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This article describes the amalgamated of polyboric acid (PBA) and Aminoethyl-3-Aminopropyltriethoxysilane (AEAPTES) by straightforward extrusion process to produce composite (PBA/AEAPTES). It showed basic nature due to amine functionalities on surface of PBA. The composite is applied for the fabrication of pyran derivatives. These reactions are noteworthy for their large product yields, environmental friendliness, quick reaction times, wide range of substrates and no need of hazardous solvents. Moreover, there is no discernible decrease in activity after four reuses of the catalyst and catalyst separated by simple filtration method without any extraction. The resultant composite is characterized by FT-IR, XRD and SEM analysis. In addition, the synthesized compounds characterized by FT-IR, 1H, & 13C NMR analysis. [ABSTRACT FROM AUTHOR]

A new sustainable heterogeneous catalyst for the effective synthesis of 4H-pyran derivatives under mild reaction conditions was investigated. This heterogeneous catalyst was prepared through the complexation reaction between the naturally obtained chitosan from Callinectes sapidus shells and zinc(II) ions (Zn(II)/Chitosan), and characterized using a variety of techniques, including thermogravimetric analysis (TGA), X-ray diffraction (XRD), scanning electron microscopy (SEM), and infrared spectroscopy (IR). The corresponding 4H-pyran derivatives were obtained in good to excellent yields (58–96%) in the presence of Zn(II)/chitosan catalyst using water as solvent at 60°C for only 20 min. The catalyst was easily separated from the reaction mixture by simple filtration, resulting in the desired products with excellent purity. In comparison to numerous other catalyst systems for the synthesis of 4H-pyran derivatives, Zn(II)/chitosan, a new sustainable heterogeneous catalyst, demonstrated remarkable efficacy in an environmentally benign solvent, allowing the desired products to be produced under more environmentally friendly reaction conditions. [ABSTRACT FROM AUTHOR]

Polysubstituted derivatives of pyrans, chromenes, and chromeno[2,3-b]pyridines incorporating a 4,5-dichloroisothiazole or 5-arylisoxazole-3-carbaldehyde fragment in the molecule were synthesized by successive and one-step three-component reactions of 4,5-dichloroisothiazole-3-carbaldehyde and 5-arylisoxazole-3-carbaldehyde with various 1,3-diketones, malononitrile or its dimer. The structure of the target products was proven by X-ray structural analysis. Notably, it was found that the planes of the azole and chromene rings in the molecules of (1,2-azol-3-yl)chromenes are almost perpendicular. Intrinsic antitumor activity and synergistic enhancement of the activity in combination with known cytostatics used in the therapy of oncological diseases were found for some of the synthesized compounds. [ABSTRACT FROM AUTHOR]

This article discusses the synthesis of pentasubstituted 4H-pyran derivatives using N-heterocyclic carbene (NHC) catalysis. The researchers developed a new annulation reaction that allows for the rapid synthesis of these derivatives from readily available starting materials. They tested different substrates and found that both electron-withdrawing and electron-donating groups were tolerated. The researchers also explored the effect of different substituents and successfully conducted the reaction on a larger scale. They proposed a plausible reaction mechanism and concluded that their method could be useful for synthesizing functional molecules containing the 4H-pyran group. [Extracted from the article]

The aim of this study was to investigate the effect of bexagliflozin on glycemic control in poorly regulated diabetic cats and to evaluate for adverse events associated with this medication. Sodium-glucose cotransporter 2 inhibitors are a newer class of drugs used in the management of humans with type 2 diabetes mellitus. The objective of this study was to evaluate the effect of the orally administered drug, bexagliflozin in a group of poorly regulated diabetic cats over a 4-week study period. Five client-owned cats with poorly controlled diabetes mellitus receiving insulin therapy were enrolled. Bexagliflozin was administered once daily. Serum fructosamine, serum biochemistry profile, and 10-hour blood glucose curves were assessed at baseline (Day 0), Day 14, and Day 28. All cats had a significant reduction in insulin dose requirement (P = 0.015) and insulin was discontinued in 2 cats. There was a significant decrease in blood glucose concentration obtained from blood glucose concentration curves during the study period (P = 0.022). Serum fructosamine decreased in 4 of the 5 cats with a median decrease of 152 μmol/L (range: 103 to 241 μmol/L), which was not statistically significant (P = 0.117). No cats had any documented episodes of hypoglycemia. Adverse effects were mild. The addition of bexagliflozin significantly improved diabetic management in this group of cats.

