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(-)-β-Elemene is a primary bioactive compound derived from Curcuma wenyujin and has been widely utilized as an anti-tumor agent for various types of cancer. Due to the inefficiency of plant extraction methods for β-elemene, significant efforts have been directed toward the heterogeneous biosynthesis of β-elemene using microbial cell factories. However, there has been less emphasis on the stereochemical configuration of germacrene A and its rearranged product, β-elemene. In this study, we constructed a yeast cell factory to produce (-)-β-elemene by optimizing the mevalonate pathway and screening for germacrene A synthases (GASs) from both plant and microbial sources. Notably, we discovered that the rearranged products of GASs exhibited different conformations, and only (+)-germacrene A produced by plant-derived GASs could rearrange to form (-)-β-elemene. Building on this discovery, we further investigated the catalytic mechanisms of GASs and developed an efficient catalytic gene module for generating (+)-germacrene A. Ultimately, the engineered yeast produced 1152 mg/L of (-)-β-elemene, marking the highest titer reported in yeast to date. Overall, this work highlights the differences in the stereoconformations of catalytic products between plant- and microbial-derived germacrene A synthases and establishes a foundation for the green and efficient production of β-elemene with a specific stereochemical configuration., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Leonotis nepetifolia (L.) R. Br. (Lamiaceae) is a naturalised medicinal plant in Brazil known as 'cordão-de-frade', being used in folk medicine for the treatment of a variety of conditions such as infections and inflammations. L. nepetifolia leaf and flower essential oils were isolated by hydrodistillation, and their compounds were identified by GC-MS analysis. The leaf essential oil major constituents were germacrene D (31.5%), and β-caryophyllene (19.2%), while in flower essential oil the main constituents were β-elemene (31.2%), and germacrene D (12.1%). The essential oils were investigated against a broad spectrum of bacteria and fungi using the microdilution method, exhibiting MIC 50 values of 3.93-250 µg mL -1 . Both oils showed excellent antifungal properties, which is a very important finding since most fungi have shown increased resistance to known antifungal agents. According to these results, the essential oils of L. nepetifolia are promising sources of new antimicrobial agents, especially for yeast.

Abnormal melanin synthesis causes hyperpigmentation disorders, such as chloasma, freckles, and melanoma, which are highly multiple and prevalent. There were few reports on the anti-melanogenic effect of Curcuma wenyujin Y.H. Chen et C. Ling, and the bioactive compound has not been elucidated as well. The study aims to investigate the anti-melanogenic effect of C. wenyujin, and identify the bioactive compound, and further explore its underlying mechanism. Our results showed that the Petroleum ether fraction extracted from C. wenyujin rhizome had a significant anti-melanogenic effect, and germacrone isolated from it was confirmed as the major bioactive compound. To our data, germacrone significantly inhibited tyrosinase (TYR) activity, reduced melanosome synthesis, reduced dendrites formation of B16F10 cells, and melanosome transport to keratinocytes. Moreover, germacrone effectively decreased the hyperpigmentation in zebrafish and the skin of guinea pigs in vivo. Western-blot analysis showed that germacrone down-regulated the expression of TYR, TRP-1, TRP-2, Rab27a, Cdc42, and MITF proteins via the activation of the MAPK signaling pathway. Taken together, germacrone is an effective bioactive compound for melanogenesis inhibition. Our studies suggest that germacrone may be considered a potential candidate for skin whitening., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

The first systematic investigation of germacrane-type sesquiterpenes from Pilea cavaleriei Levl. subsp. cavaleriei was conducted. Eleven undescribed germacrane analogues named cavalinols A-K were identified. Their planar structures were determined by extensive analysis of 1D and 2D NMR spectroscopic data, and the absolute configurations were further determined by X-ray single crystal diffraction, Mosher method, and time dependent density functional theory (TDDFT) electron circular dichroism (ECD) calculation, with the aid from DFT NMR calculation and NOESY experiment. Except for the common 10-memebered ring, ten new compounds contained a p-coumaroyl sidechain connected to C-8 of the nucleus skeleton. All the isolated compounds were screened for anti-inflammatory activity in LPS stimulated RAW 264.7 cells, and compounds 5 and 6 showed moderate activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Artemisia plants are well-known for their abundant sesquiterpene compounds, which encompass various structural types and exhibit a range of biological activities. In this study, a systematic investigation of Artemisia atrovirens revealed the presence of germacrane-type sesquiterpenes for the first time. This included the discovery of 10 new compounds and three known analogues, among which were two rare dimeric germacrane-type compounds. Their structures were fully characterized through a comprehensive analysis involving MS, IR, 1D- and 2D-NMR spectroscopic data, single crystal X-ray diffraction, density functional theory (DFT) NMR calculations, and time-dependent DFT electronic circular dichroism (TDDFT ECD) calculations. Furthermore, all isolated compounds were evaluated for their anti-inflammatory activity in LPS-stimulated RAW 264.7 murine macrophages. Compound 10 demonstrated a potent inhibitory effect on NO production, with an IC 50 value of 4.01 ± 0.09 μM. This study highlights the diverse chemical repertoire of Artemisia species and underscores their potential in drug discovery and development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Trilobolide and its analogues belong to the guaianolide type of sesquiterpene lactones, which are characteristic and widely distributed within the families Asteraceae and Apiaceae. Certain guaianolides are receiving continuously increasing attention for their promising sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA)-inhibitory activity. However, because of their alkylation capabilities, they are generally toxic. Therefore, the search for compounds with significant immunobiological properties but with decreased cytotoxicities suitable for use in immune-based pharmacotherapy is ongoing. Therefore, we extended our previous investigation of the immunobiological effects of trilobolide to a series of structurally related guaianolides and germacranolides. To evaluate the relationship, we tested a series of selected derivatives containing α-methyl lactone or exomethylene lactone ring. For a wider comparison, we also included some of their glycosidic derivatives. We assessed the in vitro immunobiological effects of the tested compounds on nitric oxide (NO) production, cytokine secretion, and prostaglandin E2 (PGE2) release by mouse peritoneal cells, activated primarily by lipopolysaccharide (LPS), and evaluated their viability. The inhibitory effects of the apparently most active substance, 8-deoxylactucin, seem to be the most promising.

