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The biotransformation of vulgarin (1) , an eudesmanolides-type sesquiterpene lactone obtained from Artemisia judaica , by the microorganism, Aspergillus niger , was carried out to give three more polar metabolites; 1- epi -tetrahydrovulgarin (1α,4α-dihydroxy-5αH,6,11βH-eudesman-6,12-olide (2) , 20% yield, 1α,4α-dihydroxyeudesm-2-en-5αH,6,11βH-6,12-olide (3a) , 10% yield, and C-1 epimeric mixture (3a, b) , 4% yield, in a ratio of 4:1, 3a/3b . The structures of vulgarin and its metabolites were elucidated by 1 and 2D NMR spectroscopy in conjunction with HRESIMS. Metabolites (3a) and (3b) are epimers, and they are reported here for the first time as new metabolites obtained by biotransformation by selective reduction at C-1. Vulgarin and its metabolites were evaluated as anti-inflammatory agents using the human cyclooxygenase (COX) inhibitory assay. The obtained data showed that (1) exhibited a good preferential inhibitory activity towards COX-2 (IC50 = 07.21 ± 0.10) and had a moderate effect on COX-1 (IC50 = 11.32 ± 0.24). Meanwhile, its metabolite (3a) retained a selective inhibitory activity against COX-1 (IC50 = 15.70 ± 0.51). In conclusion, the results of this study revealed the necessity of the presence α, β unsaturated carbonyl group in (1) for better COX-2 inhibitory activity. On the other hand, the selectivity of (1) as COX-1 inhibitor may be enhanced via the reduction of C-1 carbonyl group.

The microbial transformations of lactones with a halogenoethylocyclohexane moiety were performed in a filamentous fungi culture. The selected, effective biocatalyst for this process was the Absidia glauca AM177 strain. The lactones were transformed into the hydroxy derivative, regardless of the type of halogen atom in the substrate structure. For all lactones, the antiproliferative activity was determined toward several cancer cell lines. The antiproliferative potential of halolactones was much broader than that observed for the hydroxyderivative. According to the presented results, the most potent was chlorolactone, which exhibited significant activity toward the T-cell lymphoma line (CL-1) cell line. The hydroxyderivative obtained through biotransformation was not previously described in the literature.

Parasitic weeds are noxious plants that damage crops of economic relevance, especially in Mediterranean and African countries. The strategy of suicidal germination was proposed to deal with this plague by using seed germination inducers that work as a pre-emergence herbicide and reduce the parasitic seed load before sowing. N -Substituted phthalimides with a furanone ring were found to be efficient in inducing the germination of Phelipanche ramosa and Orobanche cumana , two of the most problematic parasitic weeds of crops. However, the solubility of these compounds in water is low. A strategy for enhancing their aqueous solubility is the synthesis of host-guest complexes with cyclodextrins. Three bioactive phthalimide-lactones (PL01, PL04, and PL07) were selected and studied to form complexes of increased water solubility with α-, β-, HP-β-, and γ-cyclodextrin. The complexes obtained by the coprecipitation method, with increased aqueous solubility (up to 3.8 times), were studied for their bioactivity and they showed similar or slightly higher bioactivity than free phthalimide-lactones, even without the addition of organic solvents. A theoretical study using semiempirical calculations of molecular models including a solvation system confirmed the physicochemical empirical results. These results demonstrated that cyclodextrins can be used to improve the physicochemical and biological properties of parasitic seed germination inducers.

The parasitic weed Striga has led to billions of dollars' worth of agricultural productivity loss worldwide. Striga detects host plants using compounds of the strigolactone class of phytohormones. Early steps in the strigolactone signaling pathway involve substrate binding and hydrolysis followed by a conformational change to an "active" or "closed" state, after which it associates with a MAX2-family downstream signaling partner. The structures of the inactive and active states of strigolactone receptors are known through X-ray crystallography, and the transition pathway from the inactive to active state in apo receptors has previously been characterized using molecular dynamics simulations. However, it also has been suggested that a covalent butenolide modification of the receptor on the catalytic histidine through substrate hydrolysis promotes formation of the active state. Using molecular dynamics simulations, we show that the presence of the covalent butenolide enhances activation in both AtD14, a receptor found in Arabidopsis, and ShHTL7, a receptor found in Striga, but the enhancement is ∼50 times greater in ShHTL7. We also show that several conserved interactions with the covalent butenolide modification promote transition to the active state in both AtD14 (non-parasite) and ShHTL7 (parasite). Finally, we demonstrate that the enhanced activation of ShHTL7 likely results from disruption of ShHTL7-specific histidine interactions that inhibited activation in the apo case. These results provide a possible explanation for difference in strigolactone sensitivity seen between different strigolactone-sensitive proteins and can be used to aid the design of selective modulators to control Striga parasites., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Biodegradable materials are pivotal in the biomedical field, where how to precisely control their structure and performance is critical for their translational application. In this study, poly(L-lactide-b-ε-caprolactone) block copolymers (bPLCL) with well-defined segment structure are obtained by a first synthesis of poly(ε-caprolactone) soft block, followed by ring opening polymerization of lactide to form poly(L-lactide acid)  hard block. The pre-polymerization allows for fabrication of bPLCL with the definite compositions of soft/hard segment while preserving the individual segment of their special soft or hard segment. These priorities make the bPLCL afford biodegradable polymer with better mechanical and biodegradable controllability than the random poly(L-lactide-co-ε-caprolactone) (rPLCL) synthesized via traditional one-pot polymerization. 10 mol% ε-caprolactone introduction can result in a formation of an elastic polymer with elongation at break of 286.15% ± 55.23%. Also, bPLCL preserves the unique crystalline structure of the soft and hard segments to present a more sustainable biodegradability than the rPLCL. The combinative merits make the pre-polymerization technique a promising strategy for a scalable production of PLCL materials for potential biomedical application., (© 2023 Wiley-VCH GmbH.)

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.)

