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Pure Appl. Chem., 2012, Vol. 84, No. 6, pp. 1353-1367

Published online 2012-04-15

Antiproliferative withanolides from the Solanaceae: A structure–activity study

Huaping Zhang1, Abbas K. Samadi2, Mark S. Cohen2 and Barbara N. Timmermann1*

1 Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS 66045, USA
2 Department of Surgery, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA

Abstract: As part of our search for bioactive compounds from plant biodiversity, 29 withanolides were recently isolated from three members of the Solanaceae: Physalis longifolia, Vassobia breviflora, and Withania somnifera. Six derivatives were prepared from these naturally occurring withanolides. All compounds were evaluated for in vitro antiproliferative 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, withaferin A 4,27-diacetate, 27-O-glucopyranosylwithaferin A, withalongolide H, withalongolide C, withalongolide A, withalongolide A 4,27-diacetate, withalongolide A 4,19,27-triacetate, withalongolide B, withalongolide B 4-acetate, withalongolide B 4,19‑diacetate, withalongolide D, withalongolide E, withalongolide G, and 2,3-dihydrowithaferin A 3-O-sulfate. In order to update the growing literature on withanolides and their activities, we summarized the distribution, structural types, and antiproliferative activities for all published withanolides to date. The structure–activity relationship analysis (SARA) confirmed the importance of the presence of a ∆2-1-oxo-functionality in ring A, a 5β,6β-epoxy or 5α-chloro-6β-hydroxy grouping 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, and 28 were not contributors to the observed antiproliferative activity within the systems analyzed.