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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.)

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.

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.)

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.

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 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.)

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.)

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.)

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.)

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.

Inspired by the synthesis of polyurethane, a multifunctional fabric with hydrophobic and long-lasting flame retardancy was prepared through the phase separation and interfacial reaction process between PEI (polyethyleneimine)/BX (borax) aqueous solution and isocyanate terminated polydimethylsiloxane (PDMS-NCO) in tetrahydrofuran solution. The limit oxygen index of the treated fabric increased from 18.0 % to 33.7 %, and the total heat release decreased by 34.2 %. The enhancement of flame retardant performance and thermal stability is attributed to the enhanced char-forming capacity. After 50 cycles of water washing, the cotton fabric can still pass the vertical flammability test because of the curing effect of PDMS-NCO on functional additives. Furthermore, SEM analysis revealed that the formation of nano-rough structures on the fibers was promoted by phase separation, thus leading an increased water contact angle of sample to 139°. The materials utilized in this modified process do not contain elements such as F, Cl, Br, and P, indicating its potential as an environmentally friendly methodology for fabric functionalization., 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. All the authors listed have approved the manuscript enclosed., (Copyright © 2024. Published by Elsevier B.V.)

Anemone vitifolia is a small herb found in Asia that is used to treat a range of diseases in Chinese traditional medicine. GNPS-based molecular networking of an Anemone vitifolia specimen revealed the presence of a network containing numerous ions indicating the presence of lignans, several of which suggested that there might be previously undescribed compounds in the extract. Fractionation of the organic extract yielded five undescribed lignans, the vitifolignans, together with one known. The structures were identified based on extensive spectroscopic data analysis (NMR, HR-ESI-MS, and UV), coupling constant calculation and comparison with reported data. Their absolute configurations were determined by comparison of experimental ECD spectra with calculated spectra. Compounds 4/5 showed weak inhibition of LPS-induced NO production in mouse mononuclear macrophages., 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.)

Seven compounds, named β-sitosterol ( 1 ), daucosterol ( 2 ), (+)-pinoresinol-β-D-glucoside ( 3 ), (-)-syringaresinol 4-O-β-D-apiofuranosyl-(1→2)- β-D-glucopyranoside ( 4 ), 4-hydroxybenzoic acid ( 5 ), 2-(3', 4'-dihydroxyphenyl)-1, 3-pepper ring-5-aldehyde ( 6 ) and spinosin ( 7 ) were isolated from the rhizome of Acorus calamus var. angustatus Besser. 3 , 4 , 6 and 7 were isolated from this medicinal plant for the first time. Structures were elucidated by physicochemical properties and extensive spectroscopic analysis, as well as by comparison with literature data. The anti-inflammatory activity and related mechanisms of the seven compounds showed that compounds 1 - 7 all increased the levels of GSH-PX and SOD and decreased the levels of MDA, TNF-α, IL-1β and IL-6. Compound 4 showed the best effect of anti-inflammatory and Beclin-1 inhibition. These results suggest that compound 4 has stronger anti-inflammatory effect and provide preliminary evidence that the mechanism of action of compound 4 in attenuating LPS-induced inflammatory damage may be related to the inhibition of Beclin-1-dependent autophagy.

The importance of natural glycoconjugates containing furanoside residues causes a continued demand for the development of efficient methods for the synthesis of corresponding oligosaccharide derivatives to be used as molecular probes in glycobiological studies. Currently, the chemical synthesis of furanose-containing oligosaccharides often represents a significant challenge because of the lack of short, efficient, and reliable methods for the preparation of selectively substituted furanoside blocks. Herein, we report an easy protocol toward galactofuranose-containing molecules based on the unusual equilibrium between pyranoside and furanoside forms observed for a series of substituted galactosides. The method's utility is illustrated by the syntheses of furanoside-containing oligosaccharides related to the antigenic polysaccharides of Aspergillus fumigatus and Klebsiella pneumoniae O2ac.

