Infectious diseases are of ancient origin, and mankind has a venerable history of use of higher plant extracts for the therapy of such infections. Some such agents survive in use from earlier times--quinine, emetine, and sanguinarine, for example--but the modern use of fermentation-based antibiotics has greatly overshadowed work on agents from other sources. After a brief review of the present status of the field of antibiotics, this review focuses upon the present status of antimicrobial agents from higher plants with particular reference to agents from plants with a folkloric reputation for treatment of infections. In particular, recent work on the tropical genus Erythrina is emphasized. The use of modern microbiological techniques demonstrates that higher plants frequently exhibit significant potency against human bacterial and fungal pathogens, that many genera are involved, that many folkloric uses can be rationalized on this basis, that the active constituents are readily isolated by bioassay-directed techniques, that their chemical structures are types uncommon amongst fermentation-based agents but are familiar to natural product chemists, that their antimicrobial spectra are comparatively narrow but that their potency is often reasonable, that they are comparatively easy to synthesize and the unnatural analogues so produced can possess enhanced therapeutic potential and, thus, it is concluded that such work generates a gratifying number of novel lead structures and that the possibility of finding additional agents for human or agricultural use based upon higher plant agents is realistic.
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 assays, 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 IC50 values in the range between 0.067 and 9.3 μM.
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 IC 50 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 Δ 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.
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