12β-hydroxywithaferin A

• 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: 12β-hydroxywithaferin A
• 英文别名: (1S,2R,6S,7R,9R,11S,12S,15R,16S,17R)-6,17-dihydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-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-en-3-one
• 化学式: C₂₈H₃₈O₇
• 分子量: 486.606
• InChiKey: QTUMPYRKGLFMME-SDSVCERJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  35
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  117
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  乙酸酐 、 12β-hydroxywithaferin A 在 吡啶 作用下， 反应 18.0h， 以95%的产率得到12β-acetoxy-4,27-diacetylwithaferin 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 dipotassium hydrogenphosphate 、 葡萄糖 、 sodium chloride 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 120.0h， 以32%的产率得到15β-hydroxywithaferin A
  参考文献：
  名称：

  天然抗肿瘤剂的微生物转化。23.withaferin-A转化为withaferin-A的12个β-和15个β-羟基衍生物。

  摘要：

  用抗肿瘤内酯with aferin-A进行了微生物转化实验。秀丽隐杆线虫NRRL 1393用铁传递素-A（1a）转化为15个β-羟基吸收传递素-A（2a）和12个β-羟基-吸收传递素-A（3a）。通过溶剂萃取分离羟基化的代谢物，并通过柱和薄层色谱法纯化。羟基化代谢物的结构通过质子和碳13 NMR，IR和质谱分析以及酰化衍生物的制备来确定。化合物2a和3a抑制了体外生长的P-388淋巴细胞白血病细胞的生长和生化功能。

  DOI：

  10.1016/0039-128x(82)90030-7

文献信息

• Microbial transformations of natural antitumor agents. 23. conversion of withaferin-A to 12β- and 15β-hydroxy derivatives of withaferin-A.
  作者：J. Fuska、J. Prousek、J. Rosazza、Budesinsky M.

  DOI：10.1016/0039-128x(82)90030-7

  日期：1982.8

  Microbial transformation experiments were conducted with the antitumor lactone withaferin-A. Cunninghamella elegans NRRL 1393 transformed withaferin-A (1a) to 15 beta-hydroxywithaferin-A (2a) and 12 beta-hydroxy-withaferin-A (3a). The hydroxylated metabolites were isolated by solvent extraction and were purified by column and thin-layer chromatography. Structures of the hydroxylated metabolites were

  用抗肿瘤内酯with aferin-A进行了微生物转化实验。秀丽隐杆线虫NRRL 1393用铁传递素-A（1a）转化为15个β-羟基吸收传递素-A（2a）和12个β-羟基-吸收传递素-A（3a）。通过溶剂萃取分离羟基化的代谢物，并通过柱和薄层色谱法纯化。羟基化代谢物的结构通过质子和碳13 NMR，IR和质谱分析以及酰化衍生物的制备来确定。化合物2a和3a抑制了体外生长的P-388淋巴细胞白血病细胞的生长和生化功能。
• 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.