New indolizidine- and pyrrolidine-type alkaloids with anti-angiogenic activities from Anisodus tanguticus.

Eleven alkaloids, including five previously undescribed indolizidine alkaloids (1, 2a, 2b, 3a, and 3b) and four new pyrrolidine alkaloids (5-8), were isolated from the roots of Anisodus tanguticus. Of these, two new pairs of enantiomeric alkaloids (2a/2b and 3a/3b) are the first examples of alkaloids containing both indolizidine and pyrrolidine structural fragments. The one-carbon bridge connections with two pyrrolidine rings (6) or with a pyrrolidine ring and a pyridine ring (8) are the first reported from nature. Extensive spectroscopic techniques were used to elucidate their structures, and NMR and ECD calculations were used to determine the absolute configurations. The viability of human umbilical vein endothelial cells (HUVECs) was inhibited by compounds 2a, 2b, 3a, 4b, and 5, and compound 2b exhibited a potential anti-angiogenic effect by inhibiting the proliferation, migration, and tube formation of HUVECs. A chorioallantoic membrane assay also demonstrated the anti-angiogenic activity of 2b. In addition, compounds 2a, 2b, 3a, and 4b exhibited moderate cytotoxicity against A2780 cells.

Germacrane-type sesquiterpenoids from the flowers of Chrysanthemum indicum with hepatoprotective activity.

Two new germacrane-type sesquiterpenoids, chrysanthemolides A (1) and B (2), and four known germacrane-type sesquiterpenoids, hanphyllin (3), 3ß-hydroxy-11α,13-dihydro-costunolide (4), costunolide (5), and 6,7-dimethylmethylene-4-aldehyde-1ß-hydroxy-10(15)-ene-(4Z)-dicyclodecylene (6), were isolated and identified from the flowers of Chrysanthemum indicum. The structures of the new compounds were elucidated via high resolution electrospray ionization mass spectrometry (HR-ESI-MS), 1D and 2D nuclear magnetic resonance (NMR) spectra and electronic circular dichroism (ECD). Meanwhile, all the isolates were tested for their hepatoprotective activity in tert-butyl hydroperoxide (t-BHP) injured AML12 cells. Compounds 1, 2, and 4 showed significant protective effects at 40 µM, comparable with the positive control resveratrol at 10 µM. As the most potent one, compound 1 was chosen for further studies. Compound 1 dose-dependently increased the viability of t-BHP-injured AML12 cells. Furthermore, compound 1 decreased reactive oxygen species accumulation, while increased glutathione level, heme oxygenase-1 level and superoxide dismutase activity, through anchoring in the binding site of Kelch domain of the Kelch-like ECH-associated protein 1 (Keap1) to promote the dissociation of nuclear factor erythroid 2-related factor 2 from Keap1 and translocation to nuclei. In summary, germacrane-type sesquiterpenoids from C. indicum might be further developed to protect liver against oxidative damage.

Curcumanes E and F, two rare sesquiterpenoids with a dicyclo[3.3.1]nonane moiety, from Curcuma longa and their vasorelaxant activities.

Two new sesquiterpenoids, curcumanes E (1) and F (2), were isolated from the rhizome of Curcuma longa, and their structures and absolute configurations were examined using extensive spectroscopic analyses and ECD calculations. Interestingly, compounds 1 and 2 are diastereoisomers possessing a rare sesquiterpenoid skeleton that has been reported only once before. Both curcumanes E and F exhibit significant vasorelaxant effects against KCl-induced contraction of rat aortic rings, with EC50 values of 5.10 ± 0.79 and 5.58 ± 1.77 µM, respectively. These findings enrich the data concerning this rare type of sesquiterpenoids and further indicate that these rare sesquiterpenoids can effectively reduce blood pressure.

Six pairs of enantiomeric phthalide dimers from the rhizomes of Ligusticum chuanxiong and their absolute configurations and anti-inflammatory activities.

Six pairs of enantiomeric phthalide dimers (1-6) were isolated from the rhizomes of Ligusticum chuanxiong. Their structures and absolute configurations were elucidated by NMR spectroscopy, X-ray diffraction analyses, and electronic circular dichroism calculations. Compounds (+)-1 and (-)-1 are new phthalide dimers, featuring two classes of monomeric units (a phthalide and an unusual 2,3-seco-phthalide) with an uncommon linkage (3,6'/8,3'a). Compounds (+)-2 and (-)-3 are also novel phthalide dimers that had not been reported previously. Although (-)-2 and (+)-3 have been successfully isolated in previous studies, their absolute configurations were not unambiguously determined. As for compound 4, it was reported as a racemate in one study, and one of its enantiomers was identified in a subsequent study. Herein, all enantiomeric phthalide dimers were successfully separated, and their absolute configurations were determined. The inhibitory effects of all isolates against lipopolysaccharide-induced nitric oxide production were tested using RAW264.7 cells. The results show that compounds (+)-2, (-)-2, (+)-3, (-)-3, (+)-4, (-)-4, (+)-5, (+)-6, and (-)-6 have inhibitory activities, with compound (+)-5 being the most active (IC50 value of 4.3 ± 1.3 µM).

