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

As part of our search for bioactive compounds from plant biodiversity, 29 withanolides (, and ) were recently isolated from three members of the Solanaceae: , and . Six derivatives (, and ) were prepared from these naturally occurring withanolides. All compounds () were evaluated for 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 , withaferin A 4,27-diacetate , 27--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--sulfate ). 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 Δ-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.