Marine natural products comprise unique chemical structures and vast varieties of biological activities. This review aims to summarize halichondrin, a marine natural product, and its synthetic analogs along with its therapeutic properties and mechanisms. Halichondrin and its analogs, derived from marine sponges, exhibit potent antineoplastic properties, making them promising candidates for cancer therapeutics. These compounds, characterized by their complex molecular structures, have demonstrated significant efficacy in inhibiting microtubule dynamics, leading to cell cycle arrest and apoptosis in various cancer cell lines. Several types of halichondrins such as halichondrins B, C, norhalichondrin B, and homohalichondrin B have been discovered with similar anticancer and antitumor characteristics. Since naturally available halichondrins show hurdles in synthesis, recent advancements in synthetic methodologies have enabled the development of several halichondrin analogs, such as E7389 (eribulin), which have shown improved therapeutic indices. Eribulin has shown excellent immunomodulatory properties by several mechanisms such as reprogramming tumor microenvironments, facilitating the infiltration and activation of immune cells, and inhibiting microtubule dynamics. Despite promising results, challenges remain in the synthesis and clinical application of these compounds. This review explores the mechanisms underlying the immunomodulatory activity of halichondrin and its analogs in cancer therapy, along with their clinical applications and potential for future drug development.

Substituted tetrahydrofuran derivatives were designed and synthesized to serve as the P2 ligand for a series of potent HIV-1 protease inhibitors. Both enantiomers of the tetrahydrofuran derivatives were synthesized stereoselectivity in optically active forms using lipase-PS catalyzed enzymatic resolution as the key step. These tetrahydrofuran derivatives are designed to promote hydrogen bonding and van der Waals interactions with the backbone atoms in the S2 subsite of the HIV-1 protease active site. Several inhibitors displayed very potent HIV-1 protease inhibitory activity. A high-resolution X-ray crystal structure of an inhibitor-bound HIV-1 protease provided important insight into the ligand binding site interactions in the active site.

From both pharmaceutical and structural perspectives, the large family of prostaglandins represent a truly remarkable class of natural products. Prostaglandin A 2 is a tissue hormone naturally found in human seminal plasma and in the sea whip Plexaura homomalla with yet poorly understood biological or therapeutic effects. Herein, a novel strategy for the stereoselective construction of both naturally occurring prostaglandin A 2 epimers and first insights into their functional effects on the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) type A receptors (GABA A R) are provided. The synthesis of both epimers was achieved in only 11 steps starting from commercially available 2,5-dimethoxy-tetrahydrofuran employing an organocatalytic domino-aldol reaction, a Mizoroki-Heck reaction, a Wittig reaction as well as an oxidation-decarboxylation sequence. The (15R)-epimer significantly reduced GABA-induced currents through GABA A receptors while its (15S)-epimer did not show any significant effect. These data suggest that (15R)-PGA 2 might serve as a novel scaffold for the development of selective GABA A receptor modulators., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Arctigenin (Ar) is a promising therapeutic candidate for postmenopausal osteoporosis (PMOP). This study explores its mechanism by examining its effects on adipogenesis and osteogenesis in ovariectomized (OVX) rats. In vitro, Ar effectively suppressed the adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) from OVX rats, reducing lipid droplet formation and downregulating proteins associated with lipid synthesis. In vivo, Ar treatment significantly reduced bone loss, inhibited adipocyte development, improved lipid metabolism, and promoted bone formation in OVX rats. Mechanistically, Ar inhibited the phosphorylation of Mitogen-Activated Protein Kinase 1 (MEK1), downregulated Peroxisome Proliferator-Activated Receptor gamma (PPARγ), promoted the accumulation of β-catenin in the nucleus, and prevented the direct binding of PPARγ to β-catenin in BMSCs. This regulation of the PPARγ/Wnt signaling axis underlies its dual role in inhibiting adipogenesis and promoting osteogenesis. Notably, co-treatment with rosiglitazone (RGZ) reversed the effects of Ar on adipogenesis and osteogenesis without affecting MEK1 inhibition. These findings offer valuable insights into arctigenin's potential as a therapeutic strategy for PMOP by modulating MEK1 signaling and regulating the PPARγ/Wnt axis., (© 2024 John Wiley & Sons Ltd.)