In Pseudomonas aeruginosa , quorum sensing (QS) depends on an interconnected regulatory hierarchy involving the Las, Rhl and Pq s systems, which are collectively responsible for the co-ordinated synthesis of a diverse repertoire of N -acylhomoserine lactones (AHLs) and 2-alkyl-4-quinolones (AQs). Apparent population density-dependent phenomena such as QS may, however, be due to growth rate and/or nutrient exhaustion in batch culture. Using continuous culture, we show that growth rate and population density independently modulate the accumulation of AHLs and AQs such that the highest concentrations are observed at a slow growth rate and high population density. Carbon source (notably succinate), nutrient limitation (C, N, Fe, Mg) or growth at 25 °C generally reduces AHL and AQ levels, except for P and S limitation, which result in substantially higher concentrations of AQs, particularly AQ N -oxides, despite the lower population densities achieved. Principal component analysis indicates that ~26 % variation is due to nutrient limitation and a further 30 % is due to growth rate. The formation of N -(3-oxododecanoyl)-l-homoserine lactone (3OC12-HSL) turnover products such as the ring opened form and tetramic acid varies with the limiting nutrient limitation and anaerobiosis. Differential ratios of N -butanoyl-homoserine lactone (C4-HSL), 3OC12-HSL and the AQs as a function of growth environment are clearly apparent. Inactivation of QS by mutation of three key genes required for QS signal synthesis ( lasI , rhlI and pqsA ) substantially increases the concentrations of key substrates from the activated methyl cycle and aromatic amino acid biosynthesis, as well as ATP levels, highlighting the energetic drain that AHL and AQ synthesis and hence QS impose on P. aeruginosa .

Altersteroids A-D ( 1 - 4 ), four new 9,11-secosteroid-derived γ-lactones, were isolated from cultures of the ascomycete fungus Alternaria sp. Their structures were elucidated primarily by NMR experiments. The absolute configuration of 1 was established by X-ray crystallographic analysis of its di- p -nitrobenzenesulfonate 1a using Cu Kα radiation, whereas those for 2 - 4 were assigned by quantum-chemical calculations. Compounds 1 - 4 incorporate a γ-lactone moiety fused to the steroid D ring at C-13/C-14. Compound 3 showed moderate cytotoxicity toward four tumor cell lines and induced an apoptotic process in A549 cells. Notably, compound 3 showed equipotent activity against the cisplatin-sensitive MB49 and -resistant MB49 CisR cells, with an IC 50 value of 12.7 μM.

Phytochemical investigation of the aerial parts of Artemisia heptapotamica Poljak led to the isolation of ten known compounds, including four alkyl p -coumarates: octadecyl trans - p -coumarate ( 1 ), icosy trans - p -coumarate ( 2 ), docosyl trans - p -coumarate ( 3 ), and tetracosyl trans - p -coumarate ( 4 ), one sesquiterpene lactone: santonin ( 5 ), four flavonoids; axillarin ( 6 ), quercetin 3- O -methyl ether ( 7 ), luteolin ( 8 ), and quercetin ( 9 ), and one phenolic acid derivative: p -coumaric acid ( 10 ). The structures of the isolated compounds were identified by various spectroscopic analyses. Additionally, the antimicrobial activity of the total extract and different fractions was screened, and they exhibited no inhibition of the growth of Candida albicans , C. neoformans , Aspergillus fumigatus , methicillin-resistant Staphylococcus aureus (MRS), E. coli , Pseudomonas aeruginosa , Klebsiella pneumonia , and Vancomycin-resistant Enterococci (VRE) at the tested concentrations ranging from 8 to 200 μg/mL. The identification and tentative characterization of the secondary metabolites were conducted using LC-QToF analysis. This method helps in the putative characterization of sesquiterpene lactones, flavonoids, coumarate derivatives, and aliphatic compounds. The developed method identified 43 compounds, of which the majority were sesquiterpene lactones, such as eudesmanolides, germacranolides, and guaianolide derivatives, followed by flavonoids. The proposed LC-QToF method helps develop dereplication strategies and understand the major class of chemicals before proceeding with the isolation of compounds.

Phytotoxic macrolides attract attention as prototypes of new herbicides. However, their mechanisms of action (MOA) on plants have not yet been elucidated. This study addresses the effects of two ten-membered lactones, stagonolide A (STA) and herbarumin I (HBI) produced by the fungus Stagonospora cirsii , on Cirsium arvense , Arabidopsis thaliana and Allium cepa . Bioassay of STA and HBI on punctured leaf discs of C. arvense and A. thaliana was conducted at a concentration of 2 mg/mL to evaluate phenotypic responses, the content of pigments, electrolyte leakage from leaf discs, the level of reactive oxygen species, Hill reaction rate, and the relative rise in chlorophyll a fluorescence. The toxin treatments resulted in necrotic and bleached leaf lesions in the dark and in the light, respectively. In the light, HBI treatment caused the drop of carotenoids content in leaves on both plants. The electrolyte leakage caused by HBI was light-dependent, in contrast with that caused by STA. Both compounds induced light-independent peroxide generation in leaf cells but did not affect photosynthesis 6 h after treatment. STA (10 µg/mL) caused strong disorders in root cells of A. thaliana leading to the complete dissipation of the mitochondrial membrane potential one hour post treatment, as well as DNA fragmentation and disappearance of acidic vesicles in the division zone after 8 h; the effects of HBI (50 µg/mL) were much milder. Furthermore, STA was found to inhibit mitosis but did not affect the cytoskeleton in cells of root tips of A. cepa and C. arvense , respectively. Finally, STA was supposed to inhibit the intracellular vesicular traffic from the endoplasmic reticulum to the Golgi apparatus, thus interfering with mitosis. HBI is likely to have another main MOA, probably inhibiting the biosynthesis of carotenoids.

Within the large Compositae family, Phitosia is considered a monotypic genus of the Greek flora, with its only species P. crocifolia (Boiss. & Heldr.) Kamari & Greuter growing wild with limited distribution, exclusively on the mountains Taigetos and Parnonas in Peloponnese. P. crocifolia's chemical profile was obtained, herein, for the first time and led to the isolation of 20 compounds, thirteen of which were characterized as sesquiterpene lactones and the rest mainly as phenolic derivatives. The isolates 1: -3, 5:  - 7: and 11:  - 13: represent new chemical structures. Compounds 2: and 3: especially are substituted with a pentose moiety, a rare phenomenon in sesquiterpene lactone backbones. A series of spectrometric and spectroscopic techniques were used to elucidate their structures. The relative configurations of the unreported compounds were established via extensive analysis of NMR spectroscopic and HRESIMS data, assisted by CD spectroscopic measurements. Throughout the entire isolation procedure, selected fractions rich in sesquiterpene lactones were tested against HeLa cancerous cell line for their cytotoxic effects with the lowest IC 50 values being 18.84 µg/mL. Accordingly, among the tested isolates, compounds 5: and 9: exerted IC 50 values of 13.5 µM and 11.4 µM, respectively., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Protein kinase C delta (PKC-δ) is an important signaling molecule in human cells that has both proapoptotic as well as antiapoptotic functions. These conflicting activities can be modulated by two classes of ligands, phorbol esters and bryostatins. Phorbol esters are known tumor promoters, while bryostatins have anti-cancer properties. This is despite both ligands binding to the C1b domain of PKC-δ (δC1b) with a similar affinity. The molecular mechanism behind this discrepancy in cellular effects remains unknown. Here, we have used molecular dynamics simulations to investigate the structure and intermolecular interactions of these ligands bound to δC1b with heterogeneous membranes. We observed clear interactions between the δC1b-phorbol complex and membrane cholesterol, primarily through the backbone amide of L250 and through the K256 side-chain amine. In contrast, the δC1b-bryostatin complex did not exhibit interactions with cholesterol. Topological maps of the membrane insertion depth of the δC1b-ligand complexes suggest that insertion depth can modulate δC1b interactions with cholesterol. The lack of cholesterol interactions suggests that bryostatin-bound δC1b may not readily translocate to cholesterol-rich domains within the plasma membrane, which could significantly alter the substrate specificity of PKC-δ compared to δC1b-phorbol complexes.

