Two Undescribed Germacrane-Type Sesquiterpenoids from Salvia cavaleriei var. simplicifolia Stib. and Their Anti-Alzheimer's Disease Activity.

Two undescribed germacrane-type sesquiterpenoids, salcasins A (1) and B (2), together with three known compounds (3-5) were isolated and identified from the whole plant of Salvia cavaleriei var. simplicifolia Stib. The structures of the undescribed compounds were elucidated on the basis of spectroscopic methods, such as HR-ESI-MS, 1D and 2D NMR data. The relative configurations of 1 and 2 were established by analyzing their NOESY spectra as well as by 13C NMR calculations with DP4+ probability analyses. The absolute configurations of 1 and 2 were determined by comparing experimental and calculated ECD spectra. Furthermore, the in vivo anti-Alzheimer's disease activities of 1-5 were evaluated using Caenorhabditis elegans AD pathological model. Among all isolated compounds, salcasin A (1) significantly delayed AD-like symptoms of worm paralysis, which may be a potential anti-AD candidate agent.

Ethyl caffeate attefnuates Aß-induced toxicity in Caenorhabditis elegans AD models via the insulin/insulin-like growth factor-1 signaling pathway.

The pathogenesis of Alzheimer's disease (AD), a multifactorial progressive neurodegenerative disease associated with aging, is unclear. Ethyl caffeate is a plant polyphenol that has been reported to have neuroprotective effects, but the mechanisms by which it acts are unclear. In this study, for the first time, we investigated the molecular mechanism of its anti-AD properties using the Caernorhabditis elegans model. The results of our experiments showed that ethyl caffeate delayed the paralysis symptoms of CL4176 to a different extent and reduced the exogenous 5-hydroxytryptophan-induced paralysis phenotype. Further studies revealed that ethyl caffeate lowered Aß plaques and depressed the expression of Aß monomers and oligomers, but did not influence the mRNA levels of Aß. Moreover, it was able to bring paraquat-induced ROS levels down to near-standard conditions. Real-time quantitative PCR experiment showed a significant upregulation of the transcript abundance of daf-16, skn-1 and hsf-1, key factors associated with the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway (IIS), and their downstream genes sod-3, gst-4 and hsp-16.2. It was further shown that ethyl caffeate activated the translocation of DAF-16 and SKN-1 from the cytoplasm to the nucleus and enhanced the expression of sod-3::GFP, gst-4::GFP and hsp-16.2::GFP in transgenic nematodes. This meant that the protection against Aß toxicity by ethyl caffeate may be partly through the IIS signaling pathway. In addition, ethyl caffeate suppressed the aggregation of polyglutamine proteins in AM141, which indicated a potential protective effect against neurodegenerative diseases based on abnormal folding and aggregation of amyloid proteins. Taken together, ethyl caffeate is expected to develop as a potential drug for the management of AD.

Diterpenoid Caesalmin C Delays Aß-Induced Paralysis Symptoms via the DAF-16 Pathway in Caenorhabditis elegans.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the world. However, there is no effective drug to cure it. Caesalmin C is a cassane-type diterpenoid abundant in Caesalpinia bonduc (Linn.) Roxb. In this study, we investigated the effect of caesalmin C on Aß-induced toxicity and possible mechanisms in the transgenic Caenorhabditis elegans AD model. Our results showed that caesalmin C significantly alleviated the Aß-induced paralysis phenotype in transgenic CL4176 strain C. elegans. Caesalmin C dramatically reduced the content of Aß monomers, oligomers, and deposited spots in AD C. elegans. In addition, mRNA levels of sod-3, gst-4, and rpt-3 were up-regulated, and mRNA levels of ace-1 were down-regulated in nematodes treated with caesalmin C. The results of the RNAi assay showed that the inhibitory effect of caesalmin C on the nematode paralysis phenotype required the DAF-16 signaling pathway, but not SKN-1 and HSF-1. Further evidence suggested that caesalmin C may also have the effect of inhibiting acetylcholinesterase (AchE) and upregulating proteasome activity. These findings suggest that caesalmin C delays the progression of AD in C. elegans via the DAF-16 signaling pathway and that it could be developed into a promising medication to treat AD.

Cryptotanshinone Alleviates Oxidative Stress and Reduces the Level of Abnormally Aggregated Protein in Caenorhabditis elegans AD Models.

