Fourteen new withanolides, 1−14, named withalongolides A−N, respectively, were isolated from the aerial parts of Physalis longifolia together with eight known compounds (15−22). The structures of compounds 1−14 were elucidated through spectroscopic techniques and chemical methods. In addition, the structures of withanolides 1, 2, 3, and 6 were confirmed by X-ray crystallographic analysis. Using a MTS viability assay, eight withanolides (1, 2, 3, 7, 8, 15, 16, and 19) and four acetylated derivatives (1a, 1b, 2a, and 2b) showed potent cytotoxicity against human head and neck squamous cell carcinoma (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal fibroblast (MRC-5) cells with IC 50 values in the range between 0.067 and 9.3 μM.C lassically defined withanolides are a group of C 28 ergostane-type steroids with a C-22,26 δ-lactone group, first isolated from the genus Withania. 1 They are present primarily in the Solanaceae family, which includes the genera Acnistus, Datura, Dunalia, Jaborosa, Nicandra, Physalis, Withanolides have attracted interest in recent years mainly due to their exhibition of significant biological activities, inclusive of antimicrobial, antitumor, anti-inflammatory, immunomodulatory, and insect-antifeedant activities. 2,3,6 It has been reported that those withanolides displaying the most promising antitumor characteristics contain an α,β-unsaturated ketone in ring A, a 5β,6β-epoxy group in ring B, and a nine-carbon side chain with an α,β-unsaturated δ-lactone group. 10 The typical withanolide withaferin A (16) (Figure 1) contains these three moieties and has been shown in vitro and in vivo to suppress the growth of an array of tumor cells, including breast, pancreatic, prostate, lung, leukemia, and head and neck squamous cell carcinoma (HNSCC), by inducing apoptosis, 11 thus possessing potential application as an antiproliferative agent. As part of an ongoing study of withanolides from plant sources, 11,12 a library of 224 native plant extracts from the U.S. Great Plains was evaluated for cytotoxic activities against HNSCC and melanoma cell lines using the MTS viability assay. One of the most promising leads, Physalis longifolia Nutt. (Solanaceae), commonly known as "long leaf groundcherry", was subjected to a phytochemical investigation, and the results are presented herein, including the details of the isolation and structure elucidation of 14 new withanolides (1−14), four acetylated derivatives (1a, 1b, 2a, and 2b), and eight known compounds (15−22). Their cytotoxicity was determined against HNSCC (JMAR and MDA-1986), melanoma (B16F10 and SKMEL-28), and normal fetal fibroblast (MRC-5) cells. This constitutes the first report of a phytochemical and bioactivity study of P. longifolia. ■ RESULTS AND DISCUSSIONThe CH 2 Cl 2 −MeOH (1:1) extract of the aerial parts of the title plant and the EtOAc-soluble and n-BuOH-soluble fractions showed cytotoxicity against the above-mentioned cells with IC 50 values in the range between 0.7 and 9.8 μg/mL using a MTS assay. All ...

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