Linderangolides A-D, four new butanolides from the roots of Lindera angustifolia and their cytotoxic activity.

Four undescribed butanolides, linderangolides A-D (1-4), along with four known congeners, lincomolide A (5), (-)-epilitsenolide C2 (6), (-)-epilitsenolide C1 (7) and litseakolide H (8), were isolated from the roots of Lindera angustifolia. The planar structures of 1-4 were elucidated based on extensive spectroscopic analyses, the relative and absolute configurations of 1-4 were determined by the NOESY spectra and the comparison of calculated and experimental ECD. The cytotoxic activities of all isolated compounds were tested, 4 showed inhibitory activity against SGC-7 cells with IC50 value of 6.62 µM.

Undescribed polyketides from endophytes associated with the critically endangered conifer Abies beshanzuensis.

Four undescribed polyketides, beshanzones A (1) and B (2) as well as beshanhexanols A (3) and B (4), along with three known ones (5-7) were isolated from the rice fermentation of two endophytic fungi associated with the critically endangered Chinese endemic conifer Abies beshanzuensis. γ-Butyrolactone derivatives 1, 2, and 5 were isolated from Phomopsis sp. BSZ-AZ-2, an interesting strain that drawn our attention this time. The cyclohexanol derivatives 3, 4, 6, and 7 were obtained during a follow-up investigation on Penicillium commune BSZ-P-4-1. The chemical structures including absolute configurations of compounds 1-4 were determined by spectroscopic methods, Mo2(OAc)4 induced electronic circular dichroism (IECD), GIAO NMR calculations and DP4+ probability analyses. In particular, compound 2 contains a novel 5/5 bicyclic ring system, which might be biogenetically derived from the known compound 5 through hydrolysis followed by an Aldol reaction. All isolates were evaluated for their antimicrobial activities against a small panel of bacterial and fungal pathogens. Compounds 6 and 7 showed moderate inhibitory activities against Candida albicans, with MIC values of 16 and 32 µg/mL, respectively.

Harzianolides B-G: Undescribed Butenolides isolated from the fungus Trichoderma harzianum ZN-4.

Five undescribed γ-butyrolactones harzianolides BF (1-5), one precursor harzianolide G (6) along with two known analogues, were isolated and identified from the EtOAc extract of the liquid fermentation of Trichoderma harzianum ZN-4, which was obtained from the sediment of Zhoushan coastal area. Notably, compound 1 featured an unusual carbon skeleton with methylene-bridged furan rings system. Their structures were determined by detailed interpretation of NMR and mass spectroscopic data, and the absolute configurations were unambiguously established based on ECD quantum chemical calculations. In bioassay, 1 and 7 showed inhibitory activity against Pestalotiopsis theae, with MIC values of 25 and 50 µg/mL, respectively.

Ligustilide, A Novel Senolytic Compound Isolated from the Roots of Angelica Acutiloba.

Senescent cells accumulate with age and contribute to age-related diseases and organ dysfunctions. Early evidence suggests that removal of senescent cells using senolytic drugs improves the aging phenotype in mice and may improve the health of individuals with chronic diseases. Signs of skin aging, including wrinkles, and sagging, occur largely due to the accumulation of senescent fibroblasts within the dermis; However, there is currently no skin treatment that eliminates senescent cells. In this study, human fibroblasts subjected to replicative aging and ionizing radiation exposure are used to screen plant extracts for potential senescent cell-destructive and/or senescent cell-forming activities. Angelica acutiloba-a traditional Chinese herbal medicine-selectively kills senescent cells without affecting the proliferating cells. Among the major components of this herb, ligustilide shows promising senescent cell-destructive properties, and selectively eliminates senescent cells by inducing an apoptosis. Moreover, ligustilide markedly inhibits senescence-associated secretory phenotypes. Administration of ligustilide to mouse skin eliminates senescent cells and increases dermal collagen density and subcutaneous adipose tissue content; it selectively promotes death of senescent cells without affecting non-senescent cells. These results provide evidence that a natural compound-ligustilide-may exhibit therapeutic effects on the skin aging phenotype by specifically inducing apoptosis in senescent cells.

New Metabolites from the Marine Sponge Scopalina hapalia Collected in Mayotte Lagoon.

