Search

The vanillyl alcohol oxidase/p-cresol methylhydroxylase (VAO/PCMH) flavoprotein family comprises a broad spectrum of enzymes capable of catalyzing the oxidative bioconversions of various substrates. Among them, pinoresinol hydroxylase (PinH) from the 4-alkylphenol oxidizing subgroup initiates the oxidative degradation of (+)-pinoresinol, a lignan important for both lignin structure and plant defense. In this study, we present a detailed biochemical and structural characterization of PinH from Pseudomonas sp., with focus on its substrate specificity and product formation. PinH was expressed in E. coli and purified as FAD-containing, soluble protein. The flavoenzyme catalyzes the hydroxylation of both (+)-pinoresinol and eugenol. Structural analysis reveals its dimeric form, non-covalent flavin binding, and a large active site. AlphaFold models of the PinH-cytochrome complex demonstrate cytochrome's dual role in electron transfer and modulating PinH's conformation. A distinctive feature of PinH is a large cavity that hosts its multi-ring (+)-pinoresinol substrate. The capability of converting bulky lignans is particularly attractive for biotechnological applications aimed at producing high-value compounds from phenolic precursors. These insights expand our knowledge on the structure and mechanism of the VAO/PCMH flavoenzyme family members., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study focused on extracting holocellulose from Changbai larch waste, which is rich in hexose and beneficial for furan chemicals production. Various alkaline deep eutectic solvents (DESs) was applied in the extraction of holocellulose. DES composed of lysine (Lys) and 2-aminoethanol (MEA) with strong alkalinity had a superior ability to remove lignin, and the purity of holocellulose could reach 82.7 %. Consequently, a double-acid system formed by a temperature-controlled polyoxometalates catalyst (Ch n H 3-n PW 12 , n = 1, 2, 3,) prepared by choline chloride (ChCl) and phosphotungstic acid (H 3 PW 12 O 40 ) and different metal salts were used in the hydrolysis of holocellulose to 5-hydroxymethylfurfural (HMF) and 2-furaldehyde (FF) in a two-phase system of water and organic solvent. The yields of HMF and FF reached 43.5 % and 78.2 %, respectively, when ChH 2 PW 12 and AlCl 3 were employed under the conditions of 10 mL water/methyl isobutyl ketone (MIBK) (1:9, V:V), 9 h, and 150 °C. ChH 2 PW 12 is easy to recycle and can be used up to 5 times. This study offers a novel strategy to retain as much hemicellulose as possible to achieve holocellulose by alkaline DESs, and the one-pot process by the coordination of polyoxometalates and metal salt provides a simultaneous production of high-value furan chemicals from larch waste., 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. Published by Elsevier B.V.)

A comprehensive analysis of 89 commercial baby food samples showed the highest levels of furan in ready-to-eat full meals and vegetable purees (12-118 μg/kg). The alkylated furans (2- and 3-methylfuran, 2-ethylfuran, 2-pentylfuran) were predominantly found in these baby food categories. Furfuryl alcohol was notably abundant in ready-to-eat cereal porridge (3,550-13,100 μg/kg). The addition of lactose to self-made cereal porridge strongly influenced the formation of furfuryl alcohol. After reheating selected commercial baby food samples, a reduction of furan by 38 %, methylfurans by 28 %, and 2-ethylfuran by 26 % has been achieved. Raw materials, vegetable varieties, and storage conditions had a major impact on furan formation, which requires an adaptation of processing parameters. The most promising mitigation of furan (by 44 %) and most furan derivatives in vegetable puree were achieved by adding the additive calcium lactate gluconate. In contrast, in cereal porridge, the formation of furfuryl alcohol was reduced by 28 %., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Efficient regeneration of NAD + remains a significant challenge for oxidative biotransformations. In order to identify enzymes with higher activity and stability, a panel of NADH oxidases (Nox) was investigated in the regeneration of nicotinamide cofactors for the oxidation of hydroxymethyl furfural (HMF) to 5-hydroxymethyl-2-furancarboxylic acid (HMFCA). We present novel Nox that exhibit remarkable catalytic activities, elevated thermal and pH stabilities, and higher intrinsic flavin loadings, thus eliminating the need for external flavin addition. The kinetic analysis of the NADH oxidases indicates that AdNox, GdNox, CmNox, and LvNox exhibit V max values of 86 U/mg, 50 U/mg, 4.3 U/mg, and 23 U/mg, respectively. When these NADH oxidases were applied in a HMF oxidation reaction, LvNox demonstrated the highest HMFCA yield of 97 % in the presence of 0.1 mM NAD and 10 mM HMF. In contrast to previously reported NADH oxidases from the same family, these NADH oxidases naturally accept NADPH as a substrate. Rapid kinetics experiments identified the oxidative reaction as the rate-limiting step of the reaction. NADH oxidases achieved high atom economy, a high reaction mass efficiency and a low process mass intensity. The findings contribute significantly to the field of biocatalysis and offer potential avenues for more environmentally friendly cofactor regeneration in chemical synthesis., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Robert Kourist reports financial support was provided by European Commission. Karishma Shah reports financial support was provided by European Commission. If there are other authors, they 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 The Authors. Published by Elsevier B.V. All rights reserved.)

The biomass-derived furan aldehydes furfural (FF) and 5-hydroxymethylfurfural (HMF) are versatile platform chemicals used to produce various value-added chemicals through further valorization processes. Selectively reducing C═O in FF and HMF molecules to form furfuryl alcohol (FAL) and 2,5-bis(hydroxymethyl)furan (BHMF), represents an important research field in upgrading biomass-based furan compounds. Currently, the reduction of furan aldehydes to furan alcohols through chemical transformation often leads to unavoidable environmental issues and the formation of potential byproducts. Biocatalysis has demonstrated expanded applications in converting biomass-derived furan aldehydes into a diverse array of value-added chemicals. This process exhibits significant potential in organic synthesis and biotechnology due to its green and sustainable properties. The biocatalytic reduction of FF and HMF represents an especially important route for the selective synthesis of FAL and BHMF. This review discusses recent progress in the biosynthesis of FAL and BHMF from biomass-derived FF and HMF through biocatalytic processes. Recently discovered enzymes and whole cells used as biocatalysts for the production of furan alcohols are summarized. In addition, chemoenzymatic cascades for synthesizing furan alcohols from biomass hydrolysate and raw biomass materials are also discussed.