In this report, we investigate the toxicity of the ionophore thiomaltol (Htma) and Cu salts to melanoma. Divalent metal complexes of thiomaltol display toxicity against A375 melanoma cell culture resulting in a distinct apoptotic response at submicromolar concentrations, with toxicity of Cu(tma)2 > Zn(tma)2 >> Ni(tma)2. In metal-chelated media, Htma treatment shows little toxicity, but the combination with supplemental CuCl2, termed Cu/Htma treatment, results in toxicity that increases with suprastoichiometric concentrations of CuCl2 and correlates with the accumulation of intracellular copper. Electron microscopy and confocal laser scanning microscopy of Cu/Htma treated cells shows a rapid accumulation of copper within lysosomes over the course of hours, concurrent with the onset of apoptosis. A buildup of ubiquitinated proteins due to proteasome inhibition is seen on the same timescale and correlates with increases of copper without additional Htma.

Intron selection during the formation of prespliceosomes is a critical event in pre-mRNA splicing. Chemical modulation of intron selection has emerged as a route for cancer therapy. Splicing modulators alter the splicing patterns in cells by binding to the U2 snRNP (small nuclear ribonucleoprotein)-a complex chaperoning the selection of branch and 3' splice sites. Here we report crystal structures of the SF3B module of the U2 snRNP in complex with spliceostatin and sudemycin FR901464 analogs, and the cryo-electron microscopy structure of a cross-exon prespliceosome-like complex arrested with spliceostatin A. The structures reveal how modulators inactivate the branch site in a sequence-dependent manner and stall an E-to-A prespliceosome intermediate by covalent coupling to a nucleophilic zinc finger belonging to the SF3B subunit PHF5A. These findings support a mechanism of intron recognition by the U2 snRNP as a toehold-mediated strand invasion and advance an unanticipated drug targeting concept.

Spliceostatins and thailanstatins are intriguing natural products due to their structural features as well as their biological significance. This family of natural products has been the subject of immense synthetic interest because they exhibit very potent cytotoxicity in representative human cancer cell lines. The cytotoxic properties of these natural products are related to their ability to inhibit spliceosomes. FR901564 and spliceostatins have been shown to inhibit spliceosomes by binding to their SF3B component. Structurally, these natural products contain two highly functionalized tetrahydropyran rings with multiple stereogenic centers joined by a diene moiety and an acyclic side chain linked with an amide bond. Total syntheses of this family of natural products led to the development of useful synthetic strategies, which enabled the synthesis of potent derivatives. The spliceosome modulating properties of spliceostatins and synthetic derivatives opened the door for understanding the underlying spliceosome mechanism as well as the development of new therapies based upon small-molecule splicing modulators. This review outlines the total synthesis of spliceostatins, synthetic studies of structural derivatives, and their bioactivity.

Ewing sarcoma (ES) is the second most common pediatric bone cancer. Despite recent advances in the treatment, patients with metastatic tumors have dismal prognosis and hence novel therapies are urgently needed to combat this cancer. A recent study has shown that phosphoinositide-3 kinase (PI3K) inhibitors can synergistically increase sensitivity to bromodomain and extraterminal domain inhibitors in ES cells and therefore combined inhibition of PI3K and bromodomain and extraterminal domain bromodomain proteins might provide benefit in this cancer. Herein, we have investigated the efficacy of dual PI3K/BRD4 inhibitors, SF2523 and SF1126, for their antitumor activity in ES cell lines. The effect of SF1126 and SF2523 on cell viability and PI3K signaling was assessed on a panel of human ES cell lines. To evaluate the antitumor activity of SF1126, A673 cells were injected intrafemorally into RAG-2-/- mice and treated with 50 mg/kg SF1126 6 days per week, for 30 days. Both SF1126 and SF2523 decreased cell survival and inhibited phosphorylation of AKT in human ES cell lines. In vivo, SF1126 showed a significant reduction in tumor volume. These results suggest that dual PI3K/BRD4 inhibitor, SF1126, has antitumor activity in ES models.

Small molecules that target the spliceosome SF3B complex are potent inhibitors of cancer cell growth. The compounds affect an early stage of spliceosome assembly when U2 snRNP first engages the branch point sequence of an intron. Employing an inactive herboxidiene analog (iHB) as a competitor, we investigated factors that influence inhibitor interactions with SF3B to interfere with pre-mRNA splicing in vitro. Order-of-addition experiments show that inhibitor interactions are long lasting and affected by both temperature and the presence of ATP. Our data are also consistent with the model that not all SF3B conformations observed in structural studies are conducive to productive inhibitor interactions. Notably, SF3B inhibitors do not impact an ATP-dependent rearrangement in U2 snRNP that exposes the branch binding sequence for base pairing. We also report extended structure-activity relationship analysis of the splicing inhibitor herboxidiene. We identified features of the tetrahydropyran ring that mediate its interactions with SF3B and its ability to interfere with splicing. In the context of recent structures of SF3B bound to inhibitor, our results lead us to extend the model for early spliceosome assembly and inhibitor mechanism. We postulate that interactions between a carboxylic acid substituent of herboxidiene and positively charged SF3B1 side chains in the inhibitor binding channel are needed to maintain inhibitor occupancy while counteracting the SF3B transition to a closed state that is required for stable U2 snRNP interactions with the intron.

