2,3-dihydro-withaferin 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: 2,3-dihydro-withaferin A
• 英文别名: 2,3-dihydrowithaferin A；2,3-dihydrowithaferin-A；dihydrowithaferin A；(1S,2R,6S,7R,9R,11S,12S,15R,16S)-6-hydroxy-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]octadecan-3-one
• 化学式: C₂₈H₄₀O₆
• 分子量: 472.622
• InChiKey: YRXCLNDPESBJHL-CKNDUULBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  34
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  96.4
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2,3-dihydro-withaferin A 在 硫酸 作用下， 以 丙酮 为溶剂， 反应 6.0h， 以85%的产率得到(22R)-5β-formyl-6β,27-dihydroxy-1-oxo-4-norwith-24-enolide
  参考文献：
  名称：

  Nittala, S. Sarma; Lavie, David, Journal of the Chemical Society. Perkin transactions I, 1982, # 12, p. 2835 - 2840

  摘要：

  DOI：
• 作为产物：
  描述：

  醉茄素 A 在 palladium 10% on activated carbon 、 氢气 、 三乙胺 作用下， 以 乙醇 为溶剂， 反应 1.0h， 以98%的产率得到2,3-dihydro-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

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。
• Withanolides useful for the treatment of neurodegenerative diseases
  申请人：ImStar Therapeutics Inc.

  公开号：US10351590B2

  公开（公告）日：2019-07-16

  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.

  本文提供了式(I)（其中R1-R4如本文所定义）的岩兰内酯天然产物的合成类似物及其在治疗神经退行性疾病中的药物用途。
• 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.
• Nittala, S. Sarma; Lavie, David, Journal of the Chemical Society. Perkin transactions I, 1982, # 12, p. 2835 - 2840
  作者：Nittala, S. Sarma、Lavie, David

  DOI：——

  日期：——