Root parasitic weeds such as Striga spp. and Orobanche spp. dramatically reduce the yields of important agricultural crops and cause economic losses of over billions of US dollars worldwide. One reason for the damage by root parasitic weeds is that they germinate after specifically recognizing the host cues, strigolactones (SLs). SLs were identified ˃50 years ago as germination stimulants for root parasitic weeds, and various studies have been conducted to control parasitic weeds using SLs and related chemicals. Recently, biochemical and molecular biological approaches have revealed the SL biosynthesis and SL receptors; using these findings, various SL-related chemicals have been developed. This review summarizes recent research on SLs and their related chemicals for controlling root parasitic weeds., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

There were five sesquiterpene lactones, belonging to the eudesmanolide class, isolated from the halophyte Sonchus brachyotus DC. The structures of the compounds were determined using spectroscopic methods, including 1D and 2D NMR spectra, MS data, and optical rotation values. Compounds 4 and 5 were characterized by the position of p -hydroxyphenylacetyl group in the sugar moiety. In the evaluation of anti-inflammatory effects on LPS-activated RAW264.7 macrophages, compound 1 , 5α,6βH-eudesma-3,11(13)-dien-12,6α-olide, potently suppressed the expression of iNOS and COS-2, as well as the production of TNF-α, IL-6, and IL-10. Treatment of 1 regulates the Nrf2/HO-1 pathway.

Hepatocellular carcinoma has been known as the most frequent subtype of liver cancer with a high rate of spread, metastases, and recurrence, also dismal treatment effects. However, effective therapies for HCC are still required. Nowadays, natural products have been known as a valuable source for drug discovery. In this research, 44 sesquiterpene lactones isolated from the Elephantopus scaber Linn. (Asteraceae) were tested by MTT assay for the antitumor activities. Deoxyelephantopin (DET) was found to exert significant cytotoxicity on HepG2 and Hep3B cells. Moreover, we found that DET treatment markedly reduced the growth of HCC cells in a concentration-dependent manner, which was better than sorafenib. Furthermore, DET induced mitochondrial dysfunction, oxidative stress, and cellular apoptosis. Additionally, we found that DET and sorafenib synergistically induced apoptosis and mitochondrial dysfunction in HCC cells. DET combined with sorafenib was also efficacious in tumor xenograft model. Molecular docking experiments revealed that DET had a potentially high binding affinity with Hsp90α. Moreover, Drug Affinity Responsive Target Stability assay suggested that DET could directly target Hsp90α. Additionally, the expression of Hsp90α was both decreased in vitro and in vivo. Altogether, this study revealed that DET might be a promising agent for HCC therapy by targeting Hsp90α., (© 2022 John Wiley & Sons Ltd.)

Four sesquiterpene lactones, astrodaucanolide A - D (1: -4: ) with unique structures, toghether with two known phenylpropanoid esters (5: and 6: ) were isolated from a flower extract of Astrodaucus orientalis . The structures were established by 1D and 2D NMR spectroscopy and high-resolution mass spectrometry (HRESIMS), and the absolute configuration of 1: -4: was determined by electronic circular dichroism (ECD). Compounds 1: -4: novel architecture represents a new class of sesquiterpenes with new skeleton. A putative biosynthetic pathway for their scaffold is proposed with a germacryl cation as the precursor. The suggested biosynthesis pathway is similar to that of eudesmane sesquiterpenes with a different direction of protonation which then leads to the new skeleton, named astrodaucane by the 1,2-methyl migration., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

An LC-HRMS/MS-based molecular networking strategy was applied to investigate the potential sesquiterpene dimers of Aucklandia lappa, leading to the isolation of three undescribed guaiane-guaiane dimers and one guaiane-eudesmane dimer together with six known sesquiterpenes. The structures were determined by analyzing their 1D, 2D NMR, and HRESIMS data as well as ECD calculations. The biogenetic pathway of the sesquiterpene dimers was postulated to involve the Diels-Alder cycloaddition as the key step. All compounds exhibited their inhibitory effects on LPS-induced nitric oxide production in RAW 264.7 macrophages with IC 50 values ranging from 0.3 to 25.1 μM., 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 © 2022 Elsevier Ltd. All rights reserved.)

The recovery of bioactive compounds from crop byproducts leads to a new perspective way of waste reutilization as a part of the circular economy. The present study aimed at an exhaustive metabolite profile characterization of globe artichoke and cauliflower byproducts (leaves, stalks, and florets for cauliflower only) as a prerequisite for their valorization and future implementations. The metabolite profile of aqueous and organic extracts of byproducts was analyzed using the NMR-based metabolomics approach. Free amino acids, organic acids, sugars, polyols, polyphenols, amines, glucosinolates, fatty acids, phospho- and galactolipids, sterols, and sesquiterpene lactones were identified and quantified. In particular, globe artichoke byproducts are a source of health-beneficial compounds including chiro -inositol (up to 10.1 mg/g), scyllo -inositol (up to 1.8 mg/g), sesquiterpene lactones (cynaropicrin, grosheimin, dehydrocynaropicrin, up to 45.5 mg/g in total), inulins, and chlorogenic acid (up to 7.5 mg/g), whereas cauliflower byproducts enclose bioactive sulfur-containing compounds S -methyl-L-cysteine S -oxide (methiin, up to 20.7 mg/g) and glucosinolates. A variable content of all metabolites was observed depending on the crop type (globe artichoke vs. cauliflower) and the plant part (leaves vs. stalks). The results here reported can be potentially used in different ways, including the formulation of new plant biostimulants and food supplements.