Vasorelaxant effect of curcubisabolanin A isolated from Curcuma longa through the PI3K/Akt/eNOS signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Curcuma longa L. (Zingiberaceae) is a known blood-activating and stasis-removing traditional Chinese medicine and has relevant pharmacological properties. The rhizomes of C. longa have been used for the treatment of cardiovascular disease (CVD) in China. Previous studies have shown that sesquiterpenoids from C. longa have significant vasorelaxant effects, which are closely associated with the prevention and treatment of CVD. AIM OF THE STUDY: To explore the sesquiterpenoids with vasorelaxant effects from C. longa and investigate the underlying mechanisms. MATERIALS AND METHODS: The compound was isolated from C. longa by multiple chromatography technologies. Its structure was determined by extensive spectroscopic analyses, nuclear magnetic resonance (NMR) data calculations, electronic circular dichroism (ECD) data calculations, and optical rotation (OR) data calculations. The vasorelaxant effect of the isolated compound was evaluated by KCl- or phenylephrine (PHE)-inducing contraction of the rat thoracic aortic rings. Endothelial removal and L-NAME pretreatment experiments were used to verify the endothelium-dependent vasorelaxant effect of the isolated compound in rat thoracic aortic rings. NO production was monitored in human umbilical vein endothelial cells (HUVECs). Western blot was carried out in HUVECs to elucidate the potential mechanisms. RESULTS: A new bisabolane-type sesquiterpenoid, curcubisabolanin A [(+)-(1S,7S,9E)-bisabola-2(3),4(15),9(10)-trien-11-ol], was isolated from the rhizomes of C. longa. curcubisabolanin A exhibited endothelium-dependent relaxation on rat thoracic aortic rings, while pre-treatment of intact aortic rings with an eNOS inhibitor (L-NAME) attenuated the vasorelaxant response of curcubisabolanin A. In addition, curcubisabolanin A induced intracellular NO production and significantly increased the levels of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), and phosphorylated eNOS (p-eNOS) in HUVECs. LY294002 (a blocker of PI3K) and MK-2206 (a highly selective inhibitor of Akt) significantly decreased these effects of curcubisabolanin A. CONCLUSIONS: These findings demonstrated that the vasorelaxant effect of curcubisabolanin A was partially endothelium-dependent and was related to regulation of NO production in vascular endothelial cells through the PI3K/Akt/eNOS signaling pathway.

Isoindolines and phthalides from the rhizomes of Ligusticum chuanxiong and their relaxant effects on the uterine smooth muscle.

Three undescribed isoindoline alkaloids, (+)-(R)-3-butyl-3-ethoxyisoindolin-1-one, (+)-(3S,6S,7R)-3-butyl-6,7-dihydroxy-3-methoxy-4,5,6,7-tetrahydroisoindolin-1-one, and (-)-(3R,6S,7R)-3-butyl-6,7-dihydroxy-3-methoxy-4,5,6,7-tetrahydroisoindolin-1-one, along with nine known phthalides were isolated from a water decoction of the rhizomes of Ligusticum chuanxiong using chromatographic methods. Their structures and absolute configurations were determined by extensive spectroscopic analyses and ECD data calculations. The relaxant effects of the isolated compounds on uterine contractions induced by oxytocin were investigated using a rat uterine smooth muscle contraction model. Furthermore, the effects of riligustilide on extracellular Ca2+ influx and intracellular Ca2+ release were assessed using high-KCl solution-induced and oxytocin-induced uterine smooth muscle contraction in a Ca2+-free balanced salt solution. The results showed that all the tested phthalides had inhibitory effects on oxytocin-induced uterine smooth muscle contraction. Riligustilide, a phthalide dimer, was the most active. Further examinations indicated that riligustilide reduced uterine smooth muscle contraction by inhibiting extracellular Ca2+ influx and intracellular Ca2+ release.

Bisabolane-type sesquiterpenoids: Structural diversity and biological activity.

Bisabolane-type sesquiterpenoids, a class of monocyclic sesquiterpenoids, are widely distributed in nature and have a variety of biological activities. To provide a reference for the further research and development of these compounds, the phytochemical and biological properties of natural bisabolane-type sesquiterpenoids (356 compounds in total) isolated between 1985 and 2020 from 24 families, primarily Compositae, Zingiberaceae, Aspergillaceae, Halichondriidae, and Aplysiidae were reviewed. In vitro and in vivo studies have indicated that antibacterial, anti-inflammatory, and cytotoxic effects are the most commonly reported pharmacological properties of bisabolane-type sesquiterpenoids. Owing to their extensive significant effects, a lot of traditional medicines containing this type of compounds have been used for a long history. Thus, bisabolane-type sesquiterpenoids are a rich source of important natural products, which show great potential for the development of new drugs.

New lignans from the fruits of Leonurus japonicus and their hepatoprotective activities.

Twelve tetrahydrofuran lignans (1-12), including six new compounds (1-6), were isolated from the 70% EtOH extract of the fruits of Leonurus japonicus. Spectroscopic analyses and ECD and OR calculations were used to determine their structures. Compounds 5 and 6 were unusual alkaloidal lignans with a butyrolactam unit. Based on the beneficial effects of the fruits of L. japonicus (Chongweizi in Chinese) on the liver in traditional Chinese medicine (TCM), the hepatocyte protective activities of the isolates were studied by MTT, Hoechst 33,342 staining, and western blotting. The MTT results revealed that compounds 1, 2, 7, and 8 significantly increased the survival rates of HL-7702 cells injured by acetaminophen, with EC50 values of 10.41 ± 0.90 µM, 19.86 ± 3.13 µM, 9.68 ± 1.93 µM, and 21.35 ± 3.58 µM, respectively. In the Hoechst 33,342 fluorescence staining, compounds 1 and 7 suppressed the apoptosis of the injured HL-7702 cells. Furthermore, the western blot analysis showed that compounds 1 and 7 increased the Bcl-2/Bax protein expression ratio and procaspase-3 protein expression, indicating that compounds 1 and 7 may exert hepatoprotective activity by regulating the mitochondrial apoptotic pathway.