The genus Knema Lour. is distributed mainly in Southeast Asian and widely used in folk medicine for treating diseases such as jaundice, chronic fever, and inflammation. The chemical composition, acetylcholinesterase inhibition, and molecular docking studies of essential oil from Knema hookeriana Warb. were investigated in this study. The essential oil was achieved through hydrodistillation and was characterised using gas chromatography (GC-FID) and gas chromatography-mass spectrometry (GC-MS). The acetylcholinesterase inhibitory activity was evaluated using Ellman method while molecular docking studies were carried out using Autodock v.4.3.2. The results revealed that the essential oil examined consisted mainly of β-caryophyllene (26.2%), germacrene D (12.5%), δ-cadinene (9.2%), germacrene B (8.8%) and bicyclogermacrene (5.5%). The essential oil showed acetylcholinesterase activity with IC 50 value of 70.5 µg/mL. The enzyme-ligand molecular docking study showed that β-caryophyllene and δ-cadinene exhibited good binding affinities towards AChE with docking scores -8.1 kcal/mol and -8.3 kcal/mol, respectively.

Nine new germacranolides, sylvaticalides A-H (1-9), and three known analogues (10-12) were isolated from the aerial part of Vernonia sylvatica. Their structures were established using comprehensive spectroscopic analysis, including high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS) and 1D and 2D nuclear magnetic resonance (NMR) spectra. Their absolute configurations were determined by X-ray diffraction experiments. The anti-inflammatory activities of all isolated compounds were assessed by evaluating their inhibitory effects on the nuclear factor kappa B (NF-κB) pathway, which was activated by lipopolysaccharide (LPS)-stimulated human THP1-Dual cells, and the interferon-stimulated gene (ISG) pathway, activated by STING agonist MSA-2 in the same cell model. Compounds 1, 2 and 6 showed inhibitory effects on the NF-κB and ISG signaling pathways, with IC 50 values ranging from 4.12 to 10.57 μmol·L -1 ., (Copyright © 2024 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

GC/MS analysis of Murraya koenigii (L.) Spreng. and Murraya paniculata (L.) Jacq. leaves revealed the identification of 73 components, with an evident greater contribution of monoterpenes hydrocarbons to their total volatiles. α-Pinene (37.5%) and β-caryophyllene (27.4%) were the most abundant compounds in M. koenigii leaves and β-phellandrene (40.7%) in M. paniculata leaves, using headspace. β-Phellandrene (33.7%) was the major constituent by M. koenigii leaves where germacrene D (23.8%), and δ-elemene (22.0%) were predominant in M. paniculata leaves, using steam distillation. M. koenigii leaves oil showed quite remarkable cholinesterase inhibitory activity, where oil of M. paniculata leaves showed strong inhibitory activity against AChE (IC 50 =13.2 ± 0.9 µg/mL) and BChE (IC 50 =5.1 ± 0.3 µg/mL). Germacrene D, α-zingiberene, and δ-elemene showed higher affinity to BChE than AChE as revealed from docking scores (S = -5.65 to -6.03 Kcal/mol) for BChE and (S = -5.56 to -6.25 Kcal/mol) for AChE.

The present study provides the first information on the chemical composition and acetylcholinesterase inhibitory activity of the essential oil (EO) from the leaves of Mitrephora poilanei Weeras. & R.M.K.Saunders from Vietnam. Gas chromatography and gas chromatography-mass spectrometry analysis revealed that the main components of the M. poilanei EO were β-caryophyllene (13.2%), α-humulene (10.5%), germacrene D (8.1%), β-elemene (5.2%) and bicyclogermacrene (5.1%). The anti-acetylcholinesterase assay showed that the EO displayed moderate activity with IC 50 value of 31.16 ± 3.06 μg/mL. These findings proposed that the plant can be exploited for its anti-acetylcholinestrate potential.

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 13 C 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., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Germacranolides, secondary metabolites produced by plants, have garnered academic and industrial interest due to their diverse and complex topology as well as a wide array of pharmacological activities. Molephantin, a highly oxygenated germacranolide isolated from medicinal plants, Elephantopus mollis and Elephantopus tomentosus, has exhibited antitumor, inflammatory, and leishmanicidal activities. Its chemical structure is based on a highly strained ten-membered macrocyclic backbone with an (E,Z)-dienone moiety, which is fused with an α-methylene-γ-butyrolactone and adorned with four successive stereogenic centers. Herein, we report the first synthesis of molephantin in 12 steps starting from readily available building blocks. The synthesis features the highly diastereoselective intermolecular Barbier allylation of the β,γ-unsaturated aldehyde with optically active 3-bromomethyl-5H-furan-2-one intermediate and ensuing Nozaki-Hiyama-Kishi (NHK) macrocyclization for the construction of the highly oxygenated ten-membered macrocyclic framework. This synthetic route enabled access to another germacranolide congener, tomenphantopin F. Furthermore, cycloisomerization of molephantin into 2-deethoxy-2β-hydroxyphantomolin could be facilitated by irradiation with ultraviolet A light (λ max =370 nm), which opened a versatile and concise access to the related furanogermacranolides such as EM-2, phantomolin, 2-O-demethyltomenphantopin C, and tomenphantopin C., (© 2024 Wiley‐VCH GmbH.)

