Synthesis and In Vitro Anti-inflammatory Activity of C20 Epimeric Ocotillol-Type Triterpenes and Protopanaxadiol

Abstract

Ginseng is a perennial herb that contains various medicinal substances. The major active constituents of ginseng are ginsenosides, which have multifarious biological activities. Some pharmacological activities are closely dependent on the stereoisomers derived from the configuration at C20. In this study, the in vitro anti-inflammatory activity of C20 epimeric ocotillol-type triterpenes (2, 3, 9, and 10) and protopanaxadiol [20(S/R)-protopanaxadiol] were investigated. Epimers 2 and 3 were prepared starting from 20(S)-protopanaxadiol. Epimers 9 and 10 were synthesized from 20(R)-3-acetylprotopanaxadiol (7). The anti-inflammatory activity of 2, 3, 9, 10, 20(S)-protopanaxadiol, and 20(R)-protopanaxadiol was evaluated in cultured mouse macrophage RAW 264.7 cells. The MTT assay was used to measure the cytotoxicity. RAW 264.7 cells were stimulated by lipopolysaccharide to release the inflammatory mediators nitric oxide, prostaglandin E2, TNF-α, and interleukin-6 and anti-inflammatory mediator interleukin-10. The effect of the compounds on the overproduction of nitric oxide, prostaglandin E2, TNF-α, interleukin-6, and interleukin-10 was determined using Griess and ELISA methods. The results demonstrated that the in vitro anti-inflammatory activities of C20 epimeric ocotillol-type triterpenes and protopanaxadiol were different. Both the 20S-epimers (2 and 3) and 20R-epimers (9 and 10) inhibited the release of inflammatory mediator nitric oxide, while mainly the 20S-epimers inhibited the release of inflammatory mediator prostaglandin E2, and the 20R-epimers inhibited the release of inflammatory cytokine TNF-α. Both the 20S-epimers [2, 3, and 20(S)-protopanaxadiol] and 20R-epimers [9, 10, and 20(R)-protopanaxadiol] inhibited the release of inflammatory cytokine interleukin-6, but mainly the 20S-epimers [2, 3, and 20(S)-protopanaxadiol] increased the release of anti-inflammatory mediator interleukin-10.

Antidepressant‐like effects of 20(S)‐protopanaxadiol in a mouse model of chronic social defeat stress and the related mechanisms

“…Both P. notoginseng saponins and ginseng total saponins have significant antidepressant effects on LPS‐induced murine CD‐1 mouse models (An Kang et al, ; A. Kang et al, ) by reducing the mRNA levels of IL‐1β, IL‐6, TNF‐α, and indoleamine 2,3‐dioxygenase in the hippocampus. Moreover, PPD was recently found to protect against cerebral ischemia by inhibit inflammatory cytokine release in vitro (J. Zhang et al, ). Thus, it has been speculated that PPD exerts antidepressant‐like effects via the inhibition of the immune‐inflammatory, oxidative, and nitrosative stress pathways in the aetiology of depression, and this hypothesis needs to be explored in our future research.…”

The crystal structure of (3S,8R,10R,14R)-17-((2S,5S)-5-(2-hydroxypropan-2-yl)-2-methyltetrahydrofuran-2-yl)-4,4,8,10,14-pentamethyl-12-oxohexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate, C32H52O5

“…Comment 20(S)-ocotillol-type saponin sharing a tetrahydrofuran ring and a dammarane skeleton, are a class of rare ginsenosides [5], which was achieved by base degradation from leaves and stems of Panax quinquefolius and they play a key role in neuroprotection [6], antibacterial [7] and antitumor activities [8]. It has been reported to possess good potential for myocardial ischemia and myocardial injury [9,10].…”

The crystal structure of (8R,10R,12R,14R)- 12-hydroxy-16-(5-(2-hydroxypropan-2-yl)-2-methyltetrahydrofuran-2-yl)- 4,4,8,10,14-pentamethyltetradecahydro-3H- cyclopenta[a]phenanthrene-3,6(2H)-dione, C30H48O5

“…The ocotillol-type triterpenes are a rare kind of ginsenosides characterized by a tetrahydrofuran ring on the side chain [8][9][10][11]. It has been reported that ocotillol-type triterpenes have antibacterial, antioxidative, anti-inflammatory, neuroprotective and cardioprotective properties [12][13][14][15][16]. It is worth noting that the stereoconfiguration of the C-24 position may influence their stereoselectivity in pharmacological action and pharmacokinetics [17].…”