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. 2012;84(6):1353-1367.
doi: 10.1351/PAC-CON-11-10-08.

Anti-proliferative withanolides from the Solanaceae: a structure-activity study

Huaping Zhang  1 , Abbas K Samadi, Mark S Cohen, Barbara N Timmermann
Affiliations

Anti-proliferative withanolides from the Solanaceae: a structure-activity study

Huaping Zhang et al. Pure Appl Chem. 2012.

Abstract

As part of our search for bioactive compounds from plant biodiversity, 29 withanolides (1, 3-6, 9, 12-18, and 20-35) were recently isolated from three members of the Solanaceae: Physalis longifolia, Vassobia breviflora, and Withania somnifera. Six derivatives (2, 7, 8, 10, 11, and 19) were prepared from these naturally occurring withanolides. All compounds (1-35) were evaluated for in vitro anti-proliferative activity against an array of cell lines [melanoma cell lines (B16F10, SKMEL28); human head and neck squamous cell carcinomas (HNSCC) cell lines (JMAR, MDA1986, DR081-1); breast cancer cell line (Hs578T), and non-malignant human cell line (MRC5)]. This led to the discovery of 15 withanolides, with IC50 values in the range of 0.067-17.4 µM, including withaferin A 1, withaferin A 4,27-diacetate 2, 27-O-glucopyranosylwithaferin A 3, withalongolide H 4, withalongolide C 5, withalongolide A 6, withalongolide A 4,27-diacetate 7, withalongolide A 4,19,27-triacetate 8, withalongolide B 9, withalongolide B 4-acetate 10, withalongolide B 4,19-diacetate 11, withalongolide D 16, withalongolide E 17, withalongolide G 21, and 2,3-dihydrowithaferin A 3-O-sulfate 22). In order to update the growing literature on withanolides and their activities, we summarized the distribution, structural types and anti-proliferative activities for all published withanolides to date. The structure-activity relationship analysis (SARA) confirmed the importance of the presence of a Δ2-1-oxo- functionality in ring A, a 5β,6β-epoxy or 5α-chloro-6β-hydroxy groupings in ring B, and nine carbon side chain with a lactone moiety for cytotoxic activity. Conversely, the SARA indicated that the -OH or -OR groups at C-4, 7, 11, 12, 14, 15, 16, 17, 18, 19, 20, 23, 24, 27, 28 were not contributors to the observed anti-proliferative activity within the systems analyzed.

Keywords: Physalis longifolia; Solanaceae; Vassobia breviflora; Withania somnifera; anti-proliferative; structure classifcation; structure-activity relationship; withanolide.

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Figures

Figure 1
Figure 1
Withanolide carbon-frame and structure of withaferin A 1
Figure 2
Figure 2
Twenty two structure types of withanolides based on their carbon skeletons (1965–2011)
Figure 2
Figure 2
Twenty two structure types of withanolides based on their carbon skeletons (1965–2011)
Figure 3
Figure 3
Withanolides (1, 3–6, 9, 12–18, and 20–35) from Physalis longifolia, Vassobia breviflora, and Withania somnifera and their derivatives (2, 7, 8, 10, 11, and 19) [17, 28, 29]
Figure 4
Figure 4
Withanolides used for SARA in Table 3 (analysis from literature sources)
Figure 4
Figure 4
Withanolides used for SARA in Table 3 (analysis from literature sources)
Figure 5
Figure 5
Structure-activity relationship analysis (SARS) of withanolides
See this image and copyright information in PMC

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