The biological screening of 44 marine sponge extracts for the research of bioactive molecules, with potential application in the treatment of age-related diseases (cancer and Alzheimer's disease) and skin aging, resulted in the selection of Scopalina hapalia extract for chemical study. As no reports of secondary metabolites of S. hapalia were found in the literature, we undertook this research to further extend current knowledge of Scopalina chemistry. The investigation of this species led to the discovery of four new compounds: two butenolides sinularone J (1) and sinularone K (2), one phospholipid 1-O-octadecyl-2-pentanoyl-sn-glycero-3-phosphocholine (3) and one lysophospholipid 1-O-(3-methoxy-tetradecanoyl)-sn-glycero-3-phosphocholine (4) alongside with known lysophospholipids (5 and 6), alkylglycerols (7-10), epidioxysterols (11 and 12) and diketopiperazines (13 and 14). The structure elucidation of the new metabolites (1-4) was determined by detailed spectroscopic analysis, including 1D and 2D NMR as well as mass spectrometry. Molecular networking was also explored to complement classical investigation and unravel the chemical classes within this species. GNPS analysis provided further information on potential metabolites with additional bioactive natural compounds predicted.

Butenolides from the Coral-Derived Fungus Aspergillius terreus SCSIO41404.

Five undescribed butenolides including two pairs of enantiomers, (+)-asperteretal G (1a), (-)-asperteretal G (1b), (+)-asperteretal H (2a), (-)-asperteretal H (2b), asperteretal I (3), and para-hydroxybenzaldehyde derivative, (S)-3-(2,3-dihydroxy-3-methylbutyl)-4-hydroxybenzaldehyde (14), were isolated together with ten previously reported butenolides 4-13, from the coral-derived fungus Aspergillus terreus SCSIO41404. Enantiomers 1a/1b and 2a/2b were successfully purified by high performance liquid chromatography (HPLC) using a chiral column, and the enantiomers 1a and 1b were new natural products. Structures of the unreported compounds, including the absolute configurations, were elucidated by NMR and MS data, optical rotation, experimental and calculated electronic circular dichroism, induced circular dichroism, and X-ray crystal data. The isolated butenolides were evaluated for antibacterial, cytotoxic, and enzyme inhibitory activities. Compounds 7 and 12 displayed weak antibacterial activity, against Enterococcus faecalis (IC50 = 25 µg/mL) and Klebsiella pneumoniae (IC50 = 50 µg/mL), respectively, whereas 6 showed weak inhibitory effect on acetylcholinesterase. Nevertheless, most of the butenolides showed inhibition against pancreatic lipase (PL) with an inhibition rate of 21.2-73.0% at a concentration of 50 µg/mL.

Anti-Inflammatory, Antiallergic, and COVID-19 Main Protease (Mpro) Inhibitory Activities of Butenolides from a Marine-Derived Fungus Aspergillus terreus.

In December 2020, the U.K. authorities reported to the World Health Organization (WHO) that a new COVID-19 variant, considered to be a variant under investigation from December 2020 (VUI-202012/01), was identified through viral genomic sequencing. Although several other mutants were previously reported, VUI-202012/01 proved to be about 70% more transmissible. Hence, the usefulness and effectiveness of the newly U.S. Food and Drug Administration (FDA)-approved COVID-19 vaccines against these new variants are doubtfully questioned. As a result of these unexpected mutants from COVID-19 and due to lack of time, much research interest is directed toward assessing secondary metabolites as potential candidates for developing lead pharmaceuticals. In this study, a marine-derived fungus Aspergillus terreus was investigated, affording two butenolide derivatives, butyrolactones I (1) and III (2), a meroterpenoid, terretonin (3), and 4-hydroxy-3-(3-methylbut-2-enyl)benzaldehyde (4). Chemical structures were unambiguously determined based on mass spectrometry and extensive 1D/2D NMR analyses experiments. Compounds (1-4) were assessed for their in vitro anti-inflammatory, antiallergic, and in silico COVID-19 main protease (Mpro) and elastase inhibitory activities. Among the tested compounds, only 1 revealed significant activities comparable to or even more potent than respective standard drugs, which makes butyrolactone I (1) a potential lead entity for developing a new remedy to treat and/or control the currently devastating and deadly effects of COVID-19 pandemic and elastase-related inflammatory complications.

Bioactive aromatic butenolides from a mangrove sediment originated fungal species, Aspergillus terreus SCAU011.