Reversed-phase liquid chromatography (RPLC) offers significant advantages over traditional methods for estimating octanol-water partition constants, which are a critical parameter in drug discovery. In contrast to classical methods for determining the octanol-water partition constant, such as shake-flask techniques, RPLC is less time-consuming and easier to automate. In this study, we explored three alternative organic solvent modifiers: acetone, 2-propanol, and tetrahydrofuran for the indirect determination of the octanol-water partition constant for neutral compounds by RPLC using either isocratic retention factors or retention factors extrapolated to 100 % water for several stationary phases. The Kinetex XB C18 column with acetone-water mobile phase compositions gave the best results for the construction of correlation models for the prediction of the octanol-water partition constant of varied compounds employing isocratic retention factors for 20 % (v/v) acetone-water and retention factors extrapolated to 100 % water. Retention factors extrapolated to 100 % water were nearly as good as the isocratic retention factors with a standard error of 0.136 and Fisher statistic of 1446 for the correlation model compared with a standard error of 0.122 and Fisher statistic of 1456 for the 20 % (v/v) acetone-water model. An XTerra MS C18 column with 10 % (v/v) tetrahydrofuran-water gave the best model for predicting the octanol-water partition constants with a standard error of 0.106 and Fisher statistic of 2806., 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 work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Viridin and viridiol, along with wortmannin, metabolized by filamentous fungus Trichoderma virens, are identical furanosteroids with high-potent inhibitory activity towards phosphatidylinositol 3-kinase (PI3K) that associates the growth of tumor cells. Therefore, structure-activity relationship study (SAR) of these furanosteroids contributes to the development of novel drugs. However, rational supply methods have not been established yet. In this study, we generated an efficient method to produce both viridin and viridiol by using a unique pH regulated T. virens culture manner. Besides, we successfully obtained β-viridin (epimer of viridin) crystal and X-ray structure, of which the CAS number was registered without stereochemistry. Furthermore, applying the original method to stable isotope study, we also obtained [U- 13 C]-viridn and [U- 13 C]-viridol by using [U- 13 C 6 ]-glucose as a carbon source replacing normal glucose which can be used to elucidate the biosynthesis pathway of furanosteroids., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The separation of large polar constituents presents a substantial challenge in natural product research when employing column chromatography techniques, as the process is both complex and time-consuming. In this study, an acetonitrile/tetrahydrofuran/di-(2-ethylhexyl) phosphoric acid/aqueous saturated sodium chloride solvent system was developed and utilized for the countercurrent chromatography of polar constituents from Ginkgo biloba L. seeds. Five polar constituents were effectively isolated using an acetonitrile/tetrahydrofuran/di-(2-ethylhexyl) phosphoric acid/aqueous saturated sodium chloride (2:2:0.8:3, v / v ) solvent system using a two-step countercurrent chromatography method. In the initial countercurrent chromatography process, three constituents were successfully purified from the methanol extract: compound 1 , compound 4 , and compound 5 . Compounds 2 and 3 , co-eluted from the column, were further subjected to three inner-recycling chromatographic procedures. At last, five constituents were purified and identified, including 4'-O-methylpyridoxine ( 1 ); two indole alkaloid N-glucosides, ginkgoside B ( 2 ) and ginkgoside A ( 3 ); 2-(4-hydroxybenzyl) malic acid ( 4 ); and coniferyl alcohol ( 5 ). The results demonstrated that the acetonitrile/tetrahydrofuran/di-(2-ethylhexyl) phosphoric acid/aqueous saturated sodium chloride solvent system serves as a feasible system for the efficient countercurrent chromatography separation of polar components.

We here report an efficient DNA-compatible furan-thiol-amine reaction for macrocyclization and late-stage amine transformation. This reaction, conducted under mild conditions, enables the facile cyclization of DNA-conjugated linear peptides into thiopyrrole-grafted macrocycles regardless of ring size or side-chain modification with good to excellent conversion yields. Additionally, this strategy was employed for the late-stage transformation of terminal amines, serving as critical intermediates in the construction of DNA-encoded peptide libraries. Diverse amines were successfully converted into their corresponding thiopyrrole scaffolds, thereby expanding the structural diversity that can be achieved within DNA-encoded libraries.

The smoke-derived butenolides, karrikins (KARs), regulate many aspects of plant growth and development. However, KARs and a plant hormone, strigolactones (SLs), have high resemblance in signal perception and transduction, making it hard to delineate KARs response due to the shortage of chemical-genetic tools. Here, we identify a triazole urea KK181N1 as an inhibitor of the KARs receptor KAI2. KK181N1 selectively depress the KAR-induced phenotypes in Arabidopsis. We further elucidate the antagonistic, KAI2 binding mechanism of KK181N1, showing that KK181N1 binds to the catalytic pockets of KAI2 in a non-covalent binding manner. Our experiments also demonstrate the binding affinity of triazole urea compounds are regulated by the structured water molecule networks. By fine-tuning this network, we successfully develop a more potent derivative of KK181N1. We anticipate that these chemicals will be applicable to the elucidation of KARs biology, especially for discriminating the molecular and physiological aspects of KARs and SL signaling., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Methicillin-resistant Staphylococcus aureus (MRSA) is a major contributor to hospital-acquired infections and is highly resistant to treatment. Ongoing research focuses on developing new antimicrobial medications to prevent the spread of resistance. A facile method was employed to efficiently synthesize new pyrazolo[1,5-a]pyrimidines in 84-93 % yields by reacting 4-benzyl-1H-pyrazole-3,5-diamine with the respective α,β-unsaturated ketones. The reaction was carried out in ethanol containing 1.2 equivalents of potassium hydroxide at reflux for 5-6 h. The new products are attached to a para-substituted aryl group with variable electronic properties at pyrazolopyrimidine-C5, in addition to one of three units at C7, namely phenyl, thiophen-2-yl, or furan-2-yl units. A wide spectrum of antibacterial activity was displayed by the new pyrimidines against six different bacterial strains. In general, pyrimidines attached to furan-2-yl units at C7, in addition to another aryl unit at C5, attached to 4-Me or 4-OMe groups, demonstrate significant antibacterial activity, particularly against S. aureus strain. They had MIC/MBC of 2.5/5.1 and 2.4/4.9 μM, respectively, which exceeded that of ciprofloxacin. Moreover, they demonstrate more effective MRSA inhibitory activity than linezolid, with MIC/MBC values up to 4.9/19.7 and 2.4/19.7 μM against MRSA ATCC:33591 and ATCC:43300 strains, respectively., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Introduction: Annonaceous acetogenins are a group of natural polyketide compounds possessing notable cytotoxic and antitumor properties. Mass spectrometry (MS) techniques can be used for the structural determination of these compounds, including the location of functional groups along the long alkyl chain., Objective: This study aims to develop a convenient liquid chromatography (LC)-MS-based method for the dereplication of acetogenins in plant extracts using a molecular networking approach., Methodology: The LC-electrospray ionization (ESI)-MS/MS spectra of pure adjacent bis-tetrahydrofuran (THF) acetogenins isolated from Uvaria rufa (Annonaceae) were acquired, along with those of the crude ethyl acetate and hexanes fractions of the plant extract, followed by dereplication and molecular networking analysis using the Global Natural Products Social Molecular Networking (GNPS) platform., Results: A high level of fragmentation of the protonated molecules [M + H] + was observed at collision energies of 37.5 and 25.0 eV. The application of feature-based molecular networking (FBMN) allowed for distinguishing diastereoisomers based on different retention times in the reversed-phase high-performance liquid chromatography method. The acetogenin possessing one or more additional OH groups on the methyl-terminal chain side of the OH-flanked bis-THF ring unit were grouped separately from those lacking such substructure. Furthermore, the MS2LDA analysis revealed shared Mass2Motifs among acetogenins, confirming the structural relations within the molecular network., Conclusions: The ESI-MS/MS-based molecular networking method provided an effective strategy for the dereplication of acetogenins in plant extracts. It is anticipated that this molecular networking approach could be extended to other types of acetogenins to facilitate rapid identification of this class of compounds., (© 2024 John Wiley & Sons Ltd.)

