Promoting the Anticancer Activity with Multidentate Furan-2-Carboxamide Functionalized Aroyl Thiourea Chelation in Binuclear Half-Sandwich Ruthenium(II) Complexes.

A new set of binuclear arene ruthenium complexes [Ru2(p-cymene)2(k4-N2OS)(L1-L3)Cl2] (Ru2L1-Ru2L3) encompassing furan-2-carboxamide-based aroylthiourea derivatives (H2L1-H2L3) was synthesized and characterized by various spectral and analytical techniques. Single-crystal XRD analysis unveils the N^O and N^S mixed monobasic bidentate coordination of the ligands constructing N, S, Cl/N, O, and Cl legged piano stool octahedral geometry. DFT analysis demonstrates the predilection for the formation of stable arene ruthenium complexes. In vitro antiproliferative activity of the complexes was examined against human cervical (HeLa), breast (MCF-7), and lung (A549) cancerous and noncancerous monkey kidney epithelial (Vero) cells. All the complexes are more efficacious against HeLa and MCF-7 cells with low inhibitory doses (3.86-11.02 µM). Specifically, Ru2L3 incorporating p-cymene and -OCH3 fragments exhibits high lipophilicity, significant cytotoxicity against cancer cells, and lower toxicity on noncancerous cells. Staining analysis indicates the apoptosis-associated cell morphological changes expressively in MCF-7 cells. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) analyses reveal that Ru2L3 can raise ROS levels, reduce MMP, and trigger mitochondrial dysfunction-mediated apoptosis. The catalytic oxidation of glutathione (GSH) to its disulfide form (GSSG) by the complexes may simultaneously increase the ROS levels, alluding to their observed cytotoxicity and apoptosis induction. Flow cytometry determined the quantitative classification of late apoptosis and S-phase arrest in MCF-7 and HeLa cells. Western blotting analysis confirmed that the complexes promote apoptosis by upregulating Caspase-3 and Caspase-9 and downregulating BCL-2. Molecular docking studies unfolded the strong binding affinities of the complexes with VEGFR2, an angiogenic signaling receptor, and BCL2, Cyclin D1, and HER2 proteins typically overexpressed on tumor cells.

Collective Synthesis of Highly Oxygenated (Furano)germacranolides Derived from Elephantopus mollis and Elephantopus tomentosus.

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

One-pot Twostep Chemobiocatalytic Synthesis of a Furan Amino Acid from 5-Hydroxymethylfurfural.

Recently, catalytic valorization of biomass-derived furans has received growing interest. 5-Aminomethyl-2-furancarboxylic acid (AMFC), a furan amino acid, holds great promise in the aeras of polymer and pharmaceutical, but its synthesis remains limited. In this work, we report a chemobiocatalytic route toward AMFC by combining laccase-TEMPO system and recombinant Escherichia coli (named E. coli_TAF) harboring ω-transaminase (TA), L-alanine dehydrogenase (L-AlaDH) and formate dehydrogenase (FDH), starting from 5-hydroxymethylfurfural (HMF). In the cascade, HMF is oxidized into 5-formyl-2-furancarboxylic acid (FFCA) by laccase-TEMPO system, and then the resulting intermediate is converted into AMFC by E. coli_TAF via transamination with cheap ammonium formate instead of costly organic amine donors, theoretically generating H2O and CO2 as by-products. The tandem process was run in a one-pot twostep manner, affording AMFC with approximately 81 % yield, together with 10 % 2,5-furandicarboxylic acid (FDCA) as by-product. In addition, the scale-up production of AMFC was demonstrated, with 0.41 g/L h productivity and 8.6 g/L titer. This work may pave the way for green manufacturing of the furan-containing amino acid.

Formation of Furan from Linoleic Acid Thermal Oxidation: (E,E)-2,4-Decadienal as a Critical Intermediate Product.

