Natural withanolides: an overview

Abstract

Withanolides are a group of naturally occurring C28 steroids built on an ergostane skeleton functionalized at carbons 1, 22 and 26, commonly known as the withanolide skeleton. Over the period of August 1996 to March 2010, 360 new naturally occurring withanolides were isolated and identified. This review provides a comprehensive summary of the structural classification and distribution of these new compounds. The diverse biological and pharmacological activities of natural withanolides are also discussed based on their structural features. A total of 211 references are cited in this review.

Cytotoxic withanolide constituents of Physalis longifolia

“…The 1 H NMR spectrum (Table 1) showed the presence of three methyl groups at δ 0.60 (3H, s), 0.90 (3H,d,J = 6.6 Hz), and 1.97 (3H, s), seven protons attached to oxygenated carbons at δ 3.18 (1H, brs), 3.52 (1H, d, J = 6.1 Hz), 3.65 (1H, d, J = 9.6 Hz), 4.17 (1H, d, J = 9.6 Hz), 4.23 (1H,d,J = 12.5 Hz),4.28 (1H,d,J = 12.5 Hz),and 4.33 (1H,dt,J = 13.3,3.4 Hz), and two olefinic methine groups at δ 6.16 (1H, d, J = 10.0 Hz) and 6.95 (1H,dd,J = 10.0,6.1 Hz). The 13 C NMR (APT) and HSQC spectra for 1 (Table 2) displayed 28 carbon signals differentiated as three CH 3 , eight CH 2 (including two oxygenated at δ 61.0 and 56.7), 10 CH (including two olefins at δ 145. 7 and 132.9, three oxygenated at δ 78.…”

“…The obvious difference between 13 and 12 was the presence of a methylene ( 13 C: δ 33.8; 1 H: δ 2.30, 2H, m) instead of an oxygenated methine ( 13 C: δ 71.2; 1 H: δ 4.69), suggesting that 13 is a 6-deoxy derivative of 12. This observation was supported by the 13 C NMR high-frequency shift of C-4 (δ 41.9 in 13 and δ 36.9 in 12) and C-8 (δ 39.9 in 13 and δ 37.5 in 12), the lowfrequency shift of C-7 (δ 26.4 in 13 and δ 37.3 in 12), and HMBC correlations of 1H,d, J = 4.1 Hz)/C-2 (δ 49.7), C-3 (δ 66.1), and C-4 (δ 41.9), of H [2][3][4]dd,J = 5.9,16.8 Hz and δ 2.58,dd,J = 2.7,16.8 Hz)/C-2, C-3, C-5 (δ 153.6), C-6 (δ 33.8), and C-10 (δ 136.1), and of H-6β (δ 2.09, m)/C-4, C-5, C-7 (δ 26.4), C-8 (39.9), and C-10 in 13. Thus, the structure of 13 (withalongolide M) was determined as 28-O-β-D-glucopyranosyl-3β-hydroxy-1-oxo-19-norwitha-5-(10),24-dienolide.…”

“…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.…”

Antiproliferative withanolides from the solanaceae: A structure-activity study

“…As listed in Table 1, withanolides are predominant in 25 genera (including Acnistus, Datura, Deprea, Discopodium, Dunalia, Iochroma, Jaborosa, Lycium, Nicandra, Physalis, Solanum, Trechonaetes, Tubocapsicum, Vassobia, Withania, and Witheringia) of the Solanaceae family [2][3][4][5][6][7][10][11][12]. Not limited to the Solanaceae, withanolides have also been isolated from a smaller number of species in the Dioscoreaceae [13], Fabaceae [7], Lamiaceae [2], Myrtaceae [14], Taccaceae [2], and from two genera in the marine Alcyoniidae [15,16]. Although the large family Solanaceae is composed of six subfamilies, with the exception of Browallia viscosa, all species containing withanolides belong to the subfamily Solanoidea [3,4].…”

“…Further investigations in this field led to the discovery of many hun-dreds of additional compounds, which include 22 related but different structural types such as: (1) new withanolides exhibiting γ-lactone functionality (from 23-hydroxy-26-oic or 28-hydroxy-26-oic acids), or γ-lactol functionality (from 28-hydroxy-26-als), or δ-lactol functionality (from 22-hydroxy-26-als) in the side chain (Fig. 2); (2) new withanolides isolated from sources other than the genus Withania (Table 1); and (3) a number of structural varieties with novel skeletons derived or modified from, or biogenetically related to, the highly oxygenated withanolides by ring fission, cyclization, and skeleton rearrangements in either or both of the steroid nucleus and in the nine-carbon side chain [2][3][4][5][6][7][8]. In view of these findings, the original term "withanolide" is no longer limited to its primary definition, and it has expanded to encompass the structurally diverse variants bearing different carbon scaffolds, such as those present in acnistin, joborol, neophysalin, nicandrenone, physalin, taccalonolide, and withajardin ( Fig.…”