Furan (C₄H₄O), an unintended hazardous compound, is formed in various thermally processed foods through multiple pathways, raising concerns due to its potential carcinogenicity in humans. The aim of this comprehensive review was to synthesize and evaluate the latest research on furan, from its formation by different precursors to its presence in diverse food matrices, as well as the emerging methods for its detection and mitigation. Emphasizing the toxicity of furan, it explored evidence from in vitro and in vivo studies, including reproductive toxicity, carcinogenic effects, and related biomarkers. Additionally, this review focused on human risk assessments of furan exposure and discussed innovative research approaches to better understand its health risks. By consolidating current knowledge, this review provided a comprehensive perspective on furan's impact on human health and suggested future research directions to further research on furan., (© 2024 Institute of Food Technologists®.)

Purpose: Combination immune checkpoint inhibitors (ICI) with chemotherapeutic agents has proven to be highly promising in cancer therapy. However, low response rate, immune-related adverse events, and lack of effectively targeted co-delivery strategy are still major hurdles to overcome for this combination therapeutic regimen. Herein, programmed death-L1 (PD-L1) antibody modified and dihydrotanshinone I (DHT) loaded nanoparticle was prepared for tumor targeting drug delivery, thus achieving immune checkpoint blockade (ICB) and immunogenic cell death (ICD) synergistic anti-tumor effects., Methods: The DHT-loaded nanoparticle (DHT NP) was prepared by the emulsion solvent diffusion method. Atezolizumab (ATEZO) was thiolated with 2-iminothiolane and conjugated to the surface of DHT NP to prepare the ATEZO DHT NP. The drug encapsulation efficiency, drug loading, particle size and drug release were determined. The in vitro cellular uptake, cell proliferation inhibition and apoptosis were evaluated on the HGC-27 tumor cell. The in vivo tumor targeting, anti-tumor efficiency and immune regulation were assessed on tumor bearing mice., Results: The optimized ATEZO DHT NP was a spherical nanoparticle of about 250 nm with a continuous drug release profile. It was selectively taken up by the tumor cells through PD-L1 receptor-mediated endocytosis, which resulted in enhanced cytotoxicity and cell apoptosis. In vivo imaging further demonstrated its superior tumor tissue targeting ability. When tumor bearing mice were treated with the ATEZO DHT NP, its synergistic anti-tumor effect was much stronger than that of a single drug. Moreover, the tumor targeting delivery of DHT caused tumor necrosis and initiated ICD with release of tumor-associated antigens, which efficiently up-regulated the population of CD4 + and CD8 + T cells. Notably, there were no obvious system toxicity or tissue damage occur during the whole treatment period., Conclusion: The ATEZO DHT NP could specifically target to tumor and enhance treatment efficiency through combination of PD-L1 blockade with ICD effect., 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.)

Neaumycin B is a complex polyketide that shows phenomenal cytotoxicity against U87 glioblastoma cells. The singly anomeric spiroketal core is a notable subunit in the natural product's structure. We report a rapid and convergent approach to the spiroketal group, resulting in the formation of two isomeric singly anomeric spiroketals. We describe the origin of this rarely described outcome in spirocycle formation and subsequently propose a correction to a stereocenter in the natural product.

The treatment of patients with nonsmall cell lung cancer (NSCLC) using epidermal growth factor receptor (EGFR) inhibitors is complicated by drug-sensitive activating L858R/T790M and L858R/T790M/C797S mutations. To overcome drug resistance, a series of furopyridine (PD) compounds were virtually screened to identify potent EGFR inhibitors using molecular docking and molecular dynamics (MD) simulations based on the solvated interaction energy (SIE) method. Several PD compounds identified from virtual screening demonstrated the potential to suppress both wild-type and mutant forms of EGFR, with IC 50 values in the nanomolar range. Among these, PD18 and PD56 exhibited highly potent inhibitory activity against both wild-type and mutant forms of EGFR, surpassing the efficacy of known drugs. Additionally, both PD compounds were cytotoxic to NSCLC cell lines (A549 and H1975) while being nontoxic to normal cell lines (Vero). The interaction mechanisms of both PD compounds complexed with wild-type and mutant forms of EGFR were elucidated through 500 ns molecular dynamics simulations. The predicted binding affinity from molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) correlated well with the experimental binding affinity derived from IC 50 values. Furthermore, it was observed that van der Waals interactions, rather than electrostatic interactions, played a significant role in interacting with EGFR's active site. The strong inhibitory activity against EGFR was attributed to two key residues, M793 and S797, via hydrogen bonding, corresponding with lower solvent accessibility and a higher number of atomic contacts. Therefore, these potent compounds could be developed as promising drugs targeting both wild-type and mutant EGFR for the treatment of NSCLC.

Photoactivatable fluorescent probes are valuable tools in bioimaging for tracking cells down to single molecules and for single molecule localization microscopy. For the latter application, green emitting dyes are in demand. We herein developed an efficient green-emitting photoactivatable furanyl-BODIPY (PFB) and we established a new mechanism of photoactivation called Directed Photooxidation Induced Activation (DPIA) where the furan is photo-oxidized in a directed manner by the singlet oxygen produced by the probe. The efficient photoconverter (93-fold fluorescence enhancement at 510 nm, 49 % yield conversion) is functionalizable and allowed targeting of several subcellular structures and organelles, which were photoactivated in live cells. Finally, we demonstrated the potential of PFB in super-resolution imaging by performing PhotoActivated Localization Microscopy (PALM) in live cells., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)

In line with our objective of designing new antileishmanial compounds for oral use, we report the synthesis and biological evaluation in vitro of original 4,5-dihydrofuran derivatives bearing an amidoxime group. Previous optimization focused on position 3 of the dihydrofuran ring involving aromatic fragments, resulting in the identification of the compound (HIT) 4-(5-benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-N'-hydroxybenzimidamide (IC 50  = 5.4 ± 1.0 μM, L. amazonensis promastigote, IC 50  = 7.9 ± 1.1 μM, L. amazonensis intracellular amastigote). In the present work, position 3 was substituted with an aliphatic moiety. This modification was guided by a ligand-based approach, given the unknown biological target or mechanism of action for this compound. The 4,5-dihydrofuran derivatives were synthesized using microwave-assisted manganese (III) acetate-based oxidative cyclization of linear β-keto-carboxylic and β-keto-sulfone substrates, overcoming synthetic challenges to obtain aliphatic derivatives of 4,5-dihydrofuran-3-carboxamides. Finally, an unexpected and interesting biological activity with the 4,5-dihydrofuran-3-carboxylate (IC 50  < 5 μM) against the amastigote form is discussed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Oscar Leonardo AVENDANO LEON reports financial support was provided by Colombia Ministry of Science Technology and Innovation. If there are other authors, they 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 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Despite the efficacy of strong emission control plans that have been implemented the last few decades, polychlorinated dibenzo- p -dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) may still be released from anthropogenic sources such as sinter plants, and municipal and hazardous waste incinerators. Monitoring for PCDDs and PCDFs in gaseous emissions from such facilities is important due to the acute toxicity of these compounds even at trace levels. Currently, most of these samples from the African continent are being analysed abroad at high cost, with the direct consequence that the number of measurements are kept to a minimum. In this context, we developed a more affordable analytical approach for the measurement of PCDD/Fs sampled onto Amberlite XAD-2 sorbent, which relies on a novel extraction, clean-up, and analysis method with the aim of reducing both the cost and the complexity of standard methods while maintaining high quality results. A simple, sequential, 3 hour end-over-end tumbling extraction procedure was developed employing acetone :  n -hexane (1 : 9) as extraction solvent. This was combined with a dimethyl sulfoxide (DMSO) clean-up to remove aliphatic interferences, prior to direct analysis by gas chromatography triple quadrupole mass spectrometry. The Unites States Environmental Protection Agency Method 23, in contrast, requires a 16 hour Soxhlet extraction with toluene and multiple column chromatography steps. The end-over-end tumbling extraction yielded an average recovery of 79% for PCDD/Fs usually monitored in gaseous samples, whilst an average recovery of 89% was achieved for the DMSO clean-up procedure. In addition, an overall average recovery of 78% and a Z -score of -1.1 was obtained using the developed method for the proficiency testing of a solid reference material, proving the method is fit for purpose. It was then successfully applied to the analysis of air emissions from a medical waste incinerator, which further showed that the alternative approach may deliver quality, fast, and cost-effective analysis of gaseous PCDD/Fs sampled onto Amberlite XAD-2 sorbent in a developing country context.