The linoleic acid reaction models were set at 150 °C for 120 min, and its oxidation process was monitored by nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry (GC-MS). Results showed that no furan was formed from linoleic acid without heating, while furan accumulated throughout the heating process. Linoleic acid ran out within 30 min, which indicated that furan was formed mainly from the intermediate oxidation products of linoleic acid after 30 min. It should be noticed that the content of (E,E)-2,4-decadienal reached maximum once the linoleic acid ran out and then decreased with the formation of furan. Multivariate statistical analysis suggested that (E,E)-2,4-decadienal was the most important aldehyde related to furan formation during linoleic acid oxidation. To prove this assumption, the variation of furan from (E,E)-2,4-decadienal reaction models heating at 150 °C for 60 min was also studied. Results showed that the content of furan increased with the oxidation of (E,E)-2,4-decadienal. Furthermore, NMR and GC-MS data proved that (E,E)-2,4-decadienal could be oxidized to 4,5-epoxy-(E)-2-decenal. In conclusion, our results supported (E,E)-2,4-decadienal and trans-4,5-epoxy-(E)-2-decenal as critical intermediate products of furan formation from linoleic acid oxidation.

Exploration of the P1 residue in 3CL protease inhibitors leading to the discovery of a 2-tetrahydrofuran P1 replacement.

The virally encoded 3C-like protease (3CLpro) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CLpro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CLpro in SARS-CoV-2 virus is described herein.

Characterization of Key Aging Aroma Compounds in Aged Jiangxiangxing Baijiu and Their Formation Influencing Factors during the Storge Process.

Long-term storage Baijiu has an appealing sensory property, yet the chemical makeup is rarely reported. This study investigated a 30-year-old Jiangxiangxing (JXX) Baijiu and recognized and measured 69 aroma compounds. 3-Methyl-2,4-nonanedione (2.76 µg/L), 2,5-dimethyl-4-hydroxy-3(2H)-furanone (HDMF, 46.2 µg/L), 2-ethyl-4-hydroxy-5-methyl-3(2H)-furanone (HEMF, 61.7 µg/L), and piperitone (3.66 µg/L) were detected for the first time in Baijiu. Compared with 3-year-old JXX Baijiu, 24 compounds were significantly higher in the 30-year-old, mainly including furans, pyrazines, and aromatics. Notably, 4,5-dimethyl-3-hydroxy-2(5H)-furanone (sotolon), HDMF, HEMF, vanillin, acetovanillone, and alkyl pyrazines in 30-year-old JXX Baijiu were 2-7 times higher than those of a 3-year-old, and they increased steadily during aging for 3, 15, and 30 years, assumed to be associated with the aging aroma. Following 24 months of storing JXX Baijiu under different conditions, the pottery significantly promoted the synthesis of sotolon, HDMF, HEMF, and alkyl pyrazines. These findings suggest that pottery is a potential catalyst for enhancing aged Baijiu.

Therapeutic Potential of HMF and Its Derivatives: a Computational Study.

Over the past century, chemicals and energy have increasingly been derived from non-renewable resources. The growing demand for essential chemicals and shrinking inventory make reliable, sustainable sources essential. Carbohydrates offer by far the greatest carbon supply. Furan compounds, a particular family of dehydration products, are believed to offer high chemical potential. Here, we analyze 5-HMF (5, hydroxymethylfurfural) and some of its derivatives in particular, a furan-type platform chemical. To analyze the therapeutic potential of HMF and its derivatives, this study utilized cutting-edge technologies such as computer-aided drug design, virtual screening, molecular docking, and molecular dynamic simulation. We conducted 189 docking simulations and examined some of the most promising dock poses using the molecular dynamic simulator. As for the receptors for our compounds, the leading candidates are human acetylcholinesterase, beta-lactamases, P. aeruginosa LasR, and S. aureus tyrosyl-tRNA synthetases. Out of all derivatives considered in this study, 2,5-furandicarboxylic acid (FCA) performed best.

Marine plant-based biorefinery for sustainable 2,5-furandicarboxylic acid production: A review.

Marine plants, including macroalgae and seagrass, show promise as biorenewable feedstocks for sustainable chemical manufacturing. This study explores their potential in producing 2,5-furandicarboxylic acid (FDCA), a versatile platform chemical for commodity polymers. FDCA-based polyethylene 2,5-furandicarboxylate offers a sustainable alternative to petroleum-derived polyethylene terephthalate, commonly used in plastic bottles. Our research pioneers the concept of a marine plant-based FDCA biorefinery, introducing innovative approaches for sustainability and cost-effectiveness. This review outlines the use of ionic liquid-based solvents (ILS) and deep eutectic solvent (DES) systems in FDCA production. Additionally, we propose biomodification strategies involving target enzyme-encoding genes to enhance the depolymerization of non-structural storage glucans in marine plants. Our findings pave the way for eco-friendly biorefineries and biorenewable plastics.