Alzheimer's disease (AD) is one of the leading causes of dementia. As the first common neurodegenerative disease, there are no effective drugs that can reverse the progression. The present study is to report the anti-AD effect of cryptotanshinone (CTS), a natural product isolated from Salvia castanea. It is found that it can alleviate AD-like features associated with Aß1-42 toxicity in muscle cells as well as neuronal cells of Caenorhabditis elegans (C. elegans). Further studies showed that CTS reduced the level of reactive oxygen species (ROS) in nematodes, up-regulated the expression of sod-3, and enhanced superoxide dismutase activity. Cryptotanshinone reduced the level of Aß monomers and highly toxic oligomers in C. elegans while inhibiting the abnormal aggregation of polyglutamine protein. In addition, CTS upregulated the expression of hsp-16.2 and downregulated the expression of ace-2. These results suggested that CTS could alleviate oxidative stress and reduce the level of abnormally aggregated proteins and has the potential to be developed as an anti-AD drug candidate.

Isolation, Characterization, and Possible Anti-Alzheimer's Disease Activities of Bisabolane-Type Sesquiterpenoid Derivatives and Phenolics from the Rhizomes of Curcuma longa.

One new bisabolane-type sesquiterpenoid, together with four known bisabolane-type sesquiterpenoid derivatives and seven phenolics, was isolated from the rhizomes of Curcuma longa. Their structures were elucidated by extensive spectroscopic (IR, HR-ESI-MS, and NMR) data analysis. The possible anti-Alzheimer's disease (AD) activities of the isolated compounds were also evaluated using Caenorhabditis elegans AD pathological model, and 1ß-hydroxybisabola-2,10-dien-4-one had the highest possible anti-AD activity.

Eupulcherol A, a triterpenoid with a new carbon skeleton from Euphorbia pulcherrima, and its anti-Alzheimer's disease bioactivity.

Eupulcherol A (1), a novel triterpenoid with an unprecedented carbon skeleton, was isolated from Euphorbia pulcherrima. Its structure was determined by comprehensive analysis of spectroscopic data, including HRESIMS and 1D and 2D NMR, and the absolute configuration was defined by single crystal X-ray diffraction analysis. Biological studies showed that compound 1 possessed anti-Alzheimer's disease (AD) bioactivity, which could delay paralysis of transgenic AD Caenorhabditis elegans. A plausible biogenetic pathway for eupulcherol A (1) was also proposed.

Four novel sesquiterpenoids with their anti-Alzheimer's disease activity from Nardostachys chinensis.

Nardochinins A-D (1-4), four novel sesquiterpenoids, along with four known ones were isolated from the underground parts of Nardostachys chinensis Batal in ethanol. Their structures were determined by extensive spectroscopic methods and single-crystal X-ray diffraction. Nardochinin A (1) possessed a norsesquiterpene skeleton with an unusual 3/6/5/5 tetracyclic ring system, which had not appeared in natural products. Nardochinins B (2) and C (3) were the first time found naturally occurring sesquiterpenoids with a 4,5-seco-nardosinane skeleton. Besides, compound 3 represented an unprecedented 4,5-seco-nardosinane type norsesquiterpenoid with losing an isopropenyl at C-6 compared with 2 in the structural framework. Nardochinin D (4) was a novel, highly oxygenated valerenane-type sesquiterpenoid possessing a rare 3,12-epoxy group and an unusual 9,11-epoxy group. The anti-Alzheimer's disease (AD) activities of 1-4 were also evaluated using the Caenorhabditis elegans AD pathological model, and nardochinin B (2) had the highest anti-AD activity.

Norcrassin A, a novel C16 tetranorditerpenoid, and bicrotonol A, an unusual dimeric labdane-type diterpenoid, from the roots of Croton crassifolius.

A novel C16 tetranorditerpenoid, norcrassin A (1), and an unusual dimeric labdane-type diterpenoid, bicrotonol A (2), were isolated from the roots of Croton crassifolius. Norcrassin A (1) featured a new carbon skeleton with an unprecedented 5/5/5/6 tetracyclic system. Bicrotonol A (2) possessed an unusual tetrahydroxypyran ring linkage connecting two labdane diterpenoid monomers. The structures of all compounds, including the absolute configuration, were elucidated by the interpretation of their NMR spectroscopic data, high resolution mass spectrometry, and single-crystal X-ray diffraction. A plausible biosynthetic pathway of 1 is proposed. The anti-Alzheimer's Disease (AD) activities of 1 and 2 are also evaluated using the AD pathological model.