Aberrant activation of NLRP3 due to persistent tissue damage, misfolded proteins or crystal deposits has been linked to multiple chronic inflammatory disorders such as cryopyrin-associated periodic syndrome (CAPS), neurodegenerative diseases, gouty arthritis, and numerous others. Hence, there has been an increasing interest in NLRP3 inhibitors as therapeutics. A first generation of NLRP3 inhibitors bearing a sulfonylurea core such as MCC950 (developed by Pfizer) were discovered by phenotypic screening, however their mode of action was only elucidated later. Based on MCC950, second-generation inhibitors were developed, aiming to overcome some liabilities such as moderate potency and drug induced liver injury. During the optimization of these (second-generation) inhibitors, conformational studies led to the design of novel macrocycles. Here we report the discovery and optimization of this class of NLRP3 inhibitors.

The conversion of biomass-based feedstocks into high-value platform compounds remains a fundamental but challenging topic. Studies on such transformations are sparse due to the complex nature of biomass and limited upgrading strategies. Photocatalytic aerobic oxidation is a promising pathway for making pharmaceutical precursors from biomass-derived chemicals. In this study, we demonstrate the transformation of furfuryl alcohol into dihydropyranone acetyl by using a molybdenum-incorporated triphenylbenzene-dimethoxyterephthaldehyde-covalent organic framework via a singlet oxygen ( 1 O 2 )-mediated photocatalytic Achmatowicz reaction. The COF-Mo photocatalyst exhibits exceptional selectivity up to 98% in producing hydroxy-2H-pyran-3(6H)-one, a complex synthone crucial for synthesizing anti-AIDS drugs. Mo incorporation enhances the generation rate by 3.9 times, primarily due to the synergistic effect between Mo active sites and the COF backbone. More importantly, Mo clusters create a superfast charge tunnel for photogenerated electron transfer from COF to adsorbed O 2 . The metallic state and hexavalent of Mo facilitate the generation of superoxide anions and 1 O 2 , respectively, facilitating photocatalytic reactions.

Acidic hydrotropes exhibit effective performance in fractionating the constituents of lignocellulosic biomass owing to their amphiphilic characteristics. However, the requirement for excessively high concentrations may lead to the condensation and aggregation of lignin. In this case, bamboo was extracted with 70 % (w/v) tetrahydrofurfuryl alcohol (THFA) aqueous solution containing 5-20 % (w/v) p-toluenesulfonic acid (pTsOH) at 90-120 °C for 1-4 h. Results indicated that 91 % of lignin was efficiently removed from bamboo, with subsequent recovery of 73.5 % achieved through extraction with 10 % pTsOH at 110 °C for 4 h. Furthermore, the resulting lignin exhibited a relative content of β-O-4 bonds of 64.1 %, displayed a light color (L*: 70.48), boasted a purity of 99.64 %, and possessed a moderate molecular weight. These attributes position it as a valuable candidate in functional material production. The aqueous solution provides an ideal medium for efficient extraction of uncondensed, light-colored lignin, thereby furnishing insights for advancing the utilization., 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.)

Phytochemical study on the methanol extract of the stems of Tinospora crispa (L.) Hook.f. & Thomson led to the isolation of thirteen compounds including three undescribed cis-clerodane-type furanoditerpenoids (1-3) and ten known ones (4-13). Their chemical structures were determined by IR, HR-ESI-MS, 1D-, and 2D-NMR spectra. Compounds 2-4, 6 and 8 inhibited moderately NO production in LPS activated RAW 264.7 cells with the IC 50 values of 83.5, 57.6, 75.3, 78.1, and 74.7 μM, respectively., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Thirteen new microperfuranones, including five pairs of enantiomers, (±)-nigenolides A-E (1a/1b-5a/5b), and three racemate nigenolides F-H (6-8), together with four known analogues (9-12) were isolated from a deep-sea-derived Aspergillus niger 3A00562. The absolute configurations of the five pairs of enantiomers were determined by the comparison of the calculated and experimental ECD spectra. Compounds 3a, 4a, 4b, and 12 were able to inhibit RSL3-induced ferroptosis. Compound 12 inhibited ferroptosis of A375 cells and 786-O cells with EC 50 values of 0.76 μM and 0.67 μM, respectively. Compound 12 was a potential iron chelator and radical trapping antioxidant. Furthermore, compound 12 inhibited ferroptosis through down-regulating the expression of TXNIP gene., 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. Published by Elsevier Inc.)

Developing pure diastereoisomeric molecular hybrids for the selective inhibition of bacterial growth opened new avenues for combating the ever-increasing microbial resistance. Considering this, a series of diastereoisomeric pure pyrazolyl-dihydrofurans (7a-7y) were synthesized and characterized using NMR, LCMS, and X-ray crystallography. DFT based method was used to explore the configurational stability of cis over trans isomeric form. Considering 7a and 8a as representative isomeric forms with same structural framework, the difference in their bio-efficacy against bacterial and fungal strains was assessed using serial dilution method. The relatively high inhibition of bacterial growth by the cis isomeric form (7a) (MIC = 1.562 µg/mL), amoxicillin (MIC = 3.125 µg/mL) inspired us to broaden the substrate scope for synthesizing a series of pure diastereoisomeric cis forms as selective anti-bacterial agents. However, both the isomers displayed antifungal activity less than the standard drug (Fluconazole) employed in the study. All the reactions proceeded smoothly and yielded a diverse array of dihydrofuran derivatives. The developed synthetics were found to be non-cytotoxic against mouse fibroblast cells and didn't affect the seed germination of Brassica nigra seeds when treated at 1 mg/mL concentration. The experimentally determined in vitro results were further validated using in silico molecular docking and dynamics studies., 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. Published by Elsevier Ltd.)