Sesquiterpene lactone (SL) subtypes including hirsutinolide and cadinanolide have a controversial genesis. Metabolites of these classes are either described as natural products or as artifacts produced via the influence of solvents, chromatographic mobile phases, and adsorbents used in phytochemical studies. Based on this divergence, and to better understand the sensibility of these metabolites, different pH conditions were used to prepare semisynthetic SLs and evaluate the anti-inflammatory and antiproliferative activities. Therefore, glaucolide B ( 1 ) was treated with various Brønsted-Lowry and Lewis acids and bases-the same approach was applied to some of its derivatives-allowing us to obtain 14 semisynthetic SL derivatives, 10 of which are hereby reported for the first time. Hirsutinolide derivatives 7a (CC 50 = 5.0 µM; SI = 2.5) and 7b (CC 50 = 11.2 µM; SI = 2.5) and the germacranolide derivative 8a (CC 50 = 3.1 µM; SI = 3.0) revealed significant cytotoxic activity and selectivity against human melanoma SK-MEL-28 cells when compared with that against non-tumoral HUVEC cells. Additionally, compounds 7a and 7c.1 showed strongly reduced interleukin-6 (IL-6) and nitrite (NOx) release in pre-treated M1 macrophages J774A.1 when stimulated with lipopolysaccharide. Despite the fact that hirsutinolide and cadinanolide SLs may be produced via plant metabolism, this study shows that acidic and alkaline extraction and solid-phase purification processes can promote their formation., Competing Interests: The authors declare no conflicts of interest.

Gonioridleylactam ( 1 ), a new compound, is a unique dimeric aristolactam isolated from the EtOAc extract of the twigs of Goniothalamus ridleyi King. The structure of gonioridleylactam ( 1 ) consists of two different aristolactams linked together with two methylenedioxy bridges at C-3/C-3' and C-4/C-4', generating a ten-membered ring of [1,3,6,8]tetraoxecine. A new natural product, gonioridleyindole (3-hydroxymethyl-1-methyl-1 H -benz[ f ]indole-4,9-dione, 2 ), together with eight known compounds ( 3-10 ) were also isolated from this plant. Their structures were extensively characterized by spectroscopic methods and comparisons were made with the literature. Compounds 1-4 , 7 , and 9 were evaluated for their α -glucosidase inhibitory activity. Of these, 3,5-demethoxypiperolide ( 7 ) displayed the highest α -glucosidase inhibitory activity, with an IC 50 value of 1.25 µM.

Herein, we report direct electrochemical C(sp 3 )-H lactonization of 2-alkylbenzoic acids toward phthalides. The reaction provides a wide substrate scope of 2-alkylbenzoic acids bearing primary to tertiary C(sp 3 )-H bonds by utilizing a graphite anode, dichloromethane (DCM) solvent, hexafluoroisopropanol (HFIP) cosolvent, and n -Bu 4 NClO 4 electrolyte. Our synthetic approach offers a simple, intuitive, and atom-economical protocol to synthesize various phthalides (25 examples, up to 92% yield) and obtain other 5- and 6-membered lactones (10 examples, up to 83% yield).

Cyclopropane-fused lactones are highly desirable in drug and natural products synthesis. Herein, we report on a photochemical, chemoselective reaction of aryldiazoacetates with allylic alcohols that furnishes cyclopropane-fused lactone skeletons efficiently in one step. The diastereoselectivity of the protocol was precisely controlled, and chemoselective cyclopropanation of allylic alcohols via free carbene intermediate followed by transesterification constitutes a series of bicyclic lactones in high yield without the formation of ether byproducts via typical O-H insertion reactions.

Centaurea is a genus compromising over 250 herbaceous flowering species and is used traditionally to treat several ailments. Among the Egyptian Centaurea species, C. lipii was reported to be cytotoxic against multidrug-resistant cancer cells. In this context, we aimed to explore the metabolome of C. lipii and compare it to other members of the genus in pursuance of identifying its bioactive principles. An LC-MS/MS analysis approach synchronized with feature-based molecular networks was adopted to offer a holistic overview of the metabolome diversity of the Egyptian Centaurea species. The studied plants included C. alexandrina, C. calcitrapa, C. eryngioides, C. glomerata, C. lipii, C. pallescens, C. pumilio, and C. scoparia . Their constitutive metabolome showed diverse chemical classes such as cinnamic acids, sesquiterpene lactones, flavonoids, and lignans. Linking the recorded metabolome to the previously reported cytotoxicity identified sesquiterpene lactones as the major contributors to this activity. To confirm our findings, bioassay-guided fractionation of C. lipii was adopted and led to the isolation of the sesquiterpene lactone cynaropicrin with an IC 50 of 1.817 µM against the CCRF-CEM leukemia cell line. The adopted methodology highlighted the uniqueness of the constitutive metabolome of C. lipii and determined the sesquiterpene lactones to be the responsible cytotoxic metabolites.

Dibenzylbutyrolactone lignans (DBLs) are a class of natural products with a wide variety of biological activities. Due to their potential for the development of human therapeutic agents, DBLs have been subjected to various SAR studies in order to optimise activity. Previous reports have mainly considered changes on the aromatic rings and at the benzylic carbons of the compounds, whilst the effects of substituents in the lactone, at the C-9' position, have been relatively unexplored. This position has an unexploited potential for the development of novel dibenzyl butyrolactone derivatives, with previous preliminary findings revealing C-9'-hydroxymethyl analogues inducing programmed cell cycle death. Using the core structure of the bioactive natural product arctigenin, C-9' derivatives were synthesised using various synthetic pathways and with prepared derivatives providing more potent anti-proliferative activity than the C-9'-hydroxymethyl lead compound.

Herein, we disclose the first report on the generation of cyanonitrone in situ from diazoacetonitrile and nitrosoarene, and its subsequent [3+2] cycloaddition with oxabicyclic alkenes to access fused tricyclic cyanoisoxazolidines. Further, this methodology could be extended to access fused tricyclic trifluoromethylated and phosphonylated isoxazolidines. Surprisingly, the reductive ring-opening of cyanoisoxazolidines was followed by a spontaneous lactonization to produce fused tricyclic amino lactones. Moreover, the N-O bond of the obtained tricyclic trifluoromethylated isoxazolidines could be cleaved to obtain 1,3-amino alcohols.