Background: Germacrone, a naturally occurring active compound found in essential oils extracted from medicinal plants within the Zingiberaceae family, has garnered attention for its potential therapeutic applications. Extensive research has highlighted its multi-targeting capabilities, positioning it as a promising treatment for various chronic diseases, including cancer, cardiovascular conditions, and neurodegenerative disorders like Alzheimer's disease., Objective: This review aims to provide a comprehensive overview of germacrone as a scaffold for developing multi-targeting drugs with therapeutic potential against a range of chronic disorders. The study delves into the molecular mechanisms that underlie the therapeutic effects of germacrone and explores its potential targets, including NF-κB, PI3K/AKT/mTOR, p53, JAK/STAT, caspase, apoptosis, and autophagy induction., Methods: A systematic review of literature databases was conducted to gather relevant studies on germacrone and its therapeutic applications. The molecular mechanisms and potential targets of germacrone were examined to elucidate its multi-targeting capabilities., Results: Germacrone exhibits significant potential in the management of chronic diseases, with demonstrated effects on various cellular pathways. The review highlights its impact on NF-κB, PI3K/AKT/mTOR, p53, JAK/STAT, caspase, apoptosis, and autophagy induction, showcasing its versatility in targeting multiple pathways associated with chronic conditions. Germacrone has emerged as a promising candidate for the treatment of diverse chronic diseases. The understanding of its multi-targeting capabilities, coupled with its natural origin, positions it as a valuable scaffold for developing therapeutics., Conclusion: The exploration of germacrone as a structural framework for multi-targeting drugs offers a potential avenue to enhance efficacy while minimizing potential side effects. Further research and clinical trials are warranted to validate the therapeutic potential of germacrone in diverse medical contexts., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Six undescribed germacrane-type sesquiterpene lactones, millefoliumons A-F, and two known analogs were isolated from the ethyl acetate fraction of the whole plant of Achillea millefolium L. growing in Xinjiang, China. The structures of these compounds were fully elucidated by their 1D and 2D nuclear magnetic resonance (NMR), and high resolution mass (HR-ESI-MS) spectral data, and comparison with literatures. The absolute configurations of millefoliumons A-F were confirmed by experimental and calculated electronic circular dichroism data (ECD), and 13 C-NMR calculations and DP4+ probability analysis. All compounds displayed the approximate tendency to inhibit the nitric oxide (NO) release in lipopolysaccharide (LPS)-induced BV2 cells., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Highly oxidized germacranolides are mainly found in the genus Elephantopus , contain a characteristic ten-membered molecular core that is highly flexible, and exhibit potential cytotoxic properties. However, their configurations were assigned ambiguously in previous reports due to spectroscopic observation of macrocyclic systems. Herein, 17 highly oxidized germacranolides, including 12 new germacranolides ( 1 - 12 ), were isolated from Elephantopus tomentosus . Their structures were characterized by spectroscopic data analysis combined with X-ray crystallography and ECD calculations, and it was possible to propose configurational revisions of five previously reported analogues ( 13 - 17 ). Cytotoxic activities for 1 - 17 against two hepatocellular carcinoma cell lines (HepG2 and Hep3B) were tested, and compounds 1 - 10 and 13 - 16 generated IC 50 values of 2.2-9.8 μM. Furthermore, the observed cytotoxic activity of 1 was determined as being mediated by inducing the apoptosis of HepG2 and Hep3B cells via mitochondrial dysfunction.

New homo-sesquiterpenes are accessible after conversion of presilphiperfolan-8β-ol synthase (BcBOT2) with cyclopropylmethyl analogs of farnesyl diphosphate, and this biotransformation is dependent on subtle structural refinements. Two of the three cyclisation products are homo variants of germacrene D and germacrene D-4-ol while the third product reported contains a new bicyclic backbone for which no analogue in nature has been described so far. The findings on diphosphate activation are discussed and rationalised by relaxed force constants and dissociation energies computed at the DFT level of theory.

Two new germacranolides, carpelipine C (1) and carpelipine D (2), together with four known ones (3-6), were isolated from Carpesium lipskyi Winkl. flowers, a folk Tibetan herbal medicine with antipyretic-analgesic and anti-inflammatory effects. The chemical structures of new structure were illuminated by diversified spectroscopic and X-ray crystallographic analyses. Compounds 1 and 3 dramatically suppressed the synthesis of NO and decreased pre-inflammatory protein expression of iNOS and COX-2 in LPS-induced RAW264.7 cells. Furthermore, it was revealed that NF-κB/MAPK signaling pathway were involved in the anti-inflammatory process of 1 and 3, and their effects on reducing oxidative stress by activating Nrf2/HO-1 pathway were also measured. This article indicated that the traditional use of C. lipskyi to treat inflammatory diseases has a certain rationality., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

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.

The aerial parts of Ageratina vernalis provided the new germacranolide 1,10-epoxydeltoidin A ( 3 ), together with the known pentacyclic triterpenoid hopane-6 α ,22-diol ( 1 ), and the also known germacranolides deltoidin A ( 2 ) and 15-hydroxydeltoidin A ( 4 ). In addition, p TsOH catalyzed cyclization of 2 afforded the new guaianolide 5 . The absolute configuration of 2 , 4 , and 5 was assigned by vibrational circular dichroism spectroscopy, while the complete 1 H and 13 C NMR data assignments of 2 - 5 followed from 1 D- and 2 D-NMR experiments.

Three new germacrane-type sesquiterpene lactones (1-3) were isolated alongside seven known related congeners (4-10) from the leaves of Eupatorium chinense L. (Compositae). The planar structures of 1-3 were elucidated by their spectroscopic data, including 1D and 2D NMR spectra. The relative and absolute configurations of 1-3 were determined using NOESY experiments and electronic circular dichroism analyses. Compounds 1, 4, 5, and 7 inhibited protein tyrosine phosphatase (PTP) 1B activity with IC 50 values of 25, 11, 28, and 24 μM, respectively. Among these, compound 4 exhibited an inhibitory effect on T-cell PTP (TCPTP) with an IC 50 value of 25 μM. To our knowledge, this is the first study demonstrating the PTP inhibitory activity of the germacrane sesquiterpenes. The results show that compound 4 acts as an inhibitor of both PTP1B and TCPTP., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The present work involves a systematic review of the chemical composition and biological effects of essential oils from the Annonaceae species collected in Brazil from 2011 to 2021. Annonaceae is one of the most important botanical families in Brazil, as some species have economic value in the market as local and international fruit. In addition, the species have useful applications in several areas-for instance, as raw materials for use in cosmetics and perfumery and as medicinal plants. In folk medicine, species such as Annona glabra L. and Xylopia sericea A. St.-Hil. are used to treat diseases such as rheumatism and malaria. The species of Annonaceae are an important source of essential oils and are rich in compounds belonging to the classes of mono and sesquiterpenes; of these compounds, α-pinene, β-pinene, limonene, ( E )-caryophyllene, bicyclogermacrene, caryophyllene oxide, germacrene D, spathulenol, and β-elemene are the most abundant. The antimicrobial, anti-inflammatory, antileishmania, antioxidant, antiproliferative, cytotoxic, larvicidal, trypanocidal, and antimalarial activities of essential oils from the Annonaceae species in Brazil have been described in previous research, with the most studies on this topic being related to their antiproliferative or cytotoxic activities. In some studies, it was observed that the biological activity reported for these essential oils was superior to that of drugs available on the market, as is the case of the essential oil of the species Guatteria punctata (Aubl.) R. A. Howard., which showed a trypanocidal effect that was 34 times stronger than that of the reference drug benznidazol.