A new norsesquiterpenoid from Ligularia virgaurea.

A new eremophilane norsesquiterpenoid (1), together with a known eremophilane sesquiterpenoid (2), was isolated from the leaves of Ligularia virgaurea. The structure of 1 was elucidated by a combination of spectroscopic analysis (IR, 1D NMR, 2D NMR, and HR-ESI-MS), and its absolute configuration was determined by a single-crystal X-ray diffraction experiment (with copper radiation). The known compound 2 was identified by comparison of its physical and spectral data with those reported in the literature. Compound 1 was assayed for its cytotoxic activities against human cervical carcinoma cell (HeLa) and human small cell lung cancer cell (NCI-446) lines.

8ß-Eth-oxy-eremophil-3,7(11)-diene-8α,12;6α,15-diolide.

The title compound, C17H20O5, an eremophilane sesquiternoid, was isolated from the roots of Ligularia lapathifolia. The mol-ecule contains four fused rings of which the six-membered ring A adopts a half-chair conformation, the six-membered ring B adopts a chair conformation, the five-membered ring C is almost planar (r.m.s. deviation = 0.015 Å) and the five-membered ring D adopts an envelope conformation with the quaternary C atom as the flap. The methyl and the eth-oxy groups adopt a syn conformation and the A/B ring junction is cis-fused. No directional inter-molecular inter-actions could be identified in the crystal.

Antimicrobial diterpenoids from the leaves and twigs of Croton kongensis Gagnepain.

Croton kongensis Gagnepain. belongs to the genus Croton, the Euphorbiaceae family, mainly distributed in Hainan and southern Yunnan, China. The aim of present study was to acquire secondary metabolites of the ethanol extract obtained from the leaves and twigs of C. kongensis. Three new abietane-type diterpenoids, crokongenolides A-C (1-3), together with seven known diterpenoids (4-10), were isolated from the leaves and twigs of C. kongensis. The structures of the new compounds were determined by extensive spectroscopic methods (1D and 2D NMR, IR, and HRESIMS), and their absolute configurations were confirmed by single-crystal X-ray diffraction analysis or electronic circular dichroism (ECD) calculations. The absolute configuration of 4 was determined for the first time by single-crystal X-ray diffraction analysis with Cu-Kα irradiation. Some compounds were evaluated for their antimicrobial properties by assessing their inhibitory effects on Staphylococcus aureus, Candida albicans, and Escherichia coli. Compound 10 showed significant antimicrobial activity against S. aureus with MIC value of 1.56 µg/ml.

Bioactive diterpenoids and sesquiterpenoids with different skeletons from Salvia digitaloides Diels.

Salvia has been regarded as a beneficial healing herb in ancient Egypt, Rome and Greece, and is listed as an official medicine in the pharmacopoeias of many countries worldwide. Currently, Salvia is widely used to flavor and preserve food. Here, two undescribed norabietane-type diterpenoids, sadigitaloides A and B, two undescribed germacrane-type sesquiterpenoids, sadigitaloides C and D, five undescribed guaiane-type sesquiterpenoid lactones, sadigitaloides E-I, two undescribed noreudesmane-type sesquiterpenoids, sadigitaloides J and K, one known diterpenoid, three known sesquiterpenoids, and three other types of known compounds were isolated from the 95% ethanol extract of the whole plants of Salvia digitaloides. Their structures and absolute configurations were characterized using 1D and 2D NMR spectroscopic techniques, electronic circular dichroism (ECD) calculations, HRESIMS experiments, and single-crystal X-ray diffraction analysis. Some compounds were evaluated for their anti-inflammatory activities against lipopolysaccharide (LPS)-induced TNF-α production in rat macrophage NR8383 cells. Sadigitaloide A showed noticeable anti-inflammatory activity at a concentration of 100.0 µM. At a concentration of 60 µM, sadigitaloide B exhibited better protection of dopaminergic neurons than the positive control n-butylidenephthalide in the Caenorhabditis elegans model injured by 6-OHDA. The phytotoxic activities of some compounds were attributed to considerable inhibitory effects on the growth of the roots and hypocotyls of Raphanus sativus L seedlings, especially cis, trans-abscisic acid, whose inhibition rates were much higher than those of glyphosate at concentrations ranging from 50 to 400 ppm. These results indicated that abietane-type diterpenoids possessed excellent anti-inflammatory and neuroprotective activities and further suggested that the low-molecular-weight compounds exhibited outstanding phytotoxic activities.

