴随细胞丢失的有效能力凸显了27-苄基类似物（18）作为凋亡诱导药物候选物的潜力。
• [EN] WITHANOLIDES USEFUL FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES<br/>[FR] WITHANOLIDES UTILES POUR LE TRAITEMENT DE MALADIES NEURODÉGÉNÉRATIVES
  申请人：IMSTAR THERAPEUTICS INC

  公开号：WO2015077780A1

  公开（公告）日：2015-05-28

  Provided herein are synthetic analogs of withanolide natural products of formula (I), wherein R1-R4 are as defined herein, and their pharmaceutical uses in treating neurodegenerative diseases.

  本文提供了公式（I）的生物类似物，其中R1-R4如本文所定义，并且它们在治疗神经退行性疾病方面的药用。
• WITHANOLIDES USEFUL FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
  申请人：ImStar Therapeutics Inc.

  公开号：US20190315798A1

  公开（公告）日：2019-10-17

  Provided herein are synthetic analogs of withanolide natural products and their pharmaceutical uses in treating neurodegenerative diseases.

  本文提供了生物类固醇天然产物伪生物类及其在治疗神经退行性疾病中的药用。
• 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.
• 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.