Carpesium divaricatum Sieb. & Zucc., a traditional medicinal plant used as an inflammation-relieving remedy, is a rich source of terpenoids. At least 40 germacrane-type sesquiterpene lactones, representatives of four different structural groups, were isolated from the plant. Cytotoxicity against cancer cells in vitro is the most frequently described biological activity of the compounds. However, little is known about the selectivity of the cytotoxic effect. The anti-inflammatory activity of the germacranolides is also poorly documented. The objective of the present study was to assess the cytotoxic activity of selected C. divaricatum germacranolides-derivatives of 4,5,8,9-tetrahydroxy-3-oxo-germacran-6,12-olide towards cancer and normal cell lines (including cells of different p53 status). Moreover, to assess the anti-inflammatory effect of the compounds, the release of four proinflammatory cytokines/chemokines (IL-1β, IL-8, TNF-α and CCL2) by lipopolysaccharide-stimulated human neutrophils was measured by ELISA. The investigated sesquiterpene lactones demonstrated nonselective activity towards prostate cancer (Du145 and PC3) and normal prostate epithelial cells (PNT2) as well as against melanoma cells (A375 and HTB140) and keratinocytes (HaCaT). Cytotoxic activity against osteosarcoma cells was independent of their p53 status. In sub-cytotoxic concentrations (0.5-2.5 µM) the studied compounds significantly decreased cytokine/chemokine release by lipopolysaccharide-stimulated human leukocytes.

Croton ferrugineus Kunth is an endemic species of Ecuador used in traditional medicine both for wound healing and as an antiseptic. In this study, fresh Croton ferrugineus leaves were collected and subjected to hydrodistillation for extraction of the essential oil. The chemical composition of the essential oil was determined by gas chromatography equipped with a flame ionization detector and gas chromatography coupled to a mass spectrometer using a non-polar and a polar chromatographic column. The antibacterial activity was assayed against three Gram-positive bacteria, one Gram-negative bacterium and one dermatophyte fungus. The radical scavenging properties of the essential oil was evaluated by means of DPPH and ABTS assays. The chemical analysis allowed us to identify thirty-five compounds representing more than 99.95% of the total composition. Aliphatic sesquiterpene hydrocarbon trans-caryophyllene was the main constituent with 20.47 ± 1.25%. Other main compounds were myrcene (11.47 ± 1.56%), β-phellandrene (10.55 ± 0.02%), germacrene D (7.60 ± 0.60%), and α-humulene (5.49 ± 0.38%). The essential oil from Croton ferrugineus presented moderate activity against Candida albicans (ATCC 10231) with an MIC of 1000 μg/mL, a scavenging capacity SC 50 of 901 ± 20 µg/mL with the ABTS method, and very strong antiglucosidase activity with an IC 50 of 146 ± 20 µg/mL.

Hedyosmum racemosum (Ruiz & Pav.) G. is a native species of Ecuador used in traditional medicine for treatment of rheumatism, bronchitis, cold, cough, asthma, bone pain, and stomach pain. In this study, fresh H. racemosum leaves of male and female specimens were collected and subjected to hydrodistillation for the extraction of the essential oil. The chemical composition of male and female essential oil was determined by gas chromatography-gas chromatography equipped with a flame ionization detector and coupled to a mass spectrometer using a non-polar and a polar chromatographic column. The antibacterial activity was assayed against five Gram-positive and two Gram-negative bacteria, and two dermatophytes fungi. The scavenging radical properties of the essential oil were evaluated by DPPH and ABTS assays. The chemical analysis allowed us to identify forty-three compounds that represent more than 98% of the total composition. In the non-polar and polar column, α-phellandrene was the principal constituent in male (28.24 and 25.90%) and female (26.47 and 23.90%) essential oil. Other main compounds were methyl chavicol, germacrene D, methyl eugenol, and α-pinene. Female essential oil presented a strong activity against Klebsiella pneumoniae (ATCC 9997) with an minimum inhibitory concentration (MIC) of 500 μg/mL and a scavenging capacity SC 50 of 800 µg/mL.

This study made it possible to characterise by GC (in combination with retention indices), GC-MS and 13 C NMR, the chemical composition of the essential oils from Solanum rugosum and Solanum erianthum , two Solanaceae of the Ivorian flora. The two essential oils were characterised by a very high proportion of sesquiterpenes. Specifically, the essential oil of S. rugosum was dominated by (E)- β -caryophyllene (33.7%), β -elemol (19.8%) and germacrene D (14.4%), while that of S. erianthum was mainly composed of α -humulene (38.6%), β -elemol (17.8%) and (E)- β -caryophyllene (16.7%). The chemical composition of Solanum rugosum is described here for the first time.

This study was designed to examine the chemical composition and anticholinesterase inhibitory activity of the essential oil of Pseuduvaria macrophylla (Oliv.) Merr. (Annonaceae) from Malaysia. The essential oil was obtained by hydrodistillation and fully analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The analysis led to the identification of thirty-four chemical components that represented 87.7 ± 0.5% of the total oil. The essential oil was found to be rich in germacrene D (21.1 ± 0.4%), bicyclogermacrene (10.5 ± 0.5%), δ-cadinene (5.6 ± 0.2%), α-copaene (5.1 ± 0.3%), and α-cadinol (5.0 ± 0.3%). Anticholinesterase activity was evaluated using Ellman method. The essential oil showed weak inhibitory activity against acetylcholinesterase (I%: 32.5%) and butyrylcholinesterase (I%: 35.4%) assays. Our findings demonstrate that the essential oil could be very useful for the characterization, pharmaceutical and therapeutic applications of the essential oil from Pseuduvaria macrophylla.