Reduction-Responsive Cationic Vesicles from Bolaamphiphiles with Ionizable Amino Acid or Dipeptide Polar Heads.

This paper presents a study of the aggregation of cationic bolaamphiphilic molecules into vesicles. These molecules are based on a cystamine core with protonated terminal dipeptide groups. The study found that vesicles can be formed at pH 4 for all of the dipeptide-terminated bolaamphiphiles containing different combinations of l-valine, l-phenylalanine, and l-tryptophan. The concentration for aggregation onset was determined by using pyrene as a fluorescent probe or light dispersion for compounds with tryptophan. Dynamic light scattering (DLS) studies and transmission electron microscopy (TEM) reveal that the vesicles have diameters ranging from 140 to 500 nm and show the capability of loading hydrophobic cargos, such as Nile red, and their liberation in reductive environments. Furthermore, the bolaamphiphiles are only fully protonated and prone to vesicle formation at acidic pH, making them a promising alternative for gastrointestinal delivery.

Mechanism of the Photochemical Isomerization and Oxidation of 2-Butenedial: A Theoretical Study.

Under tropospheric conditions, 2-butenedial is photochemically removed to produce secondary organic aerosol. Upon solar irradiation in the lower troposphere, the main photochemical products are ketene-enol (a key intermediate product), furanones, and maleic anhydride. The oxidative reaction mechanism was studied using the multireference method CASSCF to explore the hypersurface of the two most accessible singlet excited states, and by DFT for the ground state. Photoisomerization of 2-butenedial in the first excited state directly produces ground state ketene-enol upon nonradiative relaxation. From this intermediate, furan-2-ol and successively 3H-furan-2-one and 5H-furan-2-one are formed. The cooperative effect of two water molecules is essential to catalyze the cyclization of ketene-enol to furan-2-ol, followed by hydrogen transfers to furanones. Two water molecules are also necessary to form maleic anhydride from furan-2-ol. For this last reaction, in which one extra oxygen must be acquired, we hypothesize a mechanism with singlet oxygen as the oxidant.

Arctigenin derivatives improve exercise performance in mice: synthesis and biological evaluation.

Arctigenin (ARG) has potent antifatigue activity, but its clinical application has been restricted for its poor water solubility. In this study, seven ARG derivatives containing different amino acids coupled via an ethoxy linker were synthesized, and tested for their solubility, as well as activities to improve exercise performance in mice. All of the derivatives showed improved solubility compared to that of ARG. Derivative Z-A-6 exhibited the highest activity, showing that the mice ran a 4.88-fold greater distance in the running wheel test and swam a 2.86-fold greater time in the swimming test than those in the blank control group. Z-A-6 treatment increased the plasma superoxide dismutase and catalase concentrations as well as reduced lactic acid and blood urea nitrogen accumulation during exercise. Z-A-6 treatment enhanced the phosphorylation of adenosine monophosphate-activated protein kinase, and no acute toxicity was observed. The results will contribute to the development of potential antifatigue agents.

Electrocatalytic [3 + 2] Annulation for the Synthesis of Polysubstituted Furans.

In this report we describe an atom-economic, practical strategy for the synthesis of tri/tetra-substituted furans through electrochemical [3 + 2] annulation between alkynes and ß-keto compounds with ferrocene (Fc) as the catalyst. This protocol features the use of a graphite felt (GF) anode and a stainless steel (SST) cathode, mild conditions, and excellent tolerance with various alkynes and ß-keto compounds. Additionally, the application of this method is highlighted by the late-stage functionalization of complex structures and a gram-scale experiment.

Design, Synthesis and Aromaticity of an Alternating Cyclo[4]Thiophene[4]Furan.

A new class of conjugated macrocycle, the cyclo[4]thiophene[4]furan hexyl ester (C4TE4FE), is reported. This cycle consists of alternating α-linked thiophene-3-ester and furan-3-ester repeat units, and was prepared in a single step using Suzuki-Miyaura cross-coupling of a 2-(thiophen-2-yl)furan monomer. The ester side groups help promote a syn conformation of the heterocycles, which enables formation of the macrocycle. Cyclic voltammetry studies revealed that C4TE4FE could undergo multiple oxidations, so treatment with SbCl5 resulted in formation of the [C4TE4FE]2+ dication. Computational work, paired with 1 H NMR spectroscopy of the dication, revealed that the cycle becomes globally aromatic upon 2e- oxidation, as the annulene pathway along the outer ring becomes Hückel aromatic. The change in ring current for the cycle upon oxidation was clear from 1 H NMR spectroscopy, as the protons of the thiophene and furan rings shifted downfield by nearly 6 ppm. This work highlights the potential of sequence control in furan-based macrocycles to tune electronic properties.