While autoxidation of Polyunsaturated Fatty Acids (PUFAs) is a potential source of furan and its derivatives, the regulatory obligation to enrich powdered infant formulae (PIF) with some of these compounds might raise safety issues. The aim of this study was to investigate the impact of formulation and home storage conditions on the generation of furan and its derivatives in PIF. Furan, 2-methylfuran (2-MF) and 3-methylfuran (3-MF) were monitored by a validated SHS-GC-Q Exactive-Orbitrap MS method in six PIF formulated with high or low concentrations of different PUFAs (ALA, ARA, DHA), pro-oxidants (iron) and anti-oxidants (vitamins) and stored for 21 days under more or less oxidizing home storage conditions, including temperature (19 °C or 40 °C) and oxygen exposure (protected or not from ambient air). For the three compounds, the quality of the measurements in PIF was first confirmed with suitable linearity, limits of quantification, precision and recoveries. In a second step, the impact of the formulation was evaluated on six PIF commercial samples differing significantly in their composition in ALA, ARA, DHA, iron and/or vitamin E and C. While furan was quantifiable (2.8 µg/kg) in only one PIF with high content of DHA and iron and low level of vitamins, 2-MF was only quantifiable in two other PIF which were distinguished by a 15 to 20 % higher ALA content and 3-MF was not detected in any of the six PIF studied. In a third step, the effect of storage conditions was studied on the six PIF and the increase in storage temperature to 40 °C led to an increase of up to 33 % in the 2-MF concentration in the two PIF formulations where it was quantifiable. Nevertheless, the estimation of the Margin of Exposure (MOE) showed that the risk related to furan and its derivatives could be ruled out regardless of the formulation or storage conditions. Finally, in order to explore other derivatives and to investigate the mechanisms involved in the generation of furan compounds in PIF, a suspect screening approach was implemented on the SHS-GC-Q Exactive-Orbitrap MS data. It made it possible on the one hand to point out two additional furan derivatives in PIF, 2-ethylfuran and 2-pentylfuran. On the other hand, it enabled to discuss the oxidation pathways involved in the generation of furan compounds in PIF from profiling of known PUFA oxidation markers also detected in the samples., 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. Published by Elsevier Ltd.)

Two new furanone derivatives, byssochlanones A-B ( 1 - 2 ) were purified from the endophytic fungus Byssochlamys sp. isolated from the wetland plant, Phragmites australis . Their structures were elucidated on the basis of extensive spectroscopic analyses. Compounds 1 - 2 represented typical furanone analogues which are not common in natural products. The absolute configuration of compounds 1 - 2 were identified through quantum-chemical electronic circular dichroism (ECD) calculation compared with their experimental CD. In addition, compounds 1 - 2 were tested for their cytotoxic activities against HCT-8 and Hela cancer cell lines, and compound 2 showed moderate activity against HCT-8 cells with IC 50 value of 21.3  μ M.

Dysregulation of signal transducer and activator of transcription 3 (STAT3) is implicated in the pathogenesis of various cancers, underscoring its potential as a cancer therapeutic target. In this work, we designed and synthesized a novel series of (E)-2-cyano-3-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl) derivatives and evaluated their anti-proliferative effects on tumour cells. Among these derivatives, NW16 exhibited remarkable antiproliferative activity against HCT116 cells, with an IC 50 value of 0.28 μM, and exhibited dose- and time-dependent inhibition of the JAK/STAT3 signalling pathway. In addition, NW16 induced reactive oxygen species (ROS) production, which subsequently suppressed the ROS-dependent PI3K/AKT pathway and enhanced its antitumour efficacy. In vivo studies confirmed significant tumour-suppressive effects upon oral administration of NW16 along with favourable tolerability in a colorectal cancer xenograft model. These results indicate that NW16 could be a promising candidate for developing targeted therapy for colorectal cancer because of its multifaceted mechanism., 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 Inc. All rights reserved.)

β-Galactosidase (β-Gal) as an important glycoside hydrolase plays an important role in the early diagnosis of ovarian cancer. It is important to accurately and conveniently detect β-Gal in organisms. In this study, we developed a fluorescent probe TCF-GAL based on the tricyanofuran structure, which is linked to β-galactose through ether bonds for β-Gal detection. Probe TCF-GAL exhibited satisfactory selectivity and sensitivity toward β-Gal with the calculated LOD of 1.45 × 10 -4 U/mL. Moreover, it can be applied to image endogenous β-Gal in living SKOV3 cells with low cytotoxicity. Importantly, probe TCF-GAL was successfully employed in monitoring β-Gal in the mouse subcutaneous model of ovarian cancer. These results indicated that this probe had great potential for diagnosing β-Gal related diseases., 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 Inc. All rights reserved.)

There is a great need for versatile biomass additives sourced from renewable materials to enhance the performance of polylactic acid (PLA) composites. This study introduces a furan-based polyester elastomer called PNF-PBC that is designed to improve the mechanical and water vapor barrier characteristics of PLA. By incorporating PNF-PBC into PLA, the toughness of the PLA/PNF-PBC biocomposites was considerably enhanced through various intermolecular interactions. A 15 wt% PNF-PBC blend with PLA exhibited a 13.6-fold increase in elongation at break, while having a negligible impact on tensile strength. Furthermore, the water vapor barrier performance of PLA/PNF-PBC biocomposites was greatly boosted by a factor of 10 compared to pure PLA, making them highly suitable for food packaging materials. With its versatile properties, we anticipate that this bio-based PLA/PNF-PBC material will significantly expand the range of applications for PLA composites., 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.)

The existing information supports the use of this material as described in this safety assessment. 4-(4-Methyl-3-penten-1-yl)-2(5H)-furanone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, photoirritation/photoallergenicity, skin sensitization, and environmental safety. Data show that 4-(4-methyl-3-penten-1-yl)-2(5H)-furanone is not mutagenic. The clastogenicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for the genotoxicity endpoint material, and the exposure to 4-(4-methyl-3-penten-1-yl)-2(5H)-furanone is below the TTC (0.0025 μg/kg/day). The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class III material, and the exposure to 4-(4-methyl-3-penten-1-yl)-2(5H)-furanone is below the TTC (0.0015 mg/kg/day, 0.0015 mg/kg/day, and 0.47 mg/day, respectively). The skin sensitization endpoint was completed using the Dermal Sensitization Threshold (DST) for reactive materials (64 μg/cm 2 ); exposure is below the DST. The photoirritation/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/Vis) spectra; 4-(4-methyl-3-penten-1-yl)-2(5H)-furanone is not expected to be photoirritating/photoallergenic. The environmental endpoints were evaluated; for the hazard assessment based on the screening data, 4-(4-methyl-3-penten-1-yl)-2(5H)-furanone is not Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards. For the risk assessment, 4-(4-methyl-3-penten-1-yl)-2(5H)-furanone was not able to be risk screened as there were no reported volumes of use (VoU) for either North America or Europe in the 2019 IFRA Survey., 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. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The flavor retention plays a critical role in the presence of rich flavor profile of meat products. However, the interaction between collagen and furan derivatives has not been previously reported. In this study, the interaction between collagen and furan derivatives during heating was investigated using multidimensional spectroscopy and gas chromatography-mass spectrometry (GC-MS). The results revealed that the collagen structure was disrupted during the heating process, causing its depolymerization and an increase in the absolute value of zeta potential. The heating treatment induced a structural transformation in the collagen from large and ordered sheets to smaller and irregular aggregates. Meanwhile, the binding ability between collagen and furan derivatives was also significantly increased during the heating process due to the increased exposure of sulfhydryl groups and a rise in surface hydrophobicity. These findings will provide valuable insights into the retention of volatile compounds in the meat products., 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 Ltd. All rights reserved.)