Most of the previously reported fluorescent organic probes for cancer cell and tumor imaging have significant limitations including chemical toxicity, structural instability, low Stokes shift value, and the inability for selective accumulations in tumors during in vivo imaging. To overcome the mentioned challenges, we synthesized the fluorescent probes with protected polar functional groups to enhance the non-toxicity nature and increase the selectivity toward tumors. In addition, the structural rigidity of the fluorescent probes was increased by embedding aromatic rings in the probe structure. This issue enables us to obtain ultrabright cell images due to enhanced fluorescence quantum yield (Φ FL ) values. After synthesis and spectral characterizations, the applicability of two furan-based and imidazole-based fluorescent probes ( abbreviated as DCPEF and DBPPI, respectively) was investigated for ultrabright in vitro and in vivo imaging of cancer cells. The probe DCPEF shows the Φ FL value of 0.946 and the Stocks shift of 86 nm. In addition, probe DBPPI offers the Φ FL value of 0.400 and a Stocks shift of 150 nm. The MTT colorimetric cytotoxicity assay showed that probe DCPEF has minimal effects against HT-29 (cancer) and Vero (normal) cells. The probe DCPEF produced ultrabright fluorescence images from HT-29 cells. In addition, in vivo imaging of cancer cells showed that probe DCPEF selectively accumulates in the 4T1 tumor in mice. The spectral and chemical stability, minimal cytotoxicity, significant Stokes shift, and high degree of selectivity for tumor cells during in vivo imaging make DCPEF an appropriate candidate to be used as a standard probe for cancer cell imaging., (© 2024 Wiley-VCH GmbH.)

A new total synthesis of the natural δ-lactone cleistenolide (1) and its (6S)-stereoisomer 2 was achieved starting from d-glucose. Key steps in the synthesis of 1 involved: oxidative cleavage of the C 1 -C 2 bond in partially protected d-glucose derivative (20), and chain extension of resulting aldehyde 20a with a single C 2 fragment using (Z)-selective Wittig olefination. Synthesis of 2 involves the following key steps: periodate cleavage of the C 5 -C 6 bond in the commercially available monoacetone d-glucose (24), followed by C 2 chain elongation by using the (Z)-selective Wittig olefination. This new approach is also applied to prepare a few new 4-substituted cleistenolide analogues (3 - 18). Compounds 3 - 7 were designed using molecular hybridization, while the remaining eleven analogues were designed using the bioisosterism method. MTT assay showed that most analogues were more active than lead 1 against several malignant cells, but were completely inactive in the culture of normal foetal lung fibroblasts (MRC-5). The K562 cells appeared to be the most sensitive to the synthesized analogues. The strongest antiproliferative activity against this cell line was shown by 4-O-cinnamoyl derivative 3 and 4,6-di-O-benzyl derivative 17, with submicromolar IC 50 values (0.76 and 0.67 μM, respectively). Structural features important for the activity of this class of compounds were identified by SAR analysis., 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.)

Novel coumarin-piperazine-2(5H)-furanone hybrids 5a-l were efficiently synthesized by introducing a furanone scaffold into coumarin using piperazine as a linker. The cytotoxicity of all hybrids 5a-l were evaluated by MTT assay on human lung cancer A549 cells and normal human lung fibroblast WI-38 cells with cytarabine (CAR) as a positive control. Hybrid 5l (IC 50  = 11.28 μM) was the most toxic to A549 cells, 18-fold more toxic than the reference CAR (IC 50  = 202.57 μM). Moreover, hybrid 5l (IC 50  = 411.93 μM) was less toxic to WI-38 cells, with a much higher selectivity (5l, SI ≈ 37, WI-38/A549) than CAR (SI ≈ 2). Structure-activity relationship analysis showed that both the cytotoxicity against A549 cells and selectivity (WI-38/A549) were greatly improved when the bornyl group was incorporated in the hybrids (5c, 5f, 5i and 5l). Further, hybrid 5l was more toxic and selective against four types of human lung cancer cells (A549, Calu-1, PC-9 and H460; IC 50  = 5.72-45.46 μM; SI ≈ 9-72) than three other types of human cancer cells (SK-BR-3, 786-O and SK-OV-3, IC 50  = 39.07-130.82 μM; SI ≈ 0-2), showing remarkable specificity. In particular, hybrid 5l (IC 50  = 5.72 μM) showed the highest cytotoxicity against H460 cells with the highest selectivity of up to 72 (WI-38/H460). Flow cytometric analysis showed that hybrid 5l induced apoptosis in H460 cells in a concentration-dependent manner. Molecular docking studies revealed a high binding affinity of hybrid 5l with CDK2 protein. Hybrid 5l is expected to be a leading candidate for anti-lung cancer agents., 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.)