Benzo[b]naphtho[2,1-d]furans and 2-Phenylnaphthalenes from Streblus usambarensis.

Three new benzo[b]naphtho[2,1-d]furans, usambarins A-C (1-3), five new 2-phenylnaphthalenes, usambarins D-H (4-8), a new flavan (9), and a new phenyl-1-benzoxepin (10) as well as two known compounds (11 and 12) were isolated from the extract of the stem and roots of Streblus usambarensis (Moraceae). The structures were deduced using NMR spectroscopic and mass spectrometric analyses, and those of compounds 1 and 4 were confirmed by X-ray crystallography. Usambarin D (4) demonstrated moderate antibacterial activity (MIC 9.0 µM) against Bacillus subtilis, while none of the tested compounds were effective against Escherichia coli.

Engineering a Carboxyl Methyltransferase for the Formation of a Furan-Based Bioplastic Precursor.

FtpM from Aspergillus fumigatus was the first carboxyl methyltransferase reported to catalyse the dimethylation of dicarboxylic acids. Here the creation of mutant R166M that can catalyse the quantitative conversion of bio-derived 2,5-furandicarboxylic acid (FDCA) to its dimethyl ester (FDME), a bioplastics precursor, was reported. Wild type FtpM gave low conversion due to its reduced catalytic efficiency for the second methylation step. An AlphaFold 2 model revealed a highly electropositive active site, due to the presence of 4 arginine residues, postulated to favour the binding of the dicarboxylic acid over the intermediate monoester. The R166M mutation improved both binding and turnover of the monoester to permit near quantitative conversion to the target dimethyl ester product. The mutant also had improved activity for other diacids and a range of monoacids. R166M was incorporated into 2 multienzyme cascades for the synthesis of the bioplastics precursor FDME from bioderived 5-hydroxymethylfurfural (HMF) as well as from poly(ethylene furanoate) (PEF) plastic, demonstrating the potential to recycle waste plastic.

The Novel Chiral 2(5H)-Furanone Sulfones Possessing Terpene Moiety: Synthesis and Biological Activity.

Over the past decades, 2(5H)-furanone derivatives have been extensively studied because of their promising ability to prevent the biofilm formation by various pathogenic bacteria. Here, we report the synthesis of a series of optically active sulfur-containing 2(5H)-furanone derivatives and characterize their biological activity. Novel thioethers were obtained by an interaction of stereochemically pure 5-(l)-menthyloxy- or 5-(l)-bornyloxy-2(5H)-furanones with aromatic thiols under basic conditions. Subsequent thioethers oxidation by an excess of hydrogen peroxide in acetic acid resulted in the formation of the corresponding chiral 2(5H)-furanone sulfones. The structure of synthesized compounds was confirmed by IR and NMR spectroscopy, HRMS, and single crystal X-ray diffraction. The leading compound, 26, possessing the sulfonyl group and l-borneol moiety, exhibited the prominent activity against Staphylococcus aureus and Bacillus subtilis with MICs of 8 µg/mL. Furthermore, at concentrations of 0.4-0.5 µg/mL, the sulfone 26 increased two-fold the efficacy of aminoglycosides gentamicin and amikacin against S. aureus. The treatment of the model-infected skin wound in the rat with a combination of gentamicin and sulfone 26 speeded up the bacterial decontamination and improved the healing of the wound. The presented results provide valuable new insights into the chemistry of 2(5H)-furanone derivatives and associated biological activities.

Molecular docking of novel donor-π-acceptor dicyanomethylenedihydrofuran-based fluorescent chromophores.