Highly oxygenated germacrane-type sesquiterpenoids from the whole plant of Salvia cavaleriei H.Lév. and their biological activities.

The entire plant Salvia cavaleriei H.Lév. (Lamiaceae) is used as a traditional Chinese herbal medicine. Its leaves are edible, and the flowers can be soaked in water to make a health-care tea. In an effort to find natural bioactive chemical components, twelve undescribed germacrane-type sesquiterpenoids, salcavalins A-L, were isolated from the whole plant of S. cavaleriei and were identified as analogs. This is the first study to isolate highly oxygenated germacrane-type sesquiterpenoids from this plant. The structures of these undescribed compounds were elucidated by various spectroscopic methods, and their absolute configurations were confirmed by single-crystal X-ray diffraction analysis with Cu Kα radiation and electronic circular dichroism calculations. The biological activity of these undescribed compounds on the production of tumor necrosis factor-alpha in lipopolysaccharide induced NR8383 cells was evaluated, and salcavalins I and K showed anti-inflammatory activity to some extent. Salcavalins A-C, F and L were found to be neuroprotective with antiparkinsonic potential in a nematode (Caenorhabditis elegans) model. In addition, salcavalins F and I displayed marked phytotoxic activity against radish seeds at a low concentration of 50 ppm. Our findings provide scientific justification to show that bioactive sesquiterpenoids from the edible herb have anti-inflammatory in vitro, neuroprotective and phytotoxic activities.

Diterpenoids and C13 Nor-Isoprenoid Identified From the Leaves and Twigs of Croton yanhuii Activating Apoptosis and Pyroptosis.

Croton yanhuii (Family Euphorbiaceae) is an annual aromatic plant endemic to Yunnan Province, China, which yields an aromatic, spicy oil used as a flavoring and fragrance. The aim of the present study was to acquire secondary metabolites from the leaves and twigs of C. yanhuii and to evaluate their cytotoxic activity. Five new diterpenoids, croyanhuins A-E (1-5), and one new C13 nor-isoprenoid, croyanhuin F (6), were isolated from the leaves and twigs of C. yanhuii. Their structures and absolute configurations were determined by extensive spectroscopic methods (1D and 2D NMR, IR, and HRESIMS) and confirmed by electronic circular dichroism (ECD) spectra or single-crystal X-ray diffraction analysis. Among the new terpenoids, compounds 1 and 3 inhibited cell proliferation and viability in a dose- and time-dependent manner, whereas both induced cleavage of either caspase-3 or PARP-1 in the SW480 cell line. Additionally, we observed that Z-YVAD-FMK and Z-VAD-FMK, two caspase inhibitors, inhibited the compound-dependent cell viability loss, suggesting that either of them can induce pyroptosis and caspase-dependent apoptosis. These biological assay results revealed that compounds 1 and 3 induce different kinds of programmed cell death in SW480 cells.

Caesalpinbondin A, a Novel Diterpenoid Lactone With an Unprecedented Carbon Skeleton from the Seeds of Caesalpinia bonduc.

One novel diterpenoid lactone named caesalpinbondin A (1) that possesses an unprecedented tetracyclic ring system in which a 6/6/5-fused tricyclic ring and a 4,5-dimethyldihydrofuran-2(3H)-one were connected by a C-C single bond comprising a 5-(naphtho [2,3-b]furan-7-yl)dihydrofuran-2(3H)-one moiety was isolated from the seeds of Caesalpinia bonduc. Its chemical structure was established by extensive spectroscopic methods, and its absolute configuration was further determined by single-crystal X-ray diffraction analysis and electronic circular dichroism calculation. The biological evaluation suggested that compound 1 demonstrated potent anti-Alzheimer's disease (AD) bioactivity, which could delay paralysis of transgenic AD Caenorhabditis elegans. A possible biogenetic pathway of 1 was also proposed.