Seven new compounds including five aromatic butenolide analogues (1-5), one quinazolinone alkaloid (6) and one benzoic acid derivative (7), along with eleven known co-metabolites (8-18), were isolated from Aspergillus terreus SCAU011, a fungus from the rhizosphere sediment of a mangrove plant Rhizophora stylosa. The structures of these isolates were established by a combination of MS, NMR and ECD data analyses, as well as chemical method. Compound 3 is a rare ring-open aromatic butenolide, while 6 represents the first natural ring-open benzomalvin-type quinazolinone alkaloid. Also, the previously reported structures for asperlides A-C were proposed to be revised in the present work. The COX-2 inhibitory, α-glucosidase inhibitory, antioxidant and antibacterial activities of all the compounds were assessed. While compounds 4, 6, 11 and 18 exhibited better COX-2 inhibitory activity than the positive control celecoxib, compounds 9 and 10 showed significant α-glucosidase inhibitory activity with IC50 values of 56.1 and 12.9 µM, respectively. Meanwhile, half of the tested samples (1, 8-11 and 15-17) exerted similar or better antioxidant activity compared with the reference drug curcumin, and compounds 3, 9, 17 and 18 displayed moderate antibacterial effect against Staphylococcus aureus.

Octyl substituted butenolides from marine-derived Streptomyces koyangensis.

A new butenolide derivative (1) featuring octyl substitution at γ-position, together with four known analogues (2-5) were isolated from marine-derived Streptomyces koyangensis SCSIO 5802. The structure of 1 was elucidated by HR-MS and NMR spectroscopic data analyses. The absolute configuration of the stereo centre in lactone ring of 1 was determined by comparison of CD spectrum with those of known compounds. Compound 1 exhibited mild antiviral activity against herpes simplex virus with EC50 value of 25.4 µM.

The anti-cancer effect of flaxseed lignan derivatives on different acute myeloid leukemia cancer cells.

Flaxseeds have been known for their anti-cancerous effects due to the high abundance of lignans released upon ingestion. The most abundant lignan, secoisolariciresinol diglucoside (SDG), is ingested during the dietary intake of flax, and is then metabolized in the gut into two mammalian lignan derivatives, Enterodiol (END) and Enterolactone (ENL). These lignans were previously reported to possess anti-tumor effects against breast, colon, and lung cancer. This study aims to investigate the potential anti-cancerous effect of the flaxseed lignans SDG, END and ENL on acute myeloid leukemia cells (AML) in vitro and to decipher the underlying molecular mechanism. AML cell lines, (KG-1 and Monomac-1) and a normal lymphoblastic cell line were cultured and treated with the purified lignans. ENL was found to be the most promising lignan, as it exhibits a significant selective dose- and time-dependent cytotoxic effect in both AML cell lines, contrary to normal cells. The cytotoxic effects observed were attributed to apoptosis induction, as revealed by an increase in Annexin V staining of AML cells with increasing ENL concentrations. The increase in the percentage of cells in the pre-G phase, in addition to cell death ELISA analysis, validated cellular and DNA fragmentation respectively. Analysis of protein expression using western blots confirmed the activation of the intrinsic apoptotic pathway upon ENL treatment. This was also accompanied by an increase in ROS production intracellularly. In conclusion, this study demonstrates that ENL has promising anti-cancer effects in AML cell lines in vitro, by promoting DNA fragmentation and the intrinsic apoptotic pathway, highlighting the protective health benefits of flax seeds in leukemia.

Isokotomolide A from Cinnamomum kotoense Induce Melanoma Autophagy and Apoptosis In Vivo and In Vitro.

Melanoma is an aggressive cancer with high lethality. In order to find new anticancer agents, isokotomolide A (Iso A) and secokotomolide A (Sec A) isolated from Cinnamomum kotoense were identified to be potential bioactive agents against human melanoma but without strong antioxidative properties. Cell proliferation assay displayed Iso A and Sec A treated in the normal human skin cells showed high viabilities. It also verified that two of them possess strong antimelanoma effect in concentration-dependent manners, especially on B16F10, A2058, MeWo, and A375 cells. Wound healing assay presented their excellent antimigratory effects. Through 3-N,3-N,6-N,6-N-Tetramethylacridine-3,6-diamine (acridine orange, AO) staining and Western blot, the autophagy induced by treatment was confirmed, including autophagy-related proteins (Atgs). By using annexin V-FITC/PI double-stain, the apoptosis was confirmed, and both components also triggered the cell cycle arrest and DNA damage. We demonstrated the correlations between the mitogen-activated protein kinase (MAPK) pathway and antimelanoma, such as caspase cascade activations. To further evaluate in vivo experiments, the inhibition of tumor cell growth was verified through the histopathological staining in a xenograft model. In this study, it was confirmed that Iso A and Sec A can encourage melanoma cell death via early autophagy and late apoptosis processes.

