15β-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: 15β-hydroxywithaferin A
• 英文别名: (1S,2R,6S,7R,9R,11R,12S,13R,15R,16R)-6,13-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: PXXKKMOLJHIPMF-CVRWKVLCSA-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 、 15β-hydroxywithaferin A 在 吡啶 作用下， 反应 18.0h， 以95%的产率得到15β-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 碘 、 N,N-二异丙基乙胺 、 三苯基膦 作用下， 以 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 194.0h， 生成 15β-hydroxywithaferin A
  参考文献：
  名称：

  具有双重热休克诱导和细胞毒活性的Withaferin A和Withanolide D类似物：半合成和生物学评估

  摘要：

  Withanolides构成一类有价值的生物活性天然产物，因为已知该类化合物的某些成员表现出细胞毒活性，并且还诱导细胞保护性热休克反应。为了了解其结构与withanolide支架的双重生物活性之间的关系，我们通过涉及化学和微生物转化的半合成获得了25种withaferin A（WA）和withanolide D（WD）的类似物，包括17种新化合物。通过与三苯基膦/碘反应制备了迄今未知的WA和WD16β-羟基类似物，提供了出乎意料的5β-羟基-6α-碘类似物（碘代醇），然后用棘枝棘孢菌进行了微生物生物转化。和碱催化环化所得的16β-羟基碘醇。对这25种withanolide类似物的细胞毒性和热激诱导活性（HSA）进行评估，证实了WA型withanolides具有已知的结构-活性关系，并揭示了在两种测定法中WD类似物与其相应的WA类似物相比活性较低。醇化物的5β，6β-环氧部分有助于其细胞毒性

  DOI：

  10.1021/acs.jnatprod.7b00918

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.
• Withaferin A and Withanolide D Analogues with Dual Heat-Shock-Inducing and Cytotoxic Activities: Semisynthesis and Biological Evaluation
  作者：E. M. Kithsiri Wijeratne、Maria C. F. Oliveira、Jair Mafezoli、Ya-Ming Xu、Sandro Minguzzi、Pedro H. J. Batista、Otília D. L. Pessoa、Luke Whitesell、A. A. Leslie Gunatilaka

  DOI：10.1021/acs.jnatprod.7b00918

  日期：2018.4.27

  analogues of withaferin A (WA) and withanolide D (WD) including 17 new compounds by semisynthesis involving chemical and microbial transformations. Hitherto unknown 16β-hydroxy analogues of WA and WD were prepared by their reaction with triphenylphosphine/iodine, providing unexpected 5β-hydroxy-6α-iodo analogues (iodohydrins) followed by microbial biotransformation with Cunninghamella echinulata and base-catalyzed

  Withanolides构成一类有价值的生物活性天然产物，因为已知该类化合物的某些成员表现出细胞毒活性，并且还诱导细胞保护性热休克反应。为了了解其结构与withanolide支架的双重生物活性之间的关系，我们通过涉及化学和微生物转化的半合成获得了25种withaferin A（WA）和withanolide D（WD）的类似物，包括17种新化合物。通过与三苯基膦/碘反应制备了迄今未知的WA和WD16β-羟基类似物，提供了出乎意料的5β-羟基-6α-碘类似物（碘代醇），然后用棘枝棘孢菌进行了微生物生物转化。和碱催化环化所得的16β-羟基碘醇。对这25种withanolide类似物的细胞毒性和热激诱导活性（HSA）进行评估，证实了WA型withanolides具有已知的结构-活性关系，并揭示了在两种测定法中WD类似物与其相应的WA类似物相比活性较低。醇化物的5β，6β-环氧部分有助于其细胞毒性