Effects of tetrahydrofuran (THF) concentration on the mixed methane hydrate formation, dissociation, and stability were investigated. The experiment was conducted at 286.2 K and 6 MPa in a quiescent reactor. The presence of THF below 2.5 mol% did not show the evidence of hydrate formation. However, the concentration above 2.5 mol% enhanced the methane formation rate and the methane consumption. Increasing the THF concentration decreased the induction time as the result of the decrease in the surface tension. Moreover, the methane uptake and formation rate increased with the THF concentration due to the higher degree of hydrate nucleation. The methane recovery after the dissociation experiment showed up to 96%. Furthermore, the hydrate stability increased, and the hydrate dissociation kinetics decreased with the increase in the THF concentration. The optimum THF concentration to enhance and improve the hydrate formation kinetics and stability is its stoichiometric concentration.

The interaction mechanism between soybean protein isolate (SPI) and furan flavor compounds with different structures is studied using spectroscopy, molecular docking, and MD simulation methods. The order of binding ability between SPI and furan flavor compounds is 2-acetylfuran>furfural>5-methylfurfural. The structural differences (position and quantity of methyl groups) of three furan flavor compounds are key factors leading to the different adsorption abilities of SPI for furan flavor compounds. The findings from spectroscopy analyses suggest that the interaction between SPI and furan flavor compounds involves both static and dynamic quenching mechanisms, with static quenching being the main factor. Molecular docking and MD simulations reveal the atomic-level mechanisms underlying the stable binding for SPI and furan flavor compounds at spatiotemporal multiscale. This study provides a theoretical framework for the production and adjustment of meat essence formula in the production of soybean protein-based 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.)

Hypoxylon vinosopulvinatum DYR-1-7 is a endophytic fungus isolated from the Cinnamomum cassia Presl and has an inhibitory effect on Lasiodiplodia pseudotheobromae . Three new furanones, hypoxylonone A-C ( 1 - 3 ), as well as three known compounds ( 4 - 6 ), were isolated from an EtOAc extract of H. vinosopulvinatum DYR-1-7. The structures were determined by spectroscopic data analysis using UV, IR, 1D-, 2D-NMR and HR-ESI-MS. The absolute configurations of 1 - 3 were elucidated by electronic circular dichroism (ECD) analyses. In the antifungal bioassay, Hypoxylonone B and C exhibited strong inhibitory effects on L. pseudotheobromae with IC 50 value at the concentration of 1.01 and 2.40 μg/mL, respectively. Compound 6 showed medium antifungal activity with IC 50 value at the concentration of 10.67 μg/mL on Fusarium oxysporum . Compounds 3 and 4 displayed medium antifungul effects on Candida albicans .

Chemical investigation on the aqueous extract of Dendrobium aphyllum led to the isolation of thirty-one constituents with structures identified by analysis of the extensive spectroscopic data (1D/2D NMR, MS, UV, and ECD), including previously undescribed two bibenzyls, one furfural, and one phenolic acid, namely trigonopol D (1), trigonopol C (2), dendrofunan A (10), and 6-(4-hydroxy-3-methoxyphenyl)-3,6-dioxohexyl acetate (30), respectively, as well as twenty-seven known ones. Among them, there were one new natural product (11), seven compounds (6-7, 9, 12, 20, 28, 31) described from the genus Dendrobium for the first time, and fifteen compounds (8, 13-17, 19, 21-27, 29) isolated from D. aphyllum for the first time. Further, the antioxidant and anti-inflammatory potentials of fifteen compounds (4-5, 8, 11-12, 14-19, 22, 24, 26, and 29) with significant scavenging capacities against DPPH and hydroxyl radicals, and virtual docking activities inhibiting COX-2 and 5-LOX, respectively. Our study may draw the attention of medicinal plant taxonomists and supply potential quality markers for discrimination of D. aphyllum from other species in Dendrobium genus., 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.)

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.)

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.