This work evaluated the volatile composition, antioxidant and antiprotozoal activities of the essential oil obtained from leaves of Eugenia gracillima Kiaersk. (EGEO) grown in Brazilian Northeast area (Araripe, Brazil). The volatile compounds of EGEO were analyzed by GC and GC-MS and its chemical composition is mainly composed of sesquiterpene hydrocarbons (91.22%), oxygenated sesquiterpenes (7.45%) and monoterpene (1.01%). The most abundant volatile constituents of the EGEO were germacrene D (16.10%), γ-muurolene (15.60%), bicyclogermacrene (8.53%), germacrene B (7.43%), and Δ-elemene (6.06%). The oil showed weak to moderate antioxidant activity. EGEO was highly selective to Leishmania braziliensis and Leishmania infantum promastigotes with selective indexes of 73.66 and 71.41, respectively. EGEO did not inhibit Trypanosoma cruzi . These data suggest that the E. gracillima essential oil is a relevant source of lead compounds for development of anti- Leishmania drugs.

The aerial parts of Artemisia gmelinii Weber ex Stechm were collected from the northeast of China. The essential oil was obtained by hydrodistillation and analysed by GC-MS. A set of 66 compounds were identified representing 99.1% of the oil composition. The major compounds in the oil were cyclobutaneethanol, endo-borneol, germacrene D, eucalyptol, selin-6-en-4 α -ol, bisabolone oxide A, caryophyllene and terpinen-4-ol. Moreover, the essential oil was evaluated for its antioxidant, antidiabetic, and anticholinesterase activities in vitro . Additionally, the antioxidant potential of the oil was evaluated using DPPH and ABTS assays. The oil showed good antidiabetic activity with an IC 50 of 63.2 µg/mL, which was similar to that of the positive control acarbose, and weak anticholinesterase activities. These findings demonstrated that the essential oil of Artemisia gmelinii may be a good natural antidiabetic.

Structural elucidation of three new sesquiterpenoids, namely, (1 Z ,4 E )-lepidoza-1(10),4-dien-14-ol ( 1 ), rel -(1(10) Z ,4 S ,5 E ,7 R )-germacra-1(10),6 diene-11,14-diol ( 2 ), and rel -(1(10) Z ,4 S ,5 E ,7 R )-humula-1(10),5-diene-7,14-diol ( 3 ), isolated from the liverwort Conocephalum conicum , was accomplished by a combination of extensive NMR experiments, 1 H NMR simulation, and other means. Additionally, the change of the identity of bicyclogermacren-14-al, previously reported as a C. conicum constituent, to isolepidozen-14-al is proposed. Compounds 2 and 3 appear to be related to 1 via hydration involving a shared intermediate, a substituted cyclopropylmethyl cation, formed by a highly regio- and stereoselective protonation of 1 , followed by a stereospecific fission of the three-membered ring. In other words, an isolepidozene derivative might be a branchpoint to humulanes and germacranes; this transformation could be of, up to now, unknown, biosynthetic and/or synthetic relevance. Multivariate statistical analysis of the compositional data of C. conicum extract constituents was used to probe the hypothesized biochemical relations. The immunomodulatory effect of 1 - 3 and conocephalenol ( 4 ) was evaluated in an in vitro model on both nonstimulated and mitogen-stimulated rat splenocytes. The compounds displayed varying degrees of cytotoxicity to nonstimulated splenocytes, whereas 2 and 3 were found to exert immunosuppressive effects on concanavalin A-stimulated splenocytes while not being cytotoxic at the same concentrations.

This review summarises known sesquiterpenes whose biosyntheses proceed through the intermediate germacrene A. First, the occurrence and biosynthesis of germacrene A in Nature and its peculiar chemistry will be highlighted, followed by a discussion of 6-6 and 5-7 bicyclic compounds and their more complex derivatives. For each compound the absolute configuration, if it is known, and the reasoning for its assignment is presented., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

Polyalthia is one of the largest genera in the Annonaceae family, and has been widely used in folk medicine for the treatment of rheumatic fever, gastrointestinal ulcer, and generalized body pain. The present investigation reports on the extraction by hydrodistillation and the composition of the essential oils of four Polyalthia species (P. sumatrana, P. stenopetalla, P. cauliflora, and P. rumphii) growing in Malaysia. The chemical composition of these essential oils was determined by gas chromatography (GC-FID) and gas chromatography-mass spectrometry (GC-MS). The multivariate analysis was determined using principal component analysis (PCA) and hierarchical clustering analysis (HCA) methods. The results revealed that the studied essential oils are made up principally of bicyclogermacrene (18.8%), cis-calamenene (14.6%) and β-elemene (11.9%) for P. sumatrana; α-cadinol (13.0%) and δ-cadinene (10.2%) for P. stenopetalla; δ-elemene (38.1%) and β-cubebene (33.1%) for P. cauliflora; and finally germacrene D (33.3%) and bicyclogermacrene for P. rumphii. PCA score and HCA plots revealed that the essential oils were classified into three separated clusters of P. cauliflora (Cluster I), P. sumatrana (Cluster II), and P. stenopetalla, and P. rumphii (Cluster III) based on their characteristic chemical compositions. Our findings demonstrate that the essential oil could be useful for the characterization, pharmaceutical, and therapeutic applications of Polyalthia essential oil.

This study was aimed to investigate the chemical compositions of the essential oils from Goniothalamus macrophyllus and Goniothalamus malayanus growing in Malaysia. The essential oils were obtained by hydrodistillation and fully characterized by gas chromatography (GC-FID) and gas chromatography-mass spectrometry (GC-MS). Analyses of the essential oils from G. macrophyllus and G. malayanus resulted in 93.6 and 95.4% of the total oils, respectively. The major components of G. macrophyllus oil were germacrene D (25.1%), bicyclogermacrene (11.6%), α-copaene (6.9%) and δ-cadinene (6.4%), whereas in G. malayanus oil bicyclogermacrene (43.9%), germacrene D (21.1%) and β-elemene (8.4%) were the most abundant components.