Sarcophine and (7S, 8R)-dihydroxydeepoxysarcophine from the Red Sea soft coral Sarcophyton glaucum as in vitro and in vivo modulators of glycine receptors.

The inhibitory glycine receptor (GlyR) is a key mediator of synaptic signalling in spinal cord, brain stem, and higher centres of the central nervous system. We examined the glycinergic activity of sarcophine (SN), a marine terpenoid known for its various biological activities, and its trans-diol derivative (7S, 8R)-dihydroxy-deepoxysarcophine (DSN). SN was isolated from the Red Sea soft coral Sacrophyton glaucum, DSN was semisynthesized by hydrolysis of the epoxide ring. In cytotoxicity tests against HEK293 cells, SN and DSN had LD50 values of 29.3 ± 3.0 mM and 123.5 ± 13.0 mM, respectively. Both compounds were tested against recombinant human α1 glycine receptors in HEK293 cells using whole-cell recording techniques. Both, SN and DSN were shown for the first time to be inhibitors of recombinant glycine receptors, with KIvalues of 2.1 ± 0.3 µM for SN, and 109 ± 9 µM for DSN. Receptor inhibition was also studied in vivo in a mouse model of strychnine toxicity. Surprisingly, in mouse experiments strychnine inhibition was not augmented by either terpenoid. While DSN had no significant effect on strychnine toxicity, SN even delayed strychnine effects. This could be accounted for by assuming that strychnine and sarcophine derivatives compete for the same binding site on the receptor, so the less toxic sarcophine can prevent strychnine from binding. The combination of modulatory activity and low level of toxicity makes sarcophines attractive structures for novel glycinergic drugs.

New cytotoxic secondary metabolites against human pancreatic cancer cells from the Hypericum perforatum endophytic fungus Aspergillus terreus.

Four new compounds, including two lovastatin analogues, terrstatins A and B (1 and 2), and a pair of butenolide derivatives, (±)-asperteretone F (3a/3b), along with eleven known compounds (4-14), were isolated from the Hypericum perforatum endophytic fungus Aspergillus terreus. Their structures and absolute configurations were determined based on extensive spectroscopic analysis, experimental and calculated electronic circular dichroism (ECD) analysis. All isolates were evaluated for cytotoxic activities against five human cancer cell lines, and compounds 3a/3b and 6 showed potential cytotoxic activities against human pancreatic cancer cells, including AsPC-1, SW1990 and PANC-1 cells, with IC50 values ranging from 1.2 to 15.6 µM.

Tarragon essential oil as a source of bioactive compounds with anti-quorum sensing and anti-proteolytic activity against Pseudomonas spp. isolated from fish - in vitro, in silico and in situ approaches.

The present study aimed to evaluate the anti-quorum sensing (anti-QS) and anti-proteolytic potentials of tarragon essential oil (TEO) and its major compounds against food-associated Pseudomonas spp. The activities were verified by in vitro, in silico and in situ approaches. In this work, methyl eugenol (ME)- and ß-phellandrene (ß-PH)-rich TEO was investigated. TEO at subMIC increased the percentage of saturated fatty acids in the bacterial membranes (from 7 to 22%) and exhibited anti-quorum sensing via decreasing the efficiency of QS autoinducer synthesis [3-oxo-C12-HSL (from 2.028 µg/mL to

An anti-inflammatory isoflavone from soybean inoculated with a marine fungus Aspergillus terreus C23-3.