Diterpenoids with α-glucosidase inhibitory activities from the fruits of Vitex trifolia Linn.

Viticis Fructus, known as "Man-jing-zi", are the fruits of the traditional Chinese medicine Vitex trifolia Linn. and its variant Vitex trifolia Linn. var. simplicifolia. These fruits are used as folk medicines to treat various diseases. Although V. trifolia is useful for treating diabetes, the antidiabetic effect of its purified constituents is still under investigation. The phytochemical investigation on the ethanol extract of the fruits of V. trifolia yielded four new labdane diterpenoids vitetrolins A-D (1-4), together with seven (5-11) known analogs. The structures of these compounds were elucidated by spectroscopy techniques and the absolute configuration of 4 was determined by electronic circular dichroism (ECD) calculations. The isolated diterpenoids were evaluated for their α-glucosidase inhibitory activities. Compounds 5, 6, 8, and 9 exhibited moderate inhibitory activities against α-glucosidase with IC50 values ranging from 44.9 ± 6.1 to 70.5 ± 5.5 µM.

A new diterpenoid from the leaves and twigs of Croton lachnocarpus Benth.

A new clerodane diterpenoid, crotolanin A (1), along with three known clerodane diterpenoids, crotoeurin B (2), teucvidin (3) and teucvin (4), was isolated from the ethanol extract of the leaves and twigs of Croton lachnocarpus Benth. Their structures were identified by extensive NMR spectroscopic and HRESIMS analyses. The dopaminergic neuroprotective activity of compounds 1-4 was tested by using transgenic Caenorhabditis elegans pathological model. Compound 2 alleviated dopaminergic neuron degeneration of worms induced by 6-hydroxydopamine (6-OHDA) that represented a potential therapy for Parkinson's disease (PD).

A new highly oxygenated germacranolide from Carpesium nepalense var. lanatum (C.B.Clarke) Kitam.

A new highly oxygenated germacranolide, carcerlane A (1), together with four known highly oxygenated germacranolides (2-5), was isolated from an ethanol extract of the whole plant of Carpesium nepalense var. lanatum (C.B.Clarke) Kitam. The structures were determined by HRESIMS and extensive analysis of their spectroscopic data including IR, 1 D and 2 D NMR spectra. To our best knowledge, it was the first time to report the phytochemical investigation on this plant. The anti-Alzheimer's disease (AD) activities of 1-5 were evaluated using Caenorhabditis elegans AD pathological model. All the tested compounds showed that they have the anti-AD bioactivities of delaying worms paralysis.

Two new aromatic derivatives from Codonopsis pilosula and their α-glucosidase inhibitory activities.

The ethanol extract of the roots of Codonopsis pilosula was subjected to chromatographic fractionation, which result in the isolation and characterization of two new aromatic derivatives 2,3-dihydroxypropyl 2,4-dihydroxy-3,6-dimethylbenzoate (1) and 2-oxopropyl 3-hydroxy-4-methoxybenzoate (2), along with three known compounds pilosulinene A (3), pollenfuran B (4) and (+)-pinoresinol (5). Their structures were demonstrated by HRESIMS and spectroscopic methods including NMR and IR. It is worth noting that compound 4 was isolated for the first time from the genus Codonopsis. The potential hypoglycemic properties of compounds 2-5 were evaluated by measuring their α-glucosidase inhibitory effects. As a result, compounds 2 and 3 showed weak α-glucosidase inhibitory activities with IC50 values of 154.8 ± 11.0 µM and 24.0 ± 2.2 µM, respectively.[Formula: see text].

6ß,8ß-Dihy-droxy-eremophil-7(11)-en-8α,12-olide.

The title compound, C(15)H(22)O(4), an eremophilane sesquiternoid, was isolated from the roots of Ligularia virgaurea. Both six-membered rings (A and B) adopt chair conformations and the five-membered ring is almost planar (r.m.s. deviation = 0.016 Å). The two methyl and two hy-droxy groups adopt a syn conformation and the A/B ring junction is cis-fused. An intra-molecular O-H⋯O hydrogen bond generates an S(6) ring. In the crystal, O-H⋯O hydrogen bonds link the mol-ecules into [100] chains.