In this report, a polytetrahydrofuran-coated polyester fabric phase sorptive extraction (FPSE) for the determination of doxycycline in human urine was described. The sol-gel polytetrahydrofuran sorbent proved to be superior against other sol-gel coated cellulose and polyester membranes tested. The effect of the extraction parameters including membrane surface area, sample pH and volume, salt concentration, extraction time, stirring rate, etc., on the extraction efficiency of the analyte was studied using the "one-factor-at-a-time" (OFAT) and Box-Behnken design approaches. The analytical method proposed was validated in compliance with FDA guidelines for bioanalytical procedures. The method was linear in the determination range of 100-5000 ng/mL with the determination coefficient of 0.9953. The limit of detection (LOD) and the lower limit of quantification for doxycycline was 17 and 100 ng/mL, respectively. The relative recoveries for intra-day and inter-day studies ranged from 98.5-112.2% and 89.6-96.8%, respectively. The relative standard deviation was lower than 14.7% in all cases, exhibiting good precision. The sol-gel polytetrahydrofuran-modified FPSE membranes were reusable for at least 30 times. The greenness of the developed method was evaluated using Sample Preparation Metric of Sustainability (SPMS) and Blue Applicability Grade Index (BAGI) metric tools. Finally, the analytical scheme was successfully employed for the quantitation of urinary doxycycline collected at various time points following the administration of doxycycline-containing tablets.

Arctium lappa (Burdock) root is used in various culinary applications especially in Asian Cuisine. Arctigenin (ARC) is a polyphenolic compound abundant in the roots of the burdock plant from which it derives its name. The emergence of bacterial resistance is a growing global worry, specifically due to the declining availability of new antibiotics. Screening for the antibacterial candidates among the safe natural products is a promising approach. The present study was aimed to assess the antibacterial activity of ARC against Pseudomonas aeruginosa exploring its effect on the bacterial cell membrane. Furthermore, the anti-virulence activities and anti-quorum sensing (QS) activities of ARC were in vitro, in vivo and in silico assessed against P. aeruginosa . The current results showed the ARC antibacterial activity was owed to its disruption effect of the cell membrane. ARC at sub-MIC significantly decreased the formation of biofilm, motility, production of extracellular enzymes and in vivo protected mice against P. aeruginosa . These anti-virulence activities of ARC are owed to its interference with bacterial QS and its expression. Furthermore, ARC showed mild effect on mammalian erythrocytes, low probability to induce resistance and synergistically combined with antibiotics. In summary, the promising anti-virulence properties of ARC indicate its potential as an effective supplement to conventional antibiotics for treating severe P. aeruginosa infections.

Ion-selective electrodes (ISEs) have widespread use in the fields of clinical and environmental analyses. Tetrahydrofuran (THF) is the most used solvent for the preparation of modern ISEs, equipped with ion-selective membranes (ISMs). Until now, the influence of impurities in THF toward potentiometric instability of ion-selective membrane based ISEs was probably associated with the presence of either residual water or peroxide. To address this issue, most literature recommends redistilling THF prior to use in the preparation of the potentiometric membranes. Current study reveals that the actual THF impurity that is responsible for potential instability in the ISM includes products from the oxidation of THF, which contains the hydroxyl group and possibly carbonyl group with a boiling point of above 200 °C. The density functional theory calculation supported pathway of the chemical reaction of THF oxidation, hence, the chemical structure of the uncertain impurities was predicted. The underlying reason for the deteriorating potential stability of the ISEs is proposed as the significant hydrophilicity of these impurities that affect the partitioning of the ion sensing components in the membrane, thus enhancing the leaching of the membrane components from the membrane phase. This finding explains why redistillation of aged THF is advised.

SHP2 plays a critical role in modulating tumor growth and PD-1-related signaling pathway, thereby serving as an attractive antitumor target. To date, no antitumor drugs targeting SHP2 have been approved, and hence, the search of SHP2 inhibitors with new chemical scaffolds is urgently needed. Herein, we developed a novel SHP2 allosteric inhibitor SDUY038 with a furanyl amide scaffold, demonstrating potent binding affinity ( K D = 0.29 μM), enzymatic activity (IC 50 = 1.2 μM) and similar binding interactions to SHP099. At the cellular level, SDUY038 exhibited pan-antitumor activity (IC 50 = 7-24 μM) by suppressing pERK expression. Furthermore, SDUY038 significantly inhibited tumor growth in both xenograft and organoid models. Additionally, SDUY038 displayed acceptable bioavailability ( F = 14%) and half-life time ( t 1/2 = 3.95 h). Conclusively, this study introduces the furanyl amide scaffold as a novel class of SHP2 allosteric inhibitors, offering promising lead compounds for further development of new antitumor therapies targeting SHP2.

