Isolation, Structures, and Structure−Cytotoxic Activity Relationships of Withanolides and Physalins from Physalis angulata

Abstract

Phytochemical investigation of Physalis angulata was initiated following primary biological screening. Fractionation of CHCl3 and n-BuOH solubles of the MeOH extract from the whole plant was guided by in vitro cytotoxic activity assay using cultured HONE-1 and NUGC cells and led to the isolation of seven new withanolides, withangulatins B-H (1-7), and a new minor physalin, physalin W (8), along with 14 known compounds, including physaprun A, withaphysanolide, dihydrowithanolide E, physanolide A, withaphysalin A, and physalins B, D, F, G, I, J, T, U, and V. New compounds (1-8) were fully characterized by a combination of spectroscopic methods (1D and 2D NMR and MS) and the relative stereochemical assignments based on NOESY correlations and analysis of coupling constants. Biological evaluation of these compounds against a panel of human cancer cell lines showed broad cytotoxic activity. Withangulatin B (1) and physalins D (10) and F (11) displayed potent cytotoxic activity against a panel of human cancer cell lines with EC50 values ranging from 0.2 to 1.6 microg/mL. Structure-activity relationship analysis indicated that withanolides and physalins with 4beta-hydroxy-2-en-1-one and 5beta,6beta-epoxy moieties are potential cytotoxic agents.

Antiproliferative withanolides from the solanaceae: A structure-activity study

“…Direct comparison revealed that opening of the 5β,6β-epoxy-group of withaferin A 1 to furnish the corresponding 5β,6α-diol 29 or 6α-chloro-5β-ol 30 resulted in loss of activity. These findings confirm that the 5β,6β-epoxy-group in ring B is essential for the observed cytotoxic activity, in agreement with results previously reported in the literature for compounds with similar structural features [25][26][27].…”

“…On the other hand, esterification of the hydroxyl groups at C-4, C-19, and C-27 increased cytotoxicity when comparing withaferin A 1 with withaferin A 4,27-diacetate 2; withalongolide A 6 with withalongolide A 4,27-diacetate 7 and withalongolide A 4,19,27-triacetate 8; withalongolide B 9 with withalongolide B 4-acetate 10 and withalon-golide B 4,19-diacetate 11 ( Table 2). These results are in agreement with previously reported SARs [24][25][26][27]31]. It should be noted that the cytotoxic activity of withalongolide B 9 is comparable to that of withaferin A 1, while the triacetate derivative 8 and diacetate derivative 11 are more potent than withaferin A 1 by exhibiting submicromolar activity with IC 50 values in the range of 0.067-0.91 μM against all the cell lines tested.…”

“…Type I withanolides that display the most promising antiproliferative characteristics also contain Δ 2 -1-oxo-functionality in ring A, a 5β,6β-epoxy-group in ring B, and a nine-carbon side chain incorporating the δ-lactone functionality found in withaferin A 1 [17], withacnistin 59 [18,19], withanolide D 48 [20][21][22][23], withanolide E 36 [8,[24][25][26][27], and 4β-hydroxywithanolide E 37 (Fig. 4) [8,[24][25][26][27]. Withaferin A 1 (Fig.…”

Withanolides and Related Steroids

“…Thus, the 3-ethoxy derivative 303 isolated from P. alkekengi, was found only in trace amounts in the original extract when analyzed by HPLC (67). The 3-methoxy derivative 304 (physalin U) was initially isolated from P. minima (60) and later from P. angulata (146), while the 3-methoxy derivative 305 was isolated from P. angulata (55). The latter compound was named physalin W although this name had already been assigned to another physalin (see below).…”

Plants from Solanaceae family with possible anxiolytic effect reported on 19th century's Brazilian medical journal

“…Phytochemical: seco-steroids (physalins) (Soares et al, 2006;Abe et al, 2006;Kuo et al, 2006;Magalhães et al, 2006a;Magalhães et al, 2006b;Damu et al, 2007), alkaloids (Edeoga et al, 2005), tannins and flavonoids (Edeoga et al, 2005;Wollenweber et al, 2005), the withanolides withangulatin (Lee et al, 2008) and physagulins . Patents that were reported, both in the European Patent Office and the Brazilian National Institute of industrial Property databases, most of which concern inflammatory, allergic, parasitic, infectious or digestive diseases, including extracts from P. angulata (Balbani et al, 2009 (Zakaria et al, 2006); can cause a central nervous system depression which may be correlated with an increased parasympathetic tone (Perez et al, 1998), antioxidant (Al-Fatimi et al, 2007); antipyretic and anticancer agent (Hsieh et al, 2008;Hsu et al, 2009;Yang et al, 2010;Li et al, 2008;Li et al, 2009), mutagenic activity (Almeida et al, 2010).…”