Bioplastics are one of the answers to environmental pollution and linear material flows. The most promising bioplastic polylactide (PLA) is already replacing conventional plastics in a number of applications. The properties of PLA, however, do not fit for all potential application areas, but they can be altered by the introduction of comonomers. The copolymerization of lactide (LA) with other lactones like ϵ-caprolactone (CL) has been established for several years. Nevertheless, controlling copolymerizations remains a challenge due to the high complexity of the system. Copolymerization of LA with other monomer classes is much less investigated, but has the chance to overcome the limitations in material properties that occur when only lactones are used. The crucial factor for all copolymerizations is the catalyst. It dominates the reaction kinetics and determines the resulting microstructure. In this review, copolymerization catalysts for LA are presented divided into catalysts for the synthesis of lactone block copolymers, lactone random copolymers, and multimechanistically synthesized copolymers. The selected catalysts are highlighted either owing to their industrially applicable polymerization conditions or their non-standard mechanism., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Sesquiterpene lactones are natural products of the Asteraceae family that have shown trypanocidal activity against Trypanosoma cruzi , even exceeding the effectiveness of drugs used in the treatment of American trypanosomiasis. However, there is no agreement on their mechanism of action and their specificity to interact with parasite proteins. For this reason, we aimed to find biological targets that can interact with these compounds by reverse virtual screening with ligand pharmacophores and putative binding sites and the use of bioinformatic databases. Therefore, 41 possible biological targets were found, and four of them (with crystallized proteins), interfering directly or indirectly in the trypanosomatid redox system, were studied in detail. As a first approach, we focused on the study of trypanothione reductase, and protein-ligand interaction fingerprint analyses were performed to find binding site determinants that promote a possible inhibition of the enzyme. This study contributes to the understanding of one of the putative mechanisms of action of sesquiterpene lactones on one of the numerous suggested targets.Communicated by Ramaswamy H. Sarma.

The enantiomeric pure and natural (+)-Lactones (C ≤ 14) with aromas obtained from fruits and milk are considered flavoring compounds. The flavoring value is related to the lactones' ring size and chain length, which blend in varying concentrations to produce different stone-fruit flavors. The nature-identical and enantiomeric pure (+)-lactones are only produced through whole-cell biotransformation of yeast. The industrially important γ-decalactone and δ-decalactone are produced by a four-step aerobic-oxidation of ricinoleic acid (RA) following the lactonization mechanism. Recently, metabolic engineering strategies have opened up new possibilities for increasing productivity. Another strategy for increasing yield is to immobilize the RA and remove lactones from the broth regularly. Besides flavor impact, γ-, δ-, ε-, ω-lactones of the carbon chain (C8-C12), the macro-lactones and their derivatives are vital in pharmaceuticals and healthcare. These analogues are isolated from natural sources or commercially produced via biotransformation and chemical synthesis processes for medicinal use or as active pharmaceutical ingredients. The various approaches to biotransformation have been discussed in this review to generate more prospects from a commercial point of view. Finally, this work will be regarded as a magical brick capable of containing both traditional and genetic engineering technology while contributing to a wide range of commercial applications.

Ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) combined with multivariate statistical analysis was applied to the study of plant metabolomics to reveal the factors affecting the content of ginkgo leaf compounds. As a follow-up analysis, the terpene lactones and ginkgolic acids were quantified simultaneously using ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-QqQ-MS/MS), and subsequently total flavonol glycosides were quantified by high-performance liquid chromatography (HPLC). The results revealed that a total of 52 compounds were potentially identified by establishing a database, and 10 compounds were verified by reference standards; terpene lactones, ginkgolic acids, and flavonoids were the differential compounds; and ginkgolide A was identified as an important indicator compound for tree age. In addition, quantitative analysis showed that the contents of total flavonol glycosides and terpene lactones were highest during April and August in young ginkgo leaves, and differed based on origin. In summary, numerous compounds were rapidly detected by liquid chromatography coupled with MS, the ginkgo leaf samples were compared, and the differential metabolites were screened out. The content changing rules of the target compounds in ginkgo leaves from different regions with different tree ages and harvesting periods were clarified., 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 © 2022 Elsevier B.V. All rights reserved.)

Lactones are prevalent in biological and industrial settings, yet there is a lack of information regarding enzymes used to metabolize these compounds. One compound, γ-valerolactone (GVL), is used as a solvent to dissolve plant cell walls into sugars and aromatic molecules for subsequent microbial conversion to fuels and chemicals. Despite the promise of GVL as a renewable solvent for biomass deconstruction, residual GVL can be toxic to microbial fermentation. Here, we identified a Ca 2+ -dependent enzyme from Rhodopseudomonas palustris (Rpa3624) and showed that it can hydrolyze aliphatic and aromatic lactones and esters, including GVL. Maximum-likelihood phylogenetic analysis of other related lactonases with experimentally determined substrate preferences shows that Rpa3624 separates by sequence motifs into a subclade with preference for hydrophobic substrates. Additionally, we solved crystal structures of this β-propeller enzyme separately with either phosphate, an inhibitor, or a mixture of GVL and products to define an active site where calcium-bound water and calcium-bound aspartic and glutamic acid residues make close contact with substrate and product. Our kinetic characterization of WT and mutant enzymes combined with structural insights inform a reaction mechanism that centers around activation of a calcium-bound water molecule promoted by general base catalysis and close contacts with substrate and a potential intermediate. Similarity of Rpa3624 with other β-propeller lactonases suggests this mechanism may be relevant for other members of this emerging class of versatile catalysts., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The catalytic conversion of carbon dioxide and 1,3-butadiene into unsaturated lactone monomers provides an efficient route for converting sustainable carbon feedstocks into novel macromolecules. The chemical reactivity of this monomer is reviewed in order to highlight the many viable mechanistic pathways. Polymerization strategies, monomer alterations, and post-polymerization modifications are covered. The polymerization methods include radical, coordination, conjugate addition, ring-opening, olefin metathesis, and thiol-ene chemistries. Materials derived from these processes possess a wide range of function including responsiveness, degradability, adhesion, recyclability, and self-assembly. These aspects along with the advances in polymer chemistry that make them possible are discussed, along with a perspective on the future directions of the field., (© 2022 The Authors. Macromolecular Rapid Communications published by Wiley-VCH GmbH.)

