Anti-Hyperlipidemic sesquiterpenes and new sesquiterpene glycosides from the leaves of artichoke (Cynara scolymus L.): structure requirement and mode of action
The methanolic extract from the leaves of artichoke (Cynara scolymus L.) was found to suppress serum triglyceride elevation in olive oil-loaded mice. Through bioassay-guided separation, sesquiterpenes (cynaropicrin, aguerin B, and grosheimin) were isolated as the active components together with new sesquiterpene glycosides (cynarascolosides A–C). The oxygen functional groups at the 3- and 8-positions and exo-methylene moiety in α-methylene-γ-butyrolactone ring were found to be essential for the anti-hyperlipidemic activity of guaiane-type sesquiterpene. In addition, inhibition of gastric emptying was clarified to be partly involved in anti-hyperlipidemic activity.
Introduction
Artichoke (Cynara scolymus L., Compositae) is widely cultivated in Europe and America and its sprout is eaten as a vegetable. The leaves of artichoke are used for the treatment of hepatitis and hyperlipidemia in European traditional medicine. As various pharmacological activities of the constituents and extract from the leaves of artichoke, polyphenols such as cynarin, caffeic acid, chlorogenic acid, and luteolin were reported to inhibit oxidative stress generated by reactive oxygen species in human leukocytes.1 Cynaroside inhibited hepatic cholesterol biosynthesis without affecting hydroxymethylglutaryl (HMG)-CoA reductase activity in rat hepatocytes2 and cynaropicrin inhibited contraction of rabbit isolated thoracic aorta.3 The leaves of artichoke were also reported in various clinical trials to be effective for patients with irritable bowel syndrome4 and hyperlipoproteinemia,5 and to show choleretic effects.6
To clarify the anti-hyperlipidemic effect of artichoke, we examined the effect of methanolic (MeOH) extract and several components from the leaves of artichoke in olive oil-loaded mice. Furthermore, we also examined the structural requirements of the active constituents for anti-hyperlipidemic activity and mode of action.
Section snippets
Anti-Hyperlipidemic Activity of the Methanolic Extract from the Leaves of Artichoke
The dried leaves of artichoke (1.0 kg, cultivated in Peru) were extracted with MeOH three times under reflux for 3 h to give MeOH extract (33.1% from the dried leaves). As shown in Figure 1, the MeOH extract (125–500 mg/kg, po) significantly suppressed serum triglyceride (TG) elevation 2 h after administration of olive oil. In contrast, 6 h after administration of olive oil, increases in TG level were observed in the groups that received the extract at doses of 125 and 250 mg/kg. Orlistat, a lipase
Isolation of Cynarascolosides A–C (1–3) from the Leaves of Artichoke
The methanolic extract was partitioned into ethyl acetate (AcOEt) and water to give an AcOEt-soluble fraction (5.7%) and an aqueous layer. The aqueous layer was further extracted with n-butanol (n-BuOH) to give an n-BuOH-soluble fraction (3.9%) and a H2O-soluble fraction (23.5%). The AcOEt-soluble fraction (250 mg/kg, po) significantly suppressed the increase in serum TG 63% (P<0.05) 2 h after administration of olive oil. On the other hand, the n-BuOH and H2O-soluble fractions did not show such
Absolute Stereostructures of Cynarascolosides A–C (1–3)
Cynarascoloside A (Chart 1, Figure 2), was isolated as colorless plates of mp 246–248 °C (MeOH) with negative optical rotation ( −43.7°). The positive- and negative-ion FAB-MS of Chart 1, Figure 2 showed quasimolecular ion peaks at m/z 857 (2M+H)+, 429 (M+H)+, 855 (2M–H)−, and 427 (M–H)−, and high-resolution MS analysis of the quasimolecular ion peak (M+H)+ revealed the molecular formula of Chart 1, Figure 2 to be C21H32O9. The IR spectrum of Chart 1, Figure 2 showed absorption bands at 3436
Structural Requirements of the Active Constituents for Anti-Hyperlipidemic Activity and Mode of Action
We examined the anti-hyperlipidemic activity of the principal constituents from the leaves of artichoke. As shown in Figure 5, the sesquiterpene constituents (4–6) significantly suppressed serum TG elevation at 50 and 100 mg/kg during the early stage (2 h after olive oil administration). The activity of cynaropicrin (4), a principal sesquiterpene in artichoke, was the most potent among them. On the other hand, sesquiterpene glycosides (Chart 1, Figure 2, Chart 1, Figure 2, and 7) did not suppress
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