A new isoflavone derivative compound 1 (psoralenone) was isolated from soybean inoculated with a marine fungus Aspergillus terreus C23-3, together with seven known compounds including isoflavones 2-6, butyrolactone I (7) and blumenol A (8). Their structures were elucidated by MS, NMR, and ECD. Psoralenone displayed moderate in vitro anti-inflammatory activity in the LPS-induced RAW264.7 cell model. Compound 2 (genistein) showed moderate acetylcholinesterase (AChE) inhibitory activity whereas compounds 2, 5 (biochanin A), 6 (psoralenol), and 7 exhibited potent larvicidal activity against brine shrimp. Compounds 3 (daidzein), 4 (4'-hydroxy-6,7-dimethoxyisoflavone), and 5-7 showed broad-spectrum anti-microbial activity, and compound 7 also showed moderate 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity.

Axl and immune checkpoints inhibitors from fruiting bodies of Pleurocybella porrigens.

A novel compound (1) and three known ones (2-4) were isolated from the fruiting bodies of Pleurocybella porrigens. The structure of the novel compound was determined by 1D and 2D NMR and HRESIMS data. The biological activity of 1-3 was evaluated using the A549 lung cancer cell line. The results showed the inhibitory activity of compounds 1-3 on the expression of Axl and immune checkpoint molecules.

Analog synthesis of DAMASCENOLIDETM, an important aroma component of roses, and their odor properties.

DAMASCENOLIDETM [1, 4-(4-methylpent-3-en-1-yl)furan-2(5H)-one], which has a citrus-like odor, is an important aroma component of roses. We have previously reported on the synthesis and odor evaluation of double-bond isomers of 1 and concluded that the position and the geometric isomerism of the double-bond had a significant effect on the odor. For the purpose of deepening knowledge about structure-odor relationships, we synthesized 13 analogs of compound 1 and evaluated their odors. As a result, it was found that the presence of two double-bonds and branched methyl group at the terminal position in the side chain was essential in order to have a citrus-like odor. Substitution of the side chain with appropriate length at the appropriate 4-position of the 2(5H)-furanone ring was also an important factor in determining the quality of the odor.

Enantiomeric separation of quorum sensing autoinducer homoserine lactones using GC-MS and LC-MS.

Homoserine lactones (HSLs) are signaling molecules synthesized by Gram-negative bacteria in order to communicate in a process termed "quorum sensing." Until recently, only the L-stereoisomers of HSLs were thought to be produced and able to incite quorum sensing. However, recent studies have shown that select Gram-negative bacteria additionally produce non-trivial amounts of D-HSLs which may also play a role in quorum sensing. Current methods for the separation of HSL enantiomers cannot effectively separate all classes of HSLs and its enantiomers. More robust methods of separation and detection of D-HSLs are necessary. We have developed rapid and selective methods using liquid chromatography (LC) and gas chromatography (GC) coupled with mass spectrometry (MS) which can simultaneously enantiomerically separate all classes of HSLs. The advantages of these methods are in the MS compatibility as well as the ability to enantiomerically separate all classes of HSLs in a single run. The first enantiomeric separations of oxo- and hydroxy-HSLs by GC-MS, through the use of N,O-bis(trimethylsilyl)trifluoroacetamide-derivatizing reagents are discussed. Graphical Abstract.

Three New Butenolides from the Green Alga Caulerpa racemosa var. turbinata.

Three new butenolides, caulerpalide A and a pair of enantiomers, (+)-caulerpalide B and (-)-caulerpalide B, together with seven known compounds, have been isolated from the green alga Caulerpa racemosa var. turbinata. All these structures were determined by spectroscopic techniques. The absolute configurations of caulerpalide A, (+)-caulerpalide B and (-)-caulerpalide B were elucidated by the method of ECD calculation. This is the first separation of butenolides from the algae of genus Caulerpa. Additionally, the antibacterial activities of the nine isolated compounds were also evaluated.

Flavipesides A-C, PKS-NRPS Hybrids as Pancreatic Lipase Inhibitors from a Marine Sponge Symbiotic Fungus Aspergillus flavipes 164013.

Three unusual chlorinated PKS-NRPS hybrid metabolites, flavipesides A-C (1-3), were isolated from a strain of marine sponge symbiotic fungus Aspergillus flavipes 164013. Their structures were determined by spectroscopic data analysis, and absolute configurations were assigned by single-crystal X-ray diffraction with ECD spectral analysis. Flavipesides A-C showed potent pancreatic lipase (PL) inhibitory activity with IC50 values of 0.07-0.23 µM.