The rich and diversified Malaysian flora represents an excellent resource of new chemical structures with biological activities. The genus Xylopia L. includes aromatic plants that have both nutritional and medicinal uses. This study aims to contribute with information about the volatile components of three Xylopia species essential oils: Xylopia frutescens, Xylopia ferruginea, and Xylopia magna. In this study, essential oils were extracted from the leaves by a hydrodistillation process. The identification of the essential oil components was performed by gas chromatography (GC-FID) and gas chromatography-coupled mass spectrometry (GC-MS). The major components of the essential oils from X. frutescens were bicyclogermacrene (22.8%), germacrene D (14.2%), elemol (12.8%), and guaiol (12.8%), whereas components of the essential oils from X. magna were germacrene D (35.9%), bicyclogermacrene (22.8%), and spathulenol (11.1%). The X. ferruginea oil was dominated by bicyclogermacrene (23.6%), elemol (13.7%), guaiol (13.4%), and germacrene D (12.3%).

Eight new germacranolides, minusolides A-H ( 1 - 8 ), along with two known analogues, 9 and 10 , were isolated from the whole plant of Carpesium minus . Their structures were elucidated by spectroscopic analysis. Compounds 1 and 2 , and 6 and 9 are two pairs of rare epimers with opposite configurations at C-2 of the 2-methylbutyryloxy group. The absolute configurations were determined by X-ray diffraction studies. Compound 7 exhibited cytotoxic activities against MDA-MB-231, A549, and HCT-116 cells with IC 50 values of 6.1 ± 0.2, 8.4 ± 0.6, and 3.7 ± 0.6 μM, respectively. Compound 7 induced the apoptosis of HCT-116 cells via suppression of PARP and promoting cleavage of PARP.

Small molecule accurate recognition technology (SMART) is an emerging method for the rapid structural prediction of major constituents from crude extracts and fractions. In the present study, a targeted isolation of an Elephantopus scaber extract by SMART resulted in the obtention of 15 new (1-15) and five known germacranolide sesquiterpenes (16-20). Their structures were assigned by extensively analyzing HRESIMS, NMR, X-ray crystallographic analyses, modified Mosher's method results, and quantum chemical calculate electronic circular dichroism (ECD) spectra. All germacranolide sesquiterpenes were screened to determine their inhibitory effects with two hepatoma cell lines (HepG2 and Hep3B), and compounds 14, 16, 18, 19 and 20 showed significant cytotoxic activities against the HepG2 (IC 50 , 3.3-9.9 μM) and Hep3B (IC 50 , 4.5-8.6 μM) cell lines. Further study suggested that 18 can induce the apoptosis of hepatoma cells via mitochondrial dysfunction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Chromatographic purification of Elephantopus scaber led to 16 new germacrane-type sesquiterpene lactones (1-16), named elephantopinolide A-P, along with a known analogue (17). Their structures were confirmed by comprehensive spectroscopic analyses, single-crystal X-ray diffraction, and comparison between the experimental and calculated ECD spectra. Their hepatocellular inhibition activities against Hep3B and HepG2 cells were screened by MTT assay, and the structure-activity relationships were examined. The results revealed that 10 (IC 50 value of 2.83 μM and 1.98 μM) is more potent than sorafenib. The underlying mechanism study demonstrated that 10 could markedly induce apoptosis accompanied by increased ROS production and decreased mitochondrial membrane potential, resulting in the autophagy and G2/M phase cell arrest in Hep3B and HepG2 cells. Furthermore, signal pathways including MAPKs and AKT may play important roles in 10-induced hepatocellular carcinoma cells death., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The need for effective candidates as cytotoxic drugs that at the same time challenge cancer multidrug resistance encouraged a search for these in plants of central Argentina. Bioassay-guided fractionation of the cytotoxic extract from Dimerostemma aspilioides led to the isolation of the germacranolide tomenphantin A ( 1 ), along with three new analogues ( 2 - 4 ). These efficiently inhibited the proliferation of the leukemia cell lines K562 and CCRF-CEM and their resistant variants, Lucena 1 and CEM/ADR5000, respectively, with IC 50 values ranging from 0.40 to 7.7 μM. The structures and relative configurations of compounds 1 - 4 were elucidated by analysis of the spectroscopic data, in particular NMR spectroscopy. The most active among these was compound 1 (IC 50 = 0.40-5.1 μM), and, therefore, this was selected as a model for a mechanistic study, which revealed that its antiproliferative effect was mediated by cell cycle arrest in the G 2 /M phase followed by apoptosis. The activity of compound 1 was selective, given the absence of cytotoxicity toward peripheral blood mononuclear cells. The results show the potential of these compounds, and in particular of compound 1 , as leads for the development of drug candidates to fight sensitive and resistant leukemia cells.

Hepatic stellate cells (HSCs) were activated and secreted excessive amounts of extracellular matrix (ECM) proteins during pathogenetic progress of liver fibrosis. Germacrone (GMO) and miR-29b can play an important role in inhibiting growth of HSCs and production of type I collagen. GMO and miR-29b were co-encapsulated into nanoparticles (NPs) based on poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PEG-PLGA). Then, NPs were modified with cyclic RGD peptides (cRGDfK). cRGDfK is an effective ligand to bind integrin α v β 3 and increase the targeting ability for fibrotic liver. GMO- and miR-29b-loaded NPs exhibited great cytotoxicity to activated HSCs and significantly inhibited production of type I collagen. Liver fibrosis model of mice was induced by administration of carbon tetrachloride. Great targeting ability was achieved in liver fibrotic mice treated with cRGD-modified NPs. Significant ant-fibrotic effects have been presented based on hematoxylin and eosin (H&E), Masson and Sirius Red staining results of liver tissues collected from mice treated with drug-loaded NPs. All these results indicate GMO- and miR-29b-loaded cRGD-modified NPs have the potential for clinical use to treat liver fibrosis.

The chemical composition of the volatile fraction from Galium verum L. (leaves and flowers) and Cruciata laevipes Opiz (whole plant), Rubiaceae , was investigated. Samples from these two plant species were collected at full bloom in Val di Susa (Western Alps, Turin, Italy), distilled in a Clevenger-type apparatus, and analyzed by GC/FID and GC/MS. A total of more than 70 compounds were identified, making up 92%-98% of the total oil. Chemical investigation of their essential oils indicated a quite different composition between G. verum and C. laevipes, both in terms of the major constituents and the dominant chemical classes of the specialized metabolites. The most abundant compounds identified in the essential oils from G. verum were 2-methylbenzaldheyde (26.27%, corresponding to 11.59 μg/g of fresh plant material) in the leaves and germacrene D (27.70%; 61.63 μg/g) in the flowers. C. laevipes essential oils were instead characterized by two sesquiterpenes, namely β-caryophyllene (19.90%; 15.68 μg/g) and trans -muurola-4(15),5-diene (7.60%; 5.99 μg/g); two phenylpropanoids, benzyl alcohol (8.30%; 6.71 μg/g), and phenylacetaldehyde (7.74%; 6.26 μg/g); and the green-leaf alcohol cis -3-hexen-1-ol (9.69%; 7.84 μg/g). The ecological significance of the presence of such compounds is discussed.