Herein, we present a highly efficient method for constructing the intricate 5-5-6 fused ring system commonly found in the polycyclic furanobutenolide-derived cembranoid and norcembranoid natural product family with remarkable diastereoselectivity, utilizing an intramolecular Diels-Alder reaction as the cornerstone. Notably, employing a propargyl ether tether as the dienophile yields significant enhancements in the transformation process compared to its propargyl ester counterpart, as demonstrated in our previous total synthesis of havellockate. This advancement holds promising implications for future investigations, offering a streamlined pathway for rapidly assembling the tricyclic core characteristic of this diverse family of natural products.

Temperature-dependent rate coefficients for the reactions of 2-methyl tetrahydrofuran (MTHF) with Cl atoms in the temperature range of 268-343 K at atmospheric pressure were measured using the relative-rate method. Ethylene and propane were used as reference compounds. Quantitative analysis of the post-photolysis reaction mixture was conducted using a gas chromatograph paired with a flame ionization detector (GC-FID). A gas chromatograph connected to a mass spectrometer (GC-MS) was employed for the purpose of qualitative analysis. In the experimental temperature range, the derived Arrhenius expression for the title reaction is represented by the equation k M T H F + C l Expt 268 - 343 K = ( 1.48 ± 0.13 ) × 10 - 12 × e x p 1474.51 ± 25.16 T cm 3 molecule -1  s -1 . In addition to our experimental findings, we conducted computational calculations employing the CCSD(T)//BHandHLYP/6-31 + G(d,p) level of theory to complement our study. The canonical transition state theory (CTST) was utilized to compute the rate coefficients at 250-400 K and 760 Torr. The Arrhenius expression for the theoretically calculated "k" values is found to be k M T H F + C l Theory 250 - 400 K = ( 1.51 ± 0.10 ) × 10 - 12 × e x p 1544.97 ± 22.14 T cm 3 molecule -1  s -1 . The local reactivity parameters, such as Fukui functions ( f r 0 ), local softness ( s r 0 ), and global softness ( S ) were also calculated theoretically to understand the site-specific reactivity trend of MTHF towards Cl atoms. The atmospheric implications, branching ratios, degradation mechanism, and feasibility of the reaction are discussed in this study., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Crack is found on the soil when severe drought comes, which inspires the idea to rationalize patterning applications using dried deoxyribonucleic acid (DNA) film. DNA is one of the massively produced biomaterials in nature, showing the lyotropic liquid crystal (LC) phase in highly concentrated conditions. DNA nanostructures in the hydrated condition can be orientation controlled, which can be extended to make dryinginduced cracks. The controlled crack generation in oriented DNA films by inducing mechanical fracture through organic solvent-induced dehydration (OSID) using tetrahydrofuran (THF) is explored. The corresponding simulations show a strong correlation between the long axis of DNA due to the shrinkage during the dehydration and in the direction of crack propagation. The cracks are controlled by simple brushing and a 3D printing method. This facile way of aligning cracks will be used in potential patterning applications., (© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Acne caused by inflammation of hair follicles and sebaceous glands is a common chronic skin disease. Arctigenin (ATG) is an extract of Arctium lappa L., which has significant anti-inflammatory effects. However, the effect and mechanism of ATG in cutaneous inflammation mediated by Cutibacterium acnes (C. acnes) has not been fully evaluated. The purpose of this study was to explore the effect and potential mechanism of ATG in the treatment of acne through network pharmacology and experimental confirmation. An acne model was established by injected live C. acnes into living mice and treated with ATG. Our data showed that ATG effectively improved acne induced by live C. acnes, which was confirmed by determining ear swelling rate, estradiol concentration and hematoxylin and eosin (H&E) staining. In addition, ATG inhibited the NLRP3 inflammasome signaling pathway in mice ear tissues and reduced the secretion of pro-inflammatory cytokines IL-1β to relieve inflammation. The results of network pharmacology and molecular docking confirmed that ATG can regulate 17β-Estradiol (E2) levels through targeted to CYP19A1, and finally inhibited skin inflammation. Taken together, our results confirmed that ATG regulated E2 secretion by targeting CYP19A1, thereby inhibiting the NLRP3 inflammasome signaling pathway and improving inflammation levels in acne mice. This study provides a basis for the feasibility of ATG in treating acne in clinical practice., (© 2024 John Wiley & Sons Ltd.)

