Abstract
Five new physalins, including a novel 1,10-seco one, physalin V (1), a tricarboxylic acid cycle one, physalin VIII (5), a rare 11,15-cyclo one, physalin IX (6), and two new ones, physalins VI (2) and VII (4) were isolated from stems and leaves of Physalis angulata together with eleven known analogues (3 and 7–16). Their structures were established by MS, IR, UV, and NMR spectroscopic analysis, together with the X-ray diffraction analysis of neophysalin, physalin P (12), and the structure of physalin D1 (3) has been revised here. These isolated compounds were evaluated for their antiproliferative activities against human cancer cells (C4-2B, 22Rv1, 786-O, A-498, ACHN, and A375-S2) and inhibitory effects on nitric oxide production. Compounds 9 and 10 showed antiproliferative activities against all tested human cancer cells with IC50 values of 0.24–3.17 μM. Compounds 1, 3, 4, 9, 10, 13, 14, and 16 exhibited inhibitory activities against NO production. The IC50 values of compounds 9, 10, 13, and 16 were between 0.32 and 4.03 μM, while compounds 1, 3, 4, and 14 had IC50 values of 12.83–34.19 μM. Herein, plausible biosynthetic pathways for rare structures 1 and 6 and structure−activity relationships on the inhibition of NO production for all isolated compounds are discussed.
Highlights
The withanolides are a group of natural C28 steroids with a γ- or δ-lactone based on an ergostane skeleton, which are derived from a parent 23-hydroxy-26-oic or 22-hydroxy-26-oic acid
The EtOH extracts of stems and leaves of P. angulata were separated by silica gel, Sephadex LH-20, ODS open column chromatography, preparative TLC, and preparative HPLC to yield five new physalins, including an uncommon 1,10-seco one, physalin V (1), physalins VI (2), VII (4), and VIII (5), and a novel 11,15-cyclo one, physalin IX (6), together with eleven known analogues, 25β-hydroxyphysalin D (7)[19], physalins D1 (3), D (8)[20], B (9)[21], F (10)[22], G (11)[23], P (12)[24], H (13)[25], I (14)[20], and R (15)[26], and isophysalin B (16)[25] (Fig. 1)
The 1H and 13C NMR data of 1 were closely resembled those of physalin G (11) isolated from P. angulata[23], with the exception that signals of ring A [δH 6.49 (1 H, dd, J = 11.2, 2.0 Hz, H-4), 5.49 (1 H, ddd, J = 11.2, 9.3, 2.0 Hz, H-3), and 5.25 (1 H, br s, H-6); δC 171.8 (C-1), 141.0 (C-10), 128.8 (C-4), 125.7 (C-5), 118.3 (C-3), 71.2 (C-6), and 35.6 (C-2)] were present in 1, indicating that 1 was a 1,10-seco physalin[27, 28]. This conclusion was confirmed by the HMBC correlations from H-2a to C-1/C-3/C-4, H-3 to C-1/C-2/carbons [δC 135.5 (C-5), H-4 to C-2/C-5/C-6/C-10, and H-6 to C-1/C-5/C8/C-10 (Supplementary Fig. 3–5), suggesting the presence of the seven-membered β,γ-unsaturated lactonic ring (Fig. 2)
Summary
The withanolides are a group of natural C28 steroids with a γ- or δ-lactone based on an ergostane skeleton, which are derived from a parent 23-hydroxy-26-oic or 22-hydroxy-26-oic acid They can be further divided into 22 subtypes based on the difference of the structural skeleton, such as normal withanolides, physalins, withaphysalins, neophysalins, jaborols, and so on[1, 2]. As part of our ongoing research on isolating bioactive physalins from the genus Physalis to provide potential anticancer and anti-inflammatory medicines[11, 12, 15, 16], the EtOH extracts of the dried stems and leaves of P. angulata were isolated to afford a novel 1,10-seco physalin, physalin V (1), a tricarboxylic acid cycle one, physalin VIII (5), a rare 11,15-cyclo one, physalin IX (6), and two new ones, physalins VI (2) and VII (4), together with eleven known analogues (Fig. 1), and the structure of the known physalin D1 (3) was revised. Biosynthetic pathways for the rare physalins 1 and 6 are proposed, and structure–activity relationships for all isolated compounds are preliminarily discussed
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