Influenza virus is one of the most widespread infectious diseases in the world. It poses a serious public health threat to humans. With the emergence of drug-resistant virus strains, antiviral drugs are urgently needed to control virus transmission and disease progression. In this study, three main active substances-curcumol, curdione and germacrone-were isolated from the traditional Chinese medicine zedoary. They inhibited the replication of influenza A (H1N1) virus in a dose-dependent manner. After treatment with these compounds, the expression of viral protein and RNA synthesis were inhibited. In vivo, these compounds also reduced H1N1-induced lung damage and the load of virus in serum as well as whole blood cells. In a proteomic analysis, after treatment with germacrone, the expression of antiviral protein and the amount of intracellular virus were significantly reduced, further proving that germacrone can inhibit viral replication. Our experiments have shown that curcumol, curdione and germacrone can inhibit the replication of H1N1 virus; in particular, germacrone shows potential both in vitro and in vivo as a therapeutic drug., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Review covering up to 07/2019(-)-Parthenolide is a germacrane sesquiterpene lactone, available in ample amounts from the traditional medical plant feverfew (Tanacetum parthenium). Acting as a covalently reactive compound, it displays anti-inflammatory, redox-modulating, and epigenetic activities, as well as selective cytotoxicity towards cancer stem and progenitor cells. Furthermore, parthenolide was found to modulate microtubule dynamics by interfering with the detyrosination of α-tubulin, a specific posttranslational modification of the cytoskeleton. This review interfaces recently achieved parthenolide syntheses with strategies for bioactivity-based derivatization. Furthermore, chemical probe development from parthenolide is discussed, leading to a qualified summary of reported biological activities and implicated or identified targets. Special emphasis is given to parthenolide-induced microtubule modulation and the recently characterized tubulin carboxypeptidase enzymes involved in nerve (re)growth, cardiac muscle cell function, and metastasis development.

Background: The parasitic protozoal infections leishmaniasis, human African trypanosomiasis, and Chagas disease are neglected tropical diseases that pose serious health risks for much of the world's population. Current treatment options suffer from limitations, but plantderived natural products may provide economically advantageous therapeutic alternatives. Several germacranolide sesquiterpenoids have shown promising antiparasitic activities, but the mechanisms of activity have not been clearly established., Objective: The objective is to use in silico screening of known antiparasitic germacranolides against recognized protozoal protein targets in order to provide insight into the molecular mechanisms of activity of these natural products., Methods: Conformational analyses of the germacranolides were carried out using density functional theory, followed by molecular docking. A total of 88 Leishmania protein structures, 86 T. brucei protein structures, and 50 T. cruzi protein structures were screened against 27 antiparasitic germacranolides., Results: The in-silico screening has revealed which of the protein targets of Leishmania spp., Trypanosoma brucei, and Trypanosoma cruzi are preferred by the sesquiterpenoid ligands., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Three new germacrane sesquiterpenoid-type alkaloids with an unusual Δ 8 -7,12-lactam moiety, glechomanamides A-C ( 1 - 3 ), and two pairs of 7,12-hemiketal sesquiterpenoid epimers ( 4a / b , 5a / b ) were isolated from Salvia scapiformis . Their structures were elucidated by spectroscopic methods including HRESIMS, IR, UV, and 1D and 2D NMR and also confirmed by single-crystal X-ray diffraction analysis. The chemical transformation of compounds 1 - 5 in a solution environment was analyzed by 2D NMR spectroscopy. The aza acetallactams ( 1 - 3 ) were stable in organic solvent, while single crystals of the hemiacetal esters ( 4a / b , 5a / b ) underwent a tautomeric equilibrium after being dissolved. Single crystals of 4a , 4b , and 5a were obtained for the first time as their naturally occurring forms. Glechomanamide B ( 2 ) exhibited antiangiogenic activity by suppression of vascular endothelial growth factor (VEGF)-induced tube formation through modulation of VEGF receptor 2 (VEGFR2)-mediated signaling pathways in human umbilical vascular endothelial cells (HUVECs). In addition, compound 2 also showed the significant suppression of mRNA expression associated with glycolysis and angiogenesis biomarkers in high glucose (30 mM)-induced HUVECs. These findings suggest that compound 2 might be a potential lead compound candidate for the management of diabetic retinopathy.

Eleven new highly oxygenated germacrane-type sesquiterpenoids (1-11) and 16 known analogues (12-27) were isolated from the aerial parts of Sigesbeckia orientalis. Their structures, including absolute configurations, were determined by comprehensive spectroscopic methods especially NMR and ECD analyses. Compounds 13, 21 and 23 possessing an 8-methacryloxy group showed stronger in vitro cytotoxicity against human A549 and MDA-MB-231 cancer cell lines than other co-metabolites, with IC 50 values ranging from 6.02 to 10.77 μM comparable to the positive control adriamycin., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Adaptive evolution of enzymes benefits from catalytic promiscuity. Sesquiterpene lactones (STLs) have diverged extensively in the Asteraceae, and studies of the enzymes for two representative STLs, costunolide and artemisinin, could provide an insight into the adaptive evolution of enzymes. Costunolide appeared early in Asteraceae evolution and is widespread, whereas artemisinin is a unique STL appearing in a single Asteraceae species, Artemisia annua Therefore, costunolide is a ubiquitous STL, while artemisinin is a specialized one. In costunolide biosynthesis, germacrene A oxidase (GAO) synthesizes germacrene A acid from germacrene A. Similarly, in artemisinin biosynthesis, amorphadiene oxidase (AMO) synthesizes artemisinic acid from amorphadiene. GAO promiscuity is suggested to drive the diversification of STLs. To examine the degree of GAO promiscuity, we expressed six sesquiterpene synthases from cotton ( Gossypium arboretum ), goldenrod ( Solidago canadensis ), valerian ( Valeriana officinalis ), agarwood ( Aquilaria crassna ), tobacco ( Nicotiana tabacum ), and orange ( Citrus sinensis ) in yeast to produce seven distinct sesquiterpene substrates (germacrene D, 5- epi -aristolochene, valencene, δ-cadinene, α- and δ-guaienes, and valerenadiene). GAO or AMO was coexpressed in these yeasts to evaluate the promiscuities of GAO and AMO. Remarkably, all sesquiterpenes tested were oxidized to sesquiterpene acids by GAO, but negligible activities were found from AMO. Hence, GAO apparently has catalytic potential to evolve into different enzymes for synthesizing distinct STLs, while the recently specialized AMO demonstrates rigid substrate specificity. Mutant GAOs implanted with active site residues of AMO showed substantially reduced stability, but their per enzyme activities to produce artemisinic acid increased by 9-fold. Collectively, these results suggest promiscuous GAOs can be developed as novel catalysts for synthesizing unique sesquiterpene derivatives., (© 2019 American Society of Plant Biologists. All Rights Reserved.)