The efficient utilization of lignocellulosic hydrolysates in bioprocesses is impeded by their complex composition and the presence of toxic compounds, such as furan aldehydes, formed during lignocellulose pretreatment. Biological detoxification of these furan aldehydes offers a promising solution to enhance the utilization of lignocellulosic hydrolysates. Acinetobacter baylyi ADP1 is known to metabolize furan aldehydes, yet the complete spectrum of reaction products and dynamics remains unclear. Here, we determined the detoxification metabolites of furfural and 5-hydroxymethylfurfural in A. baylyi ADP1 and studied the kinetics of detoxification. The results indicate that detoxification in A. baylyi ADP1 follows a typical alcohol-aldehyde-acid scheme, with furoic acid and 5-hydroxymethyl-2-furancarboxylic acid as the final products for furfural and 5-hydroxymethylfurfural, respectively. Both end products were found to be less toxic for cells than their unmodified forms. These findings underscore the potential of A. baylyi ADP1 in detoxifying lignocellulosic hydrolysates for bioprocess applications., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Gambierones are sulfated polyethers produced by benthic dinoflagellates in the genera Gambierdiscus, Coolia and Fukuyoa. While relative toxicity data for gambierones suggests they are low compared with ciguatoxin analogues, gambierones have been suggested for use as marker compounds for environmental monitoring programs for the presence of Gambierdiscus in marine waters. The published structure of gambierone and analogues of it, including 44-methylgambierone (44-MeGAM), have been reported to possess 1,2- and 4,5-cis diols, while only the 1,2- diol unit has been shown to undergo periodate oxidation. An in-depth analysis of previously reported NMR data for 44-MeGAM in CD 3 OD showed that the C-4 stereochemistry of 44-MeGAM and other gamberiones was mis-assigned, that the 4-CH 2 -CHOH-CH 2 OH and OH groups are equatorially and axially oriented, respectively, rather than vice versa as previously reported. This re-examination of existing 44-MeGAM NMR data also showed that its C-12 and C-13 assignments (and those for other gambierones) should be reversed. In an effort to better understand the C-4 stereochemical and periodate reaction characteristics of gambierones (C-4 is an epimerizable hemiacetal carbon), additional NMR data was acquired in D 6 -DMSO. Unexpectedly, progressive conversion of 44-MeGAM to a long-term stable ring-A furanoid analogue was observed. A subsequent series of microscale stability trials identified several solvents that affected the solution-stability of 44-MeGAM, and these findings should be taken into consideration during isolation, handling, storage and bioassay evaluations of gambierones in future studies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J. Sam Murray reports financial support was provided by Ministry of Business Innovation and Employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Leishmaniasis, a protozoan disease affecting humans, exposes significant shortcomings in current treatments. In continuation to our previous findings on amidoxime-based antileishmanial compounds bearing a 4,5-dihydrofuran scaffold, twelve new amidoxime derivatives substituted at position 3 with an amide bearing a nitrogen heterocycle were synthesized. This series was designed to replace the sulfone and aryl group on a previously reported HIT. The synthesis of these compounds involved the following three-step pathway: manganese (III) acetate-based cyclization of a β-ketoester, followed by amidation with LiHMDS and a final reaction with hydroxylamine. Three of them, containing either bromine, chlorine, or methyl substitutions and featuring a pyridine moiety, showed an interesting toxicity-activity relationship in vitro. They exhibited IC 50 values of 15.0 µM, 16.0 µM, and 17.0 µM against the promastigote form of the parasite and IC 50 values of 0.5 µM, 0.6 µM, and 0.3 µM against the intracellular amastigote form, respectively. A selectivity index (SI) greater than 300 was established between the cytotoxic concentrations (in murine macrophages) and the effective concentrations (against the intracellular form of Leishmania amazonensis ). This SI is at least seventy times higher than that observed for Pentamidine and twenty-five times higher than that observed for the reference HIT, as previously reported.

2-Methylfuran (2-MF) is a process-related contaminant found primarily in heat-treated foods, such as coffee or canned food. The oxidative metabolic activation of 2-MF is supposed to follow the pathway established for furan, which is known to generate the highly reactive metabolite butenedial (BDA). In the case of 2-MF, generation of the BDA homologue 3-acetylacrolein (AcA) is to be expected. 2-MF metabolism to AcA was investigated in two model systems: commercial microsomal preparations and primary rat hepatocytes (pRH). To scavenge the generated 2-MF, two model nucleophils, N -acetyl-l-cysteine (AcCys) and N -α-acetyl-l-lysine (AcLys), were used, and the formation of the corresponding adducts was measured in the supernatants. The metabolic activation of 2-MF to AcA was studied using human liver microsomes as well as rat liver microsomes. Incubation of 2-MF in Supersomes allowed to identify the cytochrome P450 isoenzyme primarily responsible for 2-MF. In addition, primary rat hepatocytes were incubated with 2-MF or AcA and AcLys adduct of AcA ( N-α -acetyl-l-lysine-acetylacrolein, AcLys-AcA) determined in the cell supernatants by UHPLC-MS/MS. In model experiments, AcA formed adducts with AcCys and AcLys. The structures of both adducts were characterized. For incubations in biological activating systems, CYP 2E1 was found to be a key enzyme for the conversion of 2-MF to AcA in Supersomes. When pRH were incubated with 2-MF and AcA, AcLys-AcA was detected in the cell supernatants in a time- and dose-dependent manner. The results showed that AcA was indeed formed at the cellular level. In contrast to the AcLys-AcA adduct, no N -acetyl-l-cysteine-acetylacrolein (AcCys-AcA) adduct could be detected in pRH. AcA was determined as a reactive metabolite of 2-MF in vitro , and its adduct formation with nucleophilic cellular components was evaluated. The metabolites were characterized, and AcLys-AcA was identified as potential biomarker.

2-Methylfuran (2-MF) is a well-known industrial chemical and also formed via thermal treatment of food. One main source of 2-MF in the human diet is coffee. 2-MF is known to form 3-acetylacrolein (AcA, 4-oxopent-2-enal) via cytochrome P 450 metabolism and further reacts with amino acids in vivo. Still the reactivity toward other biomolecules is rather scarce. Therefore, AcA was synthesized, and its reaction with 2'-deoxyadenosine (dA), 2'deoxyguanosine (dG), 2'deoxycytosine (dC), and 2'-deoxythymidine (dT) was tested. For this purpose, adduct formation was performed by acid hydrolysis of 2,5-dihydro-2,5-dimethoxy-2-methylfuran (DHDMMF) as well as pure AcA. The structures of these adducts were confirmed by UPLC-ESI + -MS/MS fragmentation patterns and 1 H-/ 13 CNMR spectra. Except for dT, which showed no reactivity, all adducts of AcA were characterized, which enabled the development of sensitive quantification methods via (U)HPLC-ESI ± -MS/MS. Pure AcA was synthesized by oxidation of 2-MF using dimethyldioxirane (DMDO), and its behavior in aqueous medium was studied. Incubations of AcA and isolated DNA of primary rat hepatocytes (pRH) showed time- and dose-dependent formation of the identified DNA adducts dA-AcA, dG-AcA, or dC-AcA. In contrast, the DNA adducts dA-AcA, dG-AcA, or dC-AcA were not detected on a cellular level when pRH were incubated with 2-MF or AcA. This indicates an efficient detoxification or reaction with biomolecules in the cell, although the induction of other DNA damage, possibly also by other metabolites, cannot be ruled out in principle.