A series of donor-π-acceptor dicyanomethylenedihydrofuran (DCDHF)-based chromophores comprising different π-aryl bridges and different terminal groups was synthesized and characterized. The chromophores were synthesized via Knoevenagel condensation of the active methyl-bearing DCDHF (electron acceptor) with a tertiary amine-containing arylaldehyde (electron donor) in dry pyridine at room temperature in the presence of a few drops of acetic acid. The synthesis approach involved the development of phenyl(thienyl)vinyl-bridged dicyanomethylenedihydrofuran dyes with a tertiary amine terminal group. Both absorption and emission spectra were explored. The strong emission properties detected using the synthesized chromophores could be attributed to intramolecular charge transfer. The chemical structures of the synthesized chromophores were verified using 1 H/13 C nuclear magnetic resonance and Fourier transform infrared spectroscopy. Both tertiary amine-containing and arylaldehyde groups were found to influence the biological properties of the synthesized chromophores. The synthesized (DCDHF)-based hybrids were tested to examine antibacterial effectiveness. Derivatives 1 and 2 demonstrated activity towards Gram-positive bacteria rather than Gram-negative bacteria when compared with an amoxicillin antibiotic reference. Finally, molecular docking inspiration was undertaken to determine their binding relationships (PDB code: 1LNZ).

Advances in enzymatic conversion of biomass derived furfural and 5-hydroxymethylfurfural to value-added chemicals and solvents.

The progress of versatile chemicals and bio-based fuels using renewable biomass has gained ample importance. Furfural and 5-hydroxymethylfurfural are biomass-derived compounds that serve as the cornerstone for high-value chemicals and have a myriad of industrial applications. Despite the significant research into several chemical processes for furanic platform chemicals conversion, the harsh reaction conditions and toxic by-products render their biological conversion an ideal alternative strategy. Although biological conversion confers an array of advantages, these processes have been reviewed less. This review explicates and evaluates notable improvements in the bioconversion of 5-hydroxymethylfurfural and furfural to comprehend the current developments in the biocatalytic transformation of furan. Enzymatic conversion of HMF and furfural to furanic derivative have been explored, while the latter has substantially overlooked a foretime. This discrepancy was reviewed along with the outlook on the potential usage of 5-hydroxymethylfurfural and furfural for the furan-based value-added products' synthesis.

Electroenzymatic Reduction of Furfural to Furfuryl Alcohol by an Electron Mediator and Enzyme Orderly Assembled Biocathode.

The electroenzymatic valorization of biomass derivatives into valuable biochemicals has a promising outlook. However, bottlenecks including poor electron transfer between the electrode surface and oxidoreductase, inefficient regeneration of cofactors, and high cost of enzymes and electron mediators hindered the realistic applications of the technique. Herein, to address the above technical barriers, a novel bio-electrocatalytic system that integrates the electrochemical NADH regeneration and enzymatic reaction was constructed, using an orderly assembled composite bioelectrode consisting of an outer immobilized enzyme layer and a sandwiched redox mediator rhodium complex layer. The as-prepared composite bioelectrode was further applied for the highly selective hydrogenation of furfural into furfural alcohol. Results indicated that the enzyme activity was significantly improved, while the furfural valorization was promoted by effective interfacial electron transition and co-factor regeneration on the composite bioelectrode. Considerable high furfural conversion (96.4%) can be achieved accompanied by a furfural alcohol selectivity of 90.0% at -1.2 V (vs Ag/AgCl). The novel composite bioelectrode also showed good stability and reusability. Up to 85.1% of the original furfural alcohol selectivity can be preserved after 10 times of recycling. This work presents a promising green alternative for the valorization of furfural, which also shows great potential extending to the valorization of other biomass compounds.

Syntheses and Antibacterial Evaluation of New Penicillium Metabolites Gregatins G and Thiocarboxylics C.

Two pairs of side-chain epimeric 3-methoxycarbonyl-dihydrofuran-4-ones with structures purported for thiocarboxylics C1/2 and gregatins G1/2 , isolated from Penicillium sp. Sb62, were synthesised for the first time in five steps and 17-25 % yield. Key steps were a Suzuki cross-coupling, a Yamaguchi esterification, and a base-induced Knoevenagel-type condensation. The optimum protecting group for the 10-OH group in the dienyl side-chain, orthogonal to necessary protecting groups on O-10 of the furanone, was found to be t-butyldiphenylsilyl (TBDPS). The specific rotations of our synthetic products deviated markedly from those reported for the natural isolates. In contrast to the isolates, the synthetic products were not active against Escherichia coli and Staphylococcus aureus bacteria.