The main objective of this study was to develop a novel self-assembled micelle system to improve the oral bioavailability of the water-insoluble and thermal instable germacrone (GEM). Micelles were prepared with an improved supercritical reverse phase evaporation (ISCRPE) method, and the thin-film hydration (TFH) method was used for comparison. Physicochemical characterization confirmed the nanospherical morphology of the micelles prepared by the ISCRPE method (GEM@SDL-SCF Micelles) had smaller particle size and greater encapsulation efficiency than that of the micelles prepared by the TFH method (GEM@SDL-THF Micelles). Dilution resistance and stability experiments were performed to assess the structural integrity. In vitro GEM release was analyzed by the dialysis diffusion method, and the micelle system showed sustained and cumulative release. Furthermore, the fluorescence results from the cellular uptake study revealed improved drug absorption of GEM since the green fluorescence intensity of C6@SDL-SCF Micelles were stronger than that of C6@SDL-TFH Micelles. The transcellular transport study showed a distinct increase in the apparent permeability coefficient (AP → BL) in a Caco-2 cell transport model, and free GEM solution, GEM@SDL-TFH Micelles and GEM@SDL-SCF Micelles had permeability coefficients of 7.30 × 10 -6 , 8.01 × 10 -6 , and 10.57 × 10 -6  cm·s -1 , respectively. The pharmacokinetics study in Sprague-Dawley rats showed that the oral absorption capacity of the GEM@SDL-SCF Micelles was obviously enhanced, with a relative oral bioavailability of 298% and 147% compared with that of free GEM solution and GEM@SDL-TFH Micelles, respectively. The gastrointestinal safety assessment demonstrated that the micelles used in the experiment did not cause gastrointestinal toxicity. These results indicated that self-assembled micelles are promising nanocarriers aimed at enhancing the oral absorption of drugs with thermal sensitivity and low aqueous solubility, and micelles prepared by supercritical fluid (SCF) technology showed better performance than those prepared by the TFH method., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The Alpine wormwood Artemisia vallesiaca All. was considered the most valuable ingredient of vermouth, a celebrated aromatized wine. A. vallesiaca has a very limited geographical distribution, and the booming market of vermouth decimated its natural population, resulting in the eventual replacement of this rare species with more common and less expensive wormwoods like A. absinthium L.. Over the past years, attempts to revive the original recipe(s) of vermouth have fostered the establishment of cultivations of A. vallesiaca in pre-montane settings. In order to assist these projects, the phytochemical profile of cultivated plants and of several native populations of A. vallesiaca from the Swiss Valais were comparatively evaluated, focusing on sesquiterpene lactones and on lipophilic flavonoids, the hallmark constituents of Artemisia species. Remarkably, no significant difference was detected between the samples, despite the different origins. The lipophilic flavonoids of A. vallesiaca were similar to those of related species used in the production of vermouth, but the presence of C-9 oxygenated 11β-methyl germacranolides and eudesmanolides (herbolides) made its sesquiterpene lactone profile peculiar. In addition to known compounds, two novel germacranolides were also characterized (herbolides J and K), and the major sesquiterpene lactone from the plant, the bitter germacranolide herbolide D (4), was detected and quantified by 1 H NMR in a bitter liqueur aromatized with A. vallesiaca. Taken together, these observations qualify herbolides as marker to identify A. vallesiaca in aromatized alcohol matrixes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A germacrane sesquiterpenoid library containing 30 compounds ( 2 - 31 ) was constructed by structural modification of a major component aristolactone ( 1 ) from the traditional Chinese medicine Aristolochia yunnanensis . Compound 11 was identified as a promising anticardiac fibrosis agent by systematic screening of this library. 11 could inhibit the expression of fibronectin (FN), α-smooth muscle actin (α-SMA), and collagens in transforming growth factor β 1 (TGFβ1)-stimulated cardiac fibroblasts at a micromolar level and ameliorate myocardial fibrosis and heart function in abdominal aortic constriction (AAC) rats at 5 mg/kg dose. Mechanistic study revealed that 11 inhibited the TGFβ/small mother against decapentaplegic (Smad) signaling pathway by targeting TGFβ type I receptor (IC 50 = 14.9 ± 1.6 nM). The structure-activity relationships (SARs) study indicated that the unsaturated γ-lactone ring and oxidation of C-1 were important to the activity. These findings may provide a new type of structural motif for future anticardiac fibrosis drug development.

Repeated chromatographic purifications of aerial parts of the Tunisian plant Daucus virgatus led to the isolation of four new germacranolides, named daucovirgolides I-L (2-5), along with the Plasmodium transmission-blocking agent daucovirgolide G. The chemical structures of the new compounds were defined as mono- or di-angeloylated germacrane-type sesquiterpenoids by spectroscopic (mainly 1D and 2D NMR) and spectrometric methods (ESIMS). The low potency exhibited by daucovirgolides I-L further supports the observation that strict structural requirements do exist for the Plasmodium transmission blocking activity in the daucovirgolide series. In particular, the endocyclic double bond system seems to be crucial for bioactivity., (Copyright © 2019 Elsevier B.V. All rights reserved.)