Lysine (Lys) glycated by xylose (Xyl) at α-NH 2 [ N α (1-deoxy-D-xylulos-1-yl)lysine ( N α -Xyl-Lys ARP)] or ε-NH 2 [ N ε -(1-deoxy-D-xylulos-1-yl)lysine ( N ε -Xyl-Lys ARP)] significantly impacted the thermal degradation pathways of Amadori rearrangement products (ARPs). N α -Xyl-Lys ARP was found to undergo retro-aldolization on the sugar fragment more readily to form glyoxal/methylglyoxal than N ε -Xyl-Lys ARP. Furans and pyrazines formation during the degradation of the diglycated lysine [ N α , N ε -di(1-deoxy-d-xylulos-1-yl)lysine ( N α ,N ε -di-Xyl-Lys ARP)] was delayed at 120 °C relative to N ε -Xyl-Lys ARP. This was attributed to the complex degradation of N α ,N ε -di-Xyl-Lys ARP, which slowed the substantial formation of deoxypentosones and the effective release of Lys. At 140 °C, the dual glycated N α ,N ε -di-Xyl-Lys ARP was more conducive to promoting the redistribution of electrons and facilitating molecular rearrangement. This accelerated the efficient decomposition of dual glycated groups in N α ,N ε -di-Xyl-Lys ARP and enabled glyoxal to actively participate in Strecker degradation. Thus, the production of furans and pyrazines was substantially increased, and the variety of pyrazines was expanded from three types to eight types. An appropriate increase to pH 7.5 effectively avoided the overprotonation of hydroxyl and amino groups (pH 5.5), simultaneously enhancing furans and pyrazines yield while minimizing the formation of pyridines under alkaline conditions.

The Lamiaceae (mint family) is the largest known source of furanoclerodanes, a subset of clerodane diterpenoids with broad bioactivities including insect antifeedant properties. The Ajugoideae subfamily, in particular, accumulates significant numbers of structurally related furanoclerodanes. The biosynthetic capacity for formation of these diterpenoids is retained across most Lamiaceae subfamilies, including the early-diverging Callicarpoideae which forms a sister clade to the rest of Lamiaceae. VacCYP76BK1, a cytochrome P450 monooxygenase from Vitex agnus-castus, was previously found to catalyze the formation of the proposed precursor to furan and lactone-containing labdane diterpenoids. Through transcriptome-guided pathway exploration, we identified orthologs of VacCYP76BK1 in Ajuga reptans and Callicarpa americana. Functional characterization demonstrated that both could catalyze the oxidative cyclization of clerodane backbones to yield a furan ring. Subsequent investigation revealed a total of 10 CYP76BK1 orthologs across six Lamiaceae subfamilies. Through analysis of available chromosome-scale genomes, we identified four CYP76BK1 members as syntelogs within a conserved syntenic block across divergent subfamilies. This suggests an evolutionary lineage that predates the speciation of the Lamiaceae. Functional characterization of the CYP76BK1 orthologs affirmed conservation of function, as all catalyzed furan ring formation. Additionally, some orthologs yielded two novel lactone ring moieties. The presence of the CYP76BK1 orthologs across Lamiaceae subfamilies closely overlaps with the distribution of reported furanoclerodanes. Together, the activities and distribution of the CYP76BK1 orthologs identified here support their central role in furanoclerodane biosynthesis within the Lamiaceae family. Our findings lay the groundwork for biotechnological applications to harness the economic potential of this promising class of compounds., (© 2024 The Author(s). The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

This work focused on analyzing the properties of N-(5-nitrothiazol-2-yl)furan-2-carboxamide (C 8 H 5 N 3 O 4 S, NTFC) as a possible inhibitor of the rheumatoid arthritis process. The synthesis of NTFC was carried out and good-quality crystals were obtained and studied by NMR ( 1 H and 13 C), DEPT 135, UV-Vis, IR, MS and single-crystal X-ray diffraction. The structure of NTFC consists of two rings, thiazole and furan, and a central C-N-C(=O)-C segment, which appears to be planar. This central amide segment forms angles of 2.61 (10) and 7.97 (11)° with the planes of the thiazole and furan rings, respectively. The crystal structure of NTFC exhibits N-H...N, N-H...O and C-H...O hydrogen bonds, and C-H...π and π-π interactions that facilitate self-assembly and the formation of hydrogen-bonded dimers, which implies the appearance of R 2 2 (8) graph-set motifs in this interaction. The stability of the dimeric unit is complemented by the formation of strong intramolecular C-S...O interactions of chalcogen character, with an S...O distance of 2.6040 (18) Å. Hirshfeld surface (HS) analysis revealed that O...H/H...O interactions were dominant, accounting for 36.8% of the total HS, and that N-H...N interactions were fundamental to the formation of the dimeric structure. The molecular electrostatic potential (MEP) map showed a maximum energy of 46.73 kcal mol -1 and a minimum of -36.06 kcal mol -1 . The interaction energies of molecular pairs around NTFC are highest for those interactions linked by N-H hydrogen bonds. The properties of the NTFC ligand as a potential inhibitor of the DHODH (dihydroorotate dehydrogenase) enzyme were evaluated by molecular docking, showing coupling energies very close to those obtained with the control drug for rheumatoid arthritis, i.e. leflunomide.

The utilization of environmental friendly and renewable materials has received increasing attention recently. Lignin nanospheres (LNPs) prepared from recovered lignin and residual lignin after DESs and DESs-THF pretreatment were obtained by self-assembly in the present research. Then, films were prepared by incorporating them into polyvinyl alcohol (PVA) solution. The properties of various films were characterized and compared. Results showed that as the LNPs content increased, the UV blocking capacity of the films was gradually enhanced than PVA film. The DES-THF films showed better antioxidant properties up to 69 % due to higher phenolic hydroxyl content. The hydrophobicity of films incorporated with DESs-THF pretreated lignin was consistently better than that of DES pretreated. DES-THF-M films showed a higher T max than that of DES-M films, resulting in better thermal stability. Moreover, DES-THF-L films are lighter in color due to a lower degree of condensation, which is favorable to subsequent applications. The incorporation of LNPs improved mechanical and antioxidant properties, thermal stability, and UV shielding ability of PVA films, especially lignin after DES-THF pretreatment. In conclusion, the prepared PVA/LNPs composite films possessed good functional properties that make them potential for packaging materials., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fargesin is an important bioactive furofuran lignan isolated from different plant species. Despite presenting potent biological activities, its stereochemical characterization has relied mostly on empirical correlations of optical rotation, an approach considered risky that commonly leads to misassignments and error propagation. Additionally, the enantiomeric purity of fargesin isolates used for biological assays has not been previously investigated. Herein, we report the enantioresolution of a scalemic mixture of fargesin isolated from Aristolochia warmingii along with the first unambiguous determination of the absolute configuration of each enantiomer by means of optical rotatory dispersion, as well as electronic and vibrational circular dichroism aided by quantum-chemical calculations., (© 2024 Wiley Periodicals LLC.)

Random flaps are extensively utilized in plastic surgery due to their flexibility compared to traditional axial vascular system arrangements and their resemblance to injured skin in color, thickness, and texture. Despite these advantages, they are susceptible to ischemia-reperfusion injuries and subsequent necrosis post-transplantation. Bilobalide (BB), a sesquiterpene compound derived from Ginkgo biloba, exhibits notable antioxidant and anti-inflammatory properties and is commonly used to treat ischemiareperfusion injuries. However, its short half-life restricts its sustained efficacy in random flaps. In this study, we synthesized a multi-crosslinked, photosensitive methacryloyl hyaluronic acid(HAMA)/laponite(Lap)/bilobalide (BB) hydrogel. This dualcrosslinked hydrogel demonstrates superior mechanical properties and biocompatibility while providing a stable release of bilobalide. In vitro experiments showed that it significantly reduces edema, promotes angiogenesis, and enhances the survival of random flaps. Further network pharmacology analysis and recovery experiments suggested that the hydrogel's beneficial effects are mediated by the regulation of endoplasmic reticulum stress and specifically identified the regulation of the PERK/TXNIP/NLRP3 signaling pathway as crucial to its anti-inflammatory effects. Therefore, this HAMA/Lap/BB hydrogel promotes the survival of random flaps in rats by alleviating endoplasmic reticulum stress, providing a novel intervention strategy for the treatment of random flaps injuries., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ye jiangtian reports financial support was provided by Wenzhou Medical University. Ye Jiangtian reports a relationship with Wenzhou Medical University that includes: funding grants. If there are other authors, they 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.)