Orobanche cumana Wallr. ( Orobanche cernua Loefl.) causes severe yield losses of confectionary sunflower in China. While germination of O. cumana is stimulated by sesquiterpene lactones (STLs) from host sunflower ( Helianthus annuus L.). Dehydrocostus lactone and costunolide isolated from sunflower root exudates are known as STLs to specifically induce O. cumana germination. Two major confectionary sunflower cultivars, SH363 (highly susceptible to O. cumana ) and TH33 (resistant to O. cumana ), were planted in China. However, STLs in these two sunflower cultivars has remained unknown. To identify STLs from root and exudates of sunflower for better understanding the role of stimulants in parasitic interaction of sunflower and O. cumana , we tested dehydrocostus lactone (DCL) and costunolide (CL) in root and root exudates of susceptible and resistant sunflower cultivars. The stimulant activity of sunflower root exudate and root extract to germination of O. cumana were also determined. Dehydrocostus lactone and costunolide were identified through ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS). Both DCL and CL were found in root extracts and root exudates in the whole tested time point from two sunflower cultivars. The concentration of dehydrocostus lactone was higher than that of costunolide at the same tested growth stage of each sunflower cultivar. It was observed that higher quantity of dehydrocostus lactone in susceptible cultivar than resistant cultivar of root and root exudates at later tested developmental stages. However, the amount of CL was no significant difference between SH363 and TH33 at all tested stages. The release amount of DCL from susceptible cultivar is 3.7 folds that of resistant cultivar at 28 DAT. These findings suggested that DCL was the one of the major signal compound in these two sunflower cultivars, and lower dehydrocostus lactone might contribute to the resistance of sunflower TH33 to O. cumana .

This article describes the first total synthesis of luminamicin using a strategy combining chemical degradation with synthesis. Chemical degradation studies provided a sense of the inherent reactivity of the natural product, and deconstruction of the molecule gave rise to a key intermediate, which became the target for chemical synthesis. The core structure of the southern part of luminamicin was constructed by a 1,6-oxa-Michael reaction to form an oxa-bridged ring, followed by coupling with a functionalized organolithium species. Modified Shiina macrolactonization conditions forged the strained 10-membered lactone containing a tri-substituted olefin. Diastereoselective α-oxidation of the 10-membered lactone completed the center part to provide the key intermediate. Inspired by the degradation study, an unprecedented enol ether/maleic anhydride moiety was constructed with a one-pot chlorosulfide coupling and thiol β-elimination sequence. Finally, macrolactonization to the 14-membered ring in the presence of the highly electrophilic maleic anhydride moiety was accomplished using modified Mukaiyama reagents to complete the synthesis of luminamicin.

Using the methodology of "click" chemistry, a singular method has been developed for the synthesis of unique conjugates based on sesquiterpene lactones: dehydrocostuslactone and alantolactone with polyalkoxybenzenes. To expand the structural range of the resulting conjugates, the length of the 1,2,3-triazole spacer was varied. For all synthesized compounds, the cytotoxic profile was determined on the cell lines of tumor origin (SH-SY5Y, HeLa, Hep-2, A549) and normal Hek 293 cells. It was found that the compounds based on alantolactone 7a - d with a long spacer and substances containing dehydrocostuslactone 10a - d with a short spacer have the greatest toxic effect. The decrease in cell survival under the action of these conjugates may be due to their ability to cause dissipation of the transmembrane potential of mitochondria and inhibit the process of glycolysis, leading to cell death. The obtained results confirm the assumption that the development of conjugates based on sesquiterpene lactones and polyalkoxybenzenes can be considered as a promising strategy for the search for potential antitumor agents.

A library of more than 2500 plant extracts was screened for activity on oncogenic signaling in melanoma cells. The ethyl acetate extract from the aerial parts of Artemisia argyi displayed pronounced inhibition of the PI3K/AKT pathway. Active compounds were tracked with the aid of HPLC-based activity profiling, and altogether 21 active compounds were isolated, including one novel dimerosequiterpenoid ( 1 ), one new disesquiterpenoid ( 2 ), three new guaianolides ( 3 - 5 ), 12 known sesquiterpenoids ( 6 - 17 ), and four known flavonoids ( 19 - 22 ). A new eudesmanolide derivative ( 13b ) was isolated as an artifact formed by methanolysis. Compound 1 is the first adduct comprising a sesquiterpene lactone and a methyl jasmonate moiety. The absolute configurations of compounds 1 and 3 - 18 were established by comparison of their experimental and calculated ECD spectra. The absolute configuration for 2 was determined by X-ray diffraction analysis. Guaianolide 8 was the most potent sesquiterpene lactone, inhibiting the PI3K/AKT pathway with an IC 50 value of 8.9 ± 0.9 μM.

Interest in the marine cyanobacteria natural products aplysiatoxin (ATX) and oscillatoxin (OTX) has been renewed recently due to the discovery of many new analogues, some exhibiting intriguing biological activities. We sought to develop a collective synthesis of these natural products, hypothesizing that ATX could serve as a common biosynthetic precursor. Herein, we reveal that the core structure of ATX has unique multiple reactivities giving access to the distinct ring structures of five of the analogues, depending upon the specific conditions used. Based on these findings, syntheses of the O -Me derivative of five analogues neo-deBr-ATX-B, OTX-H, OTX-D, neo-deBr-ATX-H, and OTX-I were achieved from the main fragment of ATX as a common intermediate in a few steps. These synthetic studies also led us to revise the relative configuration in the elucidated structures of neo-deBr-ATX-B and OTX-H, and obtain unnatural 8- and 12-membered lactones from the same intermediate.

One of the goals of diversity-oriented synthesis is to achieve the structural diversity of obtained compounds. As most biologically active compounds are chiral, it is important to develop enantioselective methods of their synthesis. The application of kinetic resolution in DOS is problematic because of low efficiency (max. 50% yield) and many purification steps. The further derivatization of kinetic resolution products in DOS leads to the formation of a narrow library of compounds of the same stereochemistry. To overcome these limitations, we present a new concept in which the kinetic resolution is combined, the subsequent reaction of which in a one-pot protocol leads to the simultaneous formation of two skeletally and enantiomerically diverse platform molecules for DOS. Their further derivatization can gain access to a double-sized library of products in respect to a classical approach. The validity of our concept was evidenced in enzymatic kinetic resolution followed by a ring-closing metathesis cascade. From racemic carboxylic acid ester, a simultaneous formation of enantiopure lactones and lactams was achieved. These compounds are important building blocks in organic and medicinal chemistry and until now were synthesized in separate procedures.