This study introduces a novel approach for the separation of indacrinone (IC) enantiomers, crucial in treating edema, hypertension, and hyperuricemia. A cationic biopolymer from furan-2-ylmethylhydrazine-cellulose (FUH-CE), derived from cyanoethyl cellulose (CEC), serving as a substrate in molecular imprinting. A key innovation is the use of the Diels-Alder reaction for efficient cross-linking with bis(maleimido)ethane (BME). This chemical strategy resulted in molecularly imprinted microparticles with high selectivity for the S-IC enantiomer, which can be eluted by adjusting the solution's pH. Extensive characterization confirmed the chemical modifications and selective binding efficacy of these biopolymers. Utilizing separation columns, our method achieved an impressive chiral resolution of (±)-IC, with an enantiomeric excess (ee) of 95 % for R-IC during the loading phase and 97 % for S-IC during elution. Under optimized conditions, the biopolymer demonstrated a maximum binding capacity of 131 mg/g at pH 6. This advanced approach represents a significant advancement in chiral separation technology, offering a robust and efficient technique for the selective isolation of enantiomers. This method not only enhances potential targeted therapeutic applications but also provides a scalable solution for industrial chiral separations., 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.)

In the era of antiretroviral therapy, the prevalence of Cryptococcal infection among HIV patients in developed countries has decreased considerably. However, C. neoformans ranks top among the critical priority pathogen that affects a wide range of immunocompromised individuals. The threat of C. neoformans is because of its incredibly multifaceted intracellular survival capabilities. Cell membrane sterols especially ergosterol and enzymes of its biosynthetic pathway are considered fascinating drug targets because of their structural stability. In this study, the ergosterol biosynthetic enzymes were modeled and docked with furanone derivatives. Among the tested ligands Compound 6 has shown a potential interaction with Lanosterol 14 α-demethylase. This best-docked protein-ligand complex was taken further to molecular dynamics simulation. In addition, Compound 6 was synthesized and an in vitro study was conducted to quantify the ergosterol in Compound 6 treated cells. Altogether the computational and in vitro study demonstrates that Compound 6 has anticryptococcal activity by targeting the biosynthetic pathway of ergosterol.Communicated by Ramaswamy H. Sarma.

Polyene cyclizations are among the most complex and challenging transformations in biology. In a single reaction step, multiple carbon-carbon bonds, ring systems and stereogenic centres are constituted from simple, acyclic precursors 1-3 . Simultaneously achieving this kind of precise control over product distribution and stereochemistry poses a formidable task for chemists. In particular, the polyene cyclization of (3E,7E)-homofarnesol to the valuable naturally occurring ambergris odorant (-)-ambrox is recognized as a longstanding challenge in chemical synthesis 1,4-7 . Here we report a diastereoselective and enantioselective synthesis of (-)-ambrox and the sesquiterpene lactone natural product (+)-sclareolide by a catalytic asymmetric polyene cyclization by using a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst in the presence of fluorinated alcohols. Several experiments, including deuterium-labelling studies, suggest that the reaction predominantly proceeds through a concerted pathway in line with the Stork-Eschenmoser hypothesis 8-10 . Mechanistic studies show the importance of the enzyme-like microenvironment of the imidodiphosphorimidate catalyst for attaining exceptionally high selectivities, previously thought to be achievable only in enzyme-catalysed polyene cyclizations., (© 2024. The Author(s).)

Mitigating inflammation associated with the foreign body response (FBR) remains a significant challenge in enhancing the performance of implantable medical devices. Current anti-inflammatory approaches aim to suppress implant fibrosis, the major outcome of the FBR, but also inadvertently inhibit beneficial immune signalling necessary for tissue healing and vascularization. In a previous study, we demonstrated the feasibility of 'selective' immunosuppression targeting the NLRP3 inflammasome using the small molecule inhibitor MCC950, leading to reduced implant fibrosis without compromising healing and leading to enhanced vascularization. However, the clinical potential of MCC950 is severely limited due to its failure to pass Phase I clinical safety trials. This has triggered substantial efforts to develop safer analogues of NLRP3 inhibitors. Dapansutrile (OLT1177) is emerging as a leading candidate amongst current NLRP3 inhibitors, demonstrating both safety and effectiveness in a growing number of clinical indications and Phase 2 trials. While the anti-inflammatory effects of OLT1177 have been shown, validation of these effects in the context of implanted materials and the FBR have not yet been demonstrated. In this study, we show OLT1177 possesses beneficial effects on key cell types which drive FBR outcomes, including macrophages, fibroblasts, and smooth muscle cells. Evaluation of OLT1177 in a 28 day subcutaneous implantation model showed OLT1177 reduced fibrotic capsule formation while promoting implant vascularization. Mechanistic studies revealed that this occurred through activation of early pro-angiogenic markers while suppressing late-stage anti-angiogenic markers. These findings establish OLT1177 as a promising therapeutic approach for mitigating implant fibrosis while supporting vascularisation, suggesting a highly promising selective immunosuppressive strategy for the FBR warranting further research to explore its optimal integration into medical materials and devices.