Osteoporosis is a systemic disease with complex etiology and high prevalence, resulting in a huge economic burden. For a long time, the search for new therapeutic pharmaceuticals has never stopped. Bone loss is related to the imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. In recent years, the role of immunity and inflammation in the development of osteoporosis has studied well. For example, various cytokines, chemokines and endocrine factors regulate osteoclastogenesis via activating different macrophage subtypes, including pro-inflammatory M1 and anti-inflammatory M2. Bilobalide (Bil), an active Ginkgo biloba ingredient, has garnered great interest because of its anti-oxidant and anti-inflammatory activities. In this study, we found that Bil can attenuate osteoclast generation induced by receptor activator of nuclear factor- kappa B ligand (RANKL) through upregulating the sirtuin 3 (SIRT3) and negatively regulating NF-κB signaling. Furthermore, Bil promotes M2 polarization of macrophages in a dose-dependent manner. In vivo studies provided evidence that Bil improves bone density in osteoporosis mice models. Based on the above results, we have reason to believe that Bil has potential therapeutic value in osteoclast-mediated bone loss and offers an effective option for long-term osteoporosis management., 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.)

The furan ring is a defining feature of limonoids, a class of highly rearranged and bioactive plant tetranortriterpenoids. We recently reported an apparent complete biosynthetic pathway to these important natural furanoids. Herein, we disclose the subsequent discovery of a yield-boosting "missing link" carboxylesterase that selectively deprotects a late-stage intermediate, so triggering more efficient furan biosynthesis. This has allowed, for the first time, the isolation and structural elucidation of unknown intermediates, refining our understanding of furan formation in limonoid biosynthesis.

In this paper, LD-TCF, a targeting probe for lipid droplets (LDs) with a near-infrared emission wavelength and large Stokes shift, was fabricated for polarity detection by assembling a donor-π-acceptor (D-π-A) molecule with typical twisted intramolecular charge transfer (TICT) characteristics. Surprisingly, the fluorescence emission wavelength of the newly constructed probe LD-TCF was stretched to 703 nm, and the Stokes shift was amplified to 126 nm. Furthermore, LD-TCF could specifically answer the change in polarity efficiently and did not experience interference from other biologically active materials. Importantly, LD-TCF exhibited the ability to target lipid droplets, providing valuable insights for the early diagnosis and tracking of pathophysiological processes underlying LD polarity.

The RNA binding protein Human Antigen R (HuR) has been identified as a main regulator of the innate immune response and its inhibition can lead to beneficial anti-inflammatory effects. To this aim, we previously synthesized a novel class of small molecules named Tanshinone Mimics (TMs) able to interfere with HuR-RNA binding, and that dampen the LPS-induced immune response. Herein, we present a novel series of TMs, encompassing thiophene 3/TM9 and 4/TM10, furan 5/TM11 and 6/TM12, pyrrole 7b/TM13, and pyrazole 8. The furan-containing 5(TM11) showed the greatest inhibitory effect of the series on HuR-RNA complex formation, as suggested by RNA Electromobility Shift Assay and Time-Resolved FRET. Molecular Dynamics Calculation of HuR - 5/TM11 interaction, quantum mechanics approaches and Surface Plasmon Resonance data, all indicates that, within the novel heteroaryl substituents, the furan ring better recapitulates the chemical features of the RNA bound to HuR. Compound 5/TM11 also showed improved aqueous solubility compared to previously reported TMs. Real-time monitoring of cell growth and flow cytometry analyses showed that 5/TM11 preferentially reduced cell proliferation rather than apoptosis in murine macrophages at immunomodulatory doses. We observed its effects on the innate immune response triggered by lipopolysaccharide (LPS) in macrophages, showing that 5/TM11 significantly reduced the expression of proinflammatory cytokines as Cxcl10 and Il1b., (© 2024. The Author(s).)

TNFα and related inflammatory factor antibody drugs have been orchestrated for the treatment of inflammatory bowel disease (IBD). However, antibody drugs elicited inevitable disadvantages and small molecule drugs are in an urgent need. Herein, we described the discovery, design, synthesis, and SAR studies from furanone glycoside compound Phoenicein (hit) isolated from Chimonanthus salicifolius to D228 (lead). Remarkably, D228 exhibited good inhibitory activity on B and T lymphocyte and excellent anti-IBD efficacy in vivo . Mechanistically, D228 alleviated the inflammation response by downregulating the MyD88/TRAF6/p38 signaling. Importantly, the relationship of D228 , Phoenicein , and their aglycone 7a was deduced: D228 could be considered as a prodrug and metabolized to intermediate Phoenicein . In turn, Phoenicein released their shared active aglycone 7a . Additionally, D228 demonstrated good and balanced profiles of safety and efficacy both in vitro and in vivo . These results suggested that D228 could be used as an ideal lead and potentially utilized for IBD chemotherapy.

For the first time, a synthetic route for preparing lupane and oleanane derivatives with a hydrogenated furan ring as a cycle A of triterpene scaffold is described. Most of the synthesized compounds, furanoterpenoids and their synthetic intermediates, were non-toxic against the tested cancer and non-cancerous cell lines, and evinced significant inhibitory activity with IC 50 1.0-9.0 μM in the tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibition test. Lupane derivatives - 1-oxime 7, 1,10-seco-hydroxynitrile 11 and furanoterpenoid 14 - were selected as those expected to be the most promising compounds. The results of molecular modeling evinced the strongest binding of compound 11 to the active site of Tdp1 compared to the reference drug. Simultaneously, only compound 11 at subtoxic concentration (10 μM) produced a synergetic effect on the topotecan activity against HeLa-V cells., 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 Masson SAS. All rights reserved.)

Five new furofuran lignans and their derivatives, (-)-glaberide I 4-O-β-D-glucopyranoside (1a), (+)-glaberide I 4-O-β-D-glucopyranoside (1b), (+)-glaberide I 7'-ethoxy-4-O-β-D-glucopyranoside (2a), (-)-glaberide I 7'-ethoxy-4-O-β-D-glucopyranoside (2b), and (-)-isoeucommin A (3b), along with fifteen known analogs were isolated from the stems of Dendrobium 'Sonia'. These compounds were classified into ten pairs of enantiomers or diastereoisomers via chiral resolution, and their structures were determined based on extensive spectroscopic data. Their absolute configurations were determined by hydrolysis, comparison of experimental and calculated electronic circular dichroism (ECD) data, and single-crystal X-ray diffraction analysis. The isolates were evaluated for their ability to inhibit nitric oxide (NO) production in RAW264.7 cells. Among them, syringaresinol (5) exhibited prominent inhibition activity, with an IC 50 value of 28.4 ± 3.0 μmol·L -1 , and there was a slight difference between 5a, 5b and the racemic mixture 5., (Copyright © 2024 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)