Three sesquiterpene lactones ( 1-3 ) were isolated from the aerial part of Tithonia diversifolia (Hemsl.) A. Gray grown in the Hoa Binh province in Viet Nam. The structures of these three sesquiterpene lactones were identified as tagitinin A ( 1 ), 1 β -hydroxytirotundin 3-O-methyl ether ( 2 ), and tagitinin C ( 3 ) by analyzing spectroscopic data. For the first time, compound 2 was isolated from T. diversifolia growing in Viet Nam. Furthermore, contrary to existing literature, we determined that compound 1 was the major isolate. Compounds 1 and 3 significantly decreased numbers of acute myeloid leukemia OCI-AML3 cells by promoting apoptosis and causing cell cycle arrest at G0/G1 phase at concentrations as low as 2.5 μg/mL (compound 1 ) and 0.25 μg/mL (compound 3 ). Additionally, all three compounds showed cytotoxic activity against five human cancer cell lines (A549, T24, Huh-7, 8505, and SNU-1), with IC 50 values ranging from 1.32 ± 0.14 to 46.34 ± 2.74 μM. Overall, our findings suggest that compounds 1 and 3 may be potential anti-cancer therapeutics and thus warrant further study., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Ginkgolide is a unique terpenoid natural compound in Ginkgo biloba , and it has an important medicinal value. Proper selenium has been reported to promote plant growth and development, and improve plant quality, stress resistance, and disease resistance. In order to study the effects of exogenous selenium (Se) on the physiological growth and the content of terpene triolactones (TTLs) in G. biloba seedlings, the seedlings in this work were treated with Na 2 SeO 3 . Then, the physiological indexes, the content of the TTLs, and the expression of the related genes were determined. The results showed that a low dose of Na 2 SeO 3 was beneficial to plant photosynthesis as it promoted the growth of ginkgo seedlings and increased the root to shoot ratio. Foliar Se application significantly increased the content of soluble sugar and protein and promoted the content of TTLs in ginkgo leaves; indeed, it reached the maximum value of 7.95 mg/g in the ninth week, whereas the application of Se to the roots inhibited the synthesis of TTLs. Transcriptome analysis showed that foliar Se application promoted the expression levels of GbMECPs , GbMECT , GbHMGR , and GbMVD genes, whereas its application to the roots promoted the expression of GbDXS and GbDXR genes. The combined analysis results of metabolome and transcriptome showed that genes such as GbDXS , GbDXR , GbHMGR , GbMECPs , and GbCYP450 were significantly positively correlated with transcription factors (TFs) GbWRKY and GbAP2 / ERF , and they were also positively correlated with the contents of terpene lactones (ginkgolide A, ginkgolide B, ginkgolide M, and bilobalide). Endogenous hormones (MeJA-ILE, ETH, and GA7) were also involved in this process. The results suggested that Na 2 SeO 3 treatment affected the transcription factors related to the regulation of endogenous hormones in G. biloba , and further regulated the expression of genes related to the terpene synthesis structure, thus promoting the synthesis of ginkgo TTLs.

Phytochemical investigation of the aerial parts of Artemisia kopetdaghensis resulted in the isolation and characterization of three undescribed eudesmane-type sesquiterpene lactones, persianolide A, 4-epi-persianolide A, and 3α,4-epoxypersianolide A, together with three previously described eudesmane-type sesquiterpene lactones, 11-epi-artapshin, 1β,8α-dihydroxy-11α,13-dihydrobalchanin, and 1β-hydroxy-11-epi-colartin. The abundantly obtained 11-epi-artapshin was oxidized to undescribed 11α,13-dihydroeudesma-12,6α-olide-1,8-dione and 8β-hydroxy-11α,13-dihydroeudesma-12,6α-olide-1-one and acetylated to the undescribed 1,8-O-diacetyl-11α,13-dihydroeudesma-12,6α-olide. Structures were elucidated based on extensive spectral data analyses, including 1D and 2D NMR and HRESIMS. The absolute configuration was determined using calculated and experimental ECD spectral data. Compounds were subsequently subjected to the MTT assay to evaluate their cytotoxicity against prostate cancer cells (DU-145 and LNCaP). Related factors associated with the sequence of apoptosis were tested by ELISA, western blotting, and biochemical assay. Results suggested that 11-epi-artapshin hinders the growth of DU-145 cells through mitochondria-mediated apoptosis initiated by stimulation of ROS build-up, ΔΨm depletion, regulation of the Bax/Bcl-2 ratio, and activation of caspase 3, respectively., 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 © 2022 Elsevier Ltd. All rights reserved.)

There are several forms of kava ( Piper methysticum ) products available for human consumption, and many factors are known to influence their chemical compositions and therefore their pharmacological properties. Because of the increased popularity of kava intake, a rigorous characterization of their content diversity is prerequisite, particularly due to its known potential to cause hepatotoxicity. To understand the composition diversity of kavalactones and flavokavains in commercial kava products, we developed a UPLC-MS/MS-based analytical method for the quantification of six kavalactones (kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin and desmethoxyyangonin) and two flavokavains (flavokavains A and B) and analyzed their contents in 28 different kava products in the form of capsules, tinctures, traditional aqueous suspensions and dried powders. Our results demonstrated a great variation in terms of the total and relative abundance of the analyzed kavalactones and flavokavains among the analyzed kava preparations. More importantly, the kavalactone abundance in the product label could differ up to 90% from our experimental measurements. Therefore, more rigorous and comprehensive quality control of kava products is required with respect to the content of individual kavalactones and flavokavains. Accurate content information is essential to understand the pharmacological properties and safety of different kava products., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Optimal heat treatment of the soymilks is important to the production of tofu. In this study, soymilk with protein concentration of 40 mg/mL were heated at different temperatures for the fixed 50 s and were characterized by surface hydrophobicity, disulfide linked protein species determined by non-reducing SDS-PAGE and protein structural elements determined by the circular dichroism (CD). Tofu gels were prepared by acidifying the heated soymilks at 60 ℃ and 80 ℃ respectively and gelation time, gel mechanical properties as well as gel viscoelastic properties were determined by rheological analysis. The results showed that most soymilks' properties except surface hydrophobicity changed rapidly when heating temperature was higher than 80 ℃. Gelation time, storage modulus (G') at the end of acidifying and cooling processes as well as retardation time (λ) and recovery rate of tofu gels were affected by the heat treatments of soymilks. The distances between the standardized data describing heated soymilks and tofu gels respectively were calculated and compared. It was found that gelation time, G' and λ were most closely related to disulfide bond linked polymer, [CD] 222 and surface hydrophobicity respectively. This study will provide useful information to the improvement of tofu processing., 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 © 2022. Published by Elsevier Ltd.)