Biobased furans have emerged as chemical building blocks for the development of materials because of their diverse scaffolds and as they can be directly prepared from sugars. However, selective, efficient, and cost-effective scalable conversion of biobased furans remains elusive. Here, we report a robust transaminase (TA) from Shimia marina (SMTA) that enables the scalable amination of biobased furanaldehydes with high activity and broad substrate specificity. Crystallographic and mutagenesis analyses provide mechanistic insights and a structural basis for understanding SMTA, which enables a higher substrate conversion. The enzymatic cascade process established in this study allows one-pot synthesis of 2,5-bis(aminomethyl)furan (BAMF) and 5-(aminomethyl)furan-2-carboxylic acid from 5-hydroxymethylfurfural. The biosynthesis of various furfurylamines, including a one-pot cascade reaction for BAMF generation using whole cells, demonstrates their practical application in the pharmaceutical and polymer industries., (© 2024. The Author(s).)

Furan-containing compounds distribute widely in food, herbal medicines, industrial synthetic products, and environmental media. These compounds can undergo oxidative metabolism catalyzed by cytochrome P450 enzymes (CYP450) within organisms, which may produce reactive products, possibly reacting with biomolecules to induce toxic effects. In this work, we performed DFT calculations to investigate the CYP450-mediated metabolic mechanism of furan-ring oxidation using 2-methylfuran as a model substrate, meanwhile, we studied the regioselective competition of another hydroxylation reaction involving methyl group of 2-methylfuran. As a result, we found the toxicological-relevant cis-enedione product can be produced from O-addition directly via a concerted manner without formation of an epoxide intermediate as traditionally believed. Moreover, our calculations demonstrate the kinetic and thermodynamic feasibility of both furan-ring oxidation and methyl hydroxylation pathways, although the former pathway is a bit more favorable. We then constructed a linear model to predict the rate-limiting activation energies (ΔE*) of O-addition with 11 diverse furan substates based on their adiabatic ionization potentials (AIPs) and condensation Fukui functions (CFFs). The results show a good predictive ability (R 2 =0.94, Q 2 CV =0.87). Therefore, AIP and CFF with clear physichem meanings relevant to the mechanism, emerge as pivotal molecular descriptors to enable the fast prediction of furan-ring oxidation reactivities for quick insight into the toxicological risk of furans, using just ground-state calculations., 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 Inc. All rights reserved.)

Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 ( 22 ) for the treatment of Alzheimer's disease. A key component of the design involved a 2,5- cis -tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aβ42 IC 50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid β (Aβ) 42 in cerebrospinal fluid (CSF).

Cycloaddition reactions play a pivotal role in synthetic chemistry for the direct assembly of cyclic architectures. However, hurdles remain for extending the C4 synthon to construct diverse heterocycles via programmable [4+n]-cycloaddition. Here we report an atom-economic and modular intermolecular cycloaddition using furan-fused cyclobutanones (FCBs) as a versatile C4 synthon. In contrast to the well-documented cycloaddition of benzocyclobutenones, this is a complementary version using FCB as a C4 reagent. It involves a C-C bond activation and cycloaddition sequence, including a Rh-catalyzed enantioselective [4 + 2]-cycloaddition with imines and an Au-catalyzed diastereoselective [4 + 4]-cycloaddition with anthranils. The obtained furan-fused lactams, which are pivotal motifs that present in many natural products, bioactive molecules, and materials, are inaccessible or difficult to prepare by other methods. Preliminary antitumor activity study indicates that 6e and 6 f exhibit high anticancer potency against colon cancer cells (HCT-116, IC 50  = 0.50 ± 0.05 μM) and esophageal squamous cell carcinoma cells (KYSE-520, IC 50  =  0.89 ± 0.13 μM), respectively., (© 2024. The Author(s).)