Two new sesquiterpenoid lactone derivatives, linderin A ( 1 ) and linderin B ( 2 ) comprising a sesquiterpenoid lactone and a methyl geranylhomogentisate moiety together with six known compounds were isolated from the roots of Lindera aggregata . Their chemical structures were elucidated using extensive spectroscopic analysis including 1 D, 2 D NMR, and HR-ESI-MS data and compared with previously reported data. The absolute configurations of 1 and 2 were assigned based on the electronic circular dichroism calculation. Compound 2 showed moderate anticoagulant activity.

Development of a synthetic route applicable to d-ribose and d-xylose enabled the synthesis of cleistanolate putative structure, its five stereoisomers, and led to revision and confirmation of absolute stereochemistry of the natural product. Key steps of the synthesis included zinc-mediated THF ring-opening and stereoselective dihydroxylation under the Upjohn conditions. The first total synthesis of cleistanolate was completed in eight steps starting from d-xylose. The C-5 stereocenter of the natural product was assigned the correct (5S)-stereochemistry. Cytotoxicity of natural product was briefly investigated., 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 © 2022 Elsevier Inc. All rights reserved.)

Seven undescribed sesquiterpene lactone dimers (SLDs) (carpeabrodilactones A-G), one known SLD, and six known sesquiterpenes were isolated from the fruit of Carpesium abrotanoides L. Carpeabrodilactone A was a dimeric carabrane featuring a rare C-13-C-13' linkage. Carpeabrodilactones B and C are the first two SLDs to be described possessing a carabranolide unit and a guaianolide unit connected by an O-ether linkage. The structures of the SLDs were assigned based on HRESIMS, NMR analysis, 13 C NMR calculation, ECD calculation, and modified Mosher's method. Four SLDs showed potent cytotoxicity against K562 and/or A549 cells, with IC 50 values below 10 μM, but none inhibited protein tyrosine phosphatases at 40 μM, including PTP1B, SHP1, CD45, and TCPTP., 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 © 2022 Elsevier Ltd. All rights reserved.)

Based on a previously reported 1,4-dihydropyridinebutyrolactone virtual screening hit, nine lactone ring-opened ester and seven amide analogs were prepared. The analogs were designed to provide interactions with residues at the entrance of the ZA loop of the testis-specific bromodomain (ZA) channel to enhance the affinity and selectivity for the bromodomain and extra-terminal (BET) subfamily of bromodomains. Compound testing by AlphaScreen showed that neither the affinity nor the selectivity of the ester and lactam analogs was improved for BRD4-1 and the first bromodomain of the testis-specific bromodomain (BRDT-1). The esters retained affinity comparable to the parent compound, whereas the affinity for the amide analogs was reduced 10-fold. A representative benzyl ester analog was found to retain high selectivity for BET bromodomains as shown by a BROMOscan. X-ray analysis of the allyl ester analog in complex with BRD4-1 and BRDT-1 revealed that the ester side chain is located next to the ZA loop and solvent exposed., (© 2022 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

Cichorium intybus L. (Asteraceae), belonging to the tribe Cichorieae of the family Asteraceae, has a long history as an edible and medicinal food. Sesquiterpene lactones are commonly considered as its major active constituents. In the current study, five unreported sesquiterpene lactones, including one 12,8-guaianolide and four 12,6-guaianolides were isolated from C. intybus roots, as well as 16 known analogues. The planar structures and relative configurations of these compounds were elucidated by extensive spectroscopic analysis. The absolute configurations were determined by the time-dependent density functional theory (TDDFT)-based electronic circular dichroism (ECD) calculation method. Bioassay results showed that seven of the isolates exhibited remarkable NO production inhibitory activity in LPS-stimulated RAW264.7 macrophages, with IC 50 values ranging from 1.83 to 38.81 μM. Some of them can significantly decrease the secretion of inflammatory cytokines (TNF-α and IL-6). Cytotoxicity assays demonstrated that intybusins B, as well as four known compounds, displayed obvious inhibitory activities against four human tumor cells, with IC 50 values ranging from 9.01 to 27.07 μM., 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 © 2022 Elsevier Ltd. All rights reserved.)

Synthetic biopolymers are attractive alternatives to biobased polymers, especially because they rarely induce an immune response in a living organism. Poly ε-caprolactone (PCL) is a well-known synthetic aliphatic polyester universally used for many applications, including biomedical and environmental ones. Unlike poly lactic acid (PLA), PCL has no chiral atoms, and it is impossible to play with the stereochemistry to modify its properties. To expand the range of applications for PCL, researchers have investigated the possibility of grafting polymer chains onto the PCL backbone. As the PCL backbone is not functionalized, it must be first functionalized in order to be able to graft reactive groups onto the PCL chain. These reactive groups will then allow the grafting of new reagents and especially new polymer chains. Grafting of polymer chains is mainly carried out by "grafting from" or "grafting onto" methods. In this review we describe the main structures of the graft copolymers produced, their different synthesis methods, and their main characteristics and applications, mainly in the biomedical field.

Catalytic asymmetric dynamic kinetic resolution of configurationally labile bridged biaryls is emerging as a powerful strategy for atropisomer synthesis. However, the reported examples suffer from an inherent challenge as the reactivity is highly dependent on the torsional strain of the biaryl substrates, which significantly narrows down the scope and hampers the application. Herein, we report our discovery and development of a torsional strain-independent reaction between biaryl thionolactones and activated isocyanides. By employing auto-tandem silver catalysis, a universal synthesis of both tri- and tetra-ortho-substituted thiazole-containing biaryls was realized in high yields with high enantioselectivities. In addition, these products could be facilely converted to a novel type of bridged biaryls bearing an eight-membered lactone. Mechanistic studies were carried out to elucidate the cause of this unusual torsional strain-independent reactivity., (© 2022 Wiley-VCH GmbH.)

Molecular network analysis of Streptomyces sp. CMB-MW079 detected rare phosphorylated natural products. Miniaturized cultivation profiling (MATRIX) established optimal conditions for the production, isolation, and identification of the polyketide δ-lactone phoslactomycin E ( 1 ) and new ester homologues, phoslactomycins J and K ( 2 and 3 ), as well as unprecedented heterocyclic analogues, the tetrahydrofuran cyclolactomycins A-D ( 4 - 7 ) and γ-lactone isocyclolactomycins A-C ( 8 - 10 ). We propose a biogenetic relationship linking these cometabolites with the known lactomycins A-C which were tentatively identified as minor cometabolites.