Herboxidiene is a potent antitumor agent that targets the SF3B subunit of the spliceosome. Herboxidiene possesses a complex structural architecture with nine stereocenters and design of potent less complex structures would be of interest as a drug lead as well as a tool for studying SF3B1 function in splicing. We investigated a number of C-6 modified herboxidiene derivatives in an effort to eliminate this stereocenter and, also to understand the importance of this functionality. The syntheses of structural variants involved a Suzuki-Miyaura cross-coupling reaction as the key step. The functionalized tetrahydrofuran core has been constructed from commercially available optically active tri-O-acetyl-d-glucal. We investigated the effect of these derivatives on splicing chemistry. The C-6 alkene derivative showed very potent splicing inhibitory activity similar to herboxidiene. Furthermore, the C-6 gem-dimethyl derivative also exhibited very potent in vitro splicing inhibitory activity comparable to herboxidiene.

Cystic fibrosis is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Two main categories of drugs are being developed: correctors that improve folding of CFTR and potentiators that recover the function of CFTR. Here, we report two cryo-electron microscopy structures of human CFTR in complex with potentiators: one with the U.S. Food and Drug Administration (FDA)-approved drug ivacaftor at 3.3-angstrom resolution and the other with an investigational drug, GLPG1837, at 3.2-angstrom resolution. These two drugs, although chemically dissimilar, bind to the same site within the transmembrane region. Mutagenesis suggests that in both cases, hydrogen bonds provided by the protein are important for drug recognition. The molecular details of how ivacaftor and GLPG1837 interact with CFTR may facilitate structure-based optimization of therapeutic compounds.

Macrophages (MΘs) are key immune infiltrates in solid tumors and serve as major drivers behind tumor growth, immune suppression, and inhibition of adaptive immune responses in the tumor microenvironment (TME). Bromodomain and extraterminal (BET) protein, BRD4, which binds to acetylated lysine on histone tails, has recently been reported to promote gene transcription of proinflammatory cytokines but has rarely been explored for its role in IL4-driven MΘ transcriptional programming and MΘ-mediated immunosuppression in the TME. Herein, we report that BET bromodomain inhibitor, JQ1, blocks association of BRD4 with promoters of arginase and other IL4-driven MΘ genes, which promote immunosuppression in TME. Pharmacologic inhibition of BRD4 using JQ1 and/or PI3K using dual PI3K/BRD4 inhibitor SF2523 (previously reported by our group as a potent inhibitor to block tumor growth and metastasis in various cancer models) suppresses tumor growth in syngeneic and spontaneous murine cancer models; reduces infiltration of myeloid-derived suppressor cells; blocks polarization of immunosuppressive MΘs; restores CD8+ T-cell activity; and stimulates antitumor immune responses. Finally, our results suggest that BRD4 regulates the immunosuppressive myeloid TME, and BET inhibitors and dual PI3K/BRD4 inhibitors are therapeutic strategies for cancers driven by the MΘ-dependent immunosuppressive TME.

Niobium pentachloride functionalised perlite was prepared via a solid state dispersion technique, which was utilized as an efficient heterogeneous catalyst for the synthesis of pyrans. The immobilisation of NbCl5 over perlite was examined by Fourier-transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), Thermogravimetric analysis (TGA), scanning electron microscope (SEM) with energy dispersive spectra (EDS), and Brunauer, Emmett and Teller (BET) surface area measurements. The wt% of NbCl5-loaded perlite was optimized based on the adequacy with respect to the yield of the pyrans in various solvents. The recyclability of the catalyst was validated in synthesizing pyrans and the results marked its efficiency up to five runs. The efficacy of the NbCl5/perlite catalyst was found to be comparable and better with respect to the other heterogeneous catalysts reported. The structures of pyrans were confirmed by FT-IR, 1H and 13C NMR spectral techniques. The proposed recyclable heterogeneous NbCl5/perlite catalyst simplifies the protocol, and has minimal chemical waste, a lower reaction time and a high-yield. [ABSTRACT FROM AUTHOR]

Electrochemical activation of trialkylstannylmethyl group as an electroauxiliary for carbenium ion generation enables the intramolecular Friedel–Crafts alkylation. Electrochemical activation of stannylmethyl group forms carbenium ion which can be trapped by intramolecular (het)aromatic nucleophiles for the formation of new 6-membered cycles. [ABSTRACT FROM AUTHOR]

Spliceostatin A is a potent inhibitor of spliceosomes and exhibits excellent anticancer activity against multiple human cancer cell lines. We describe here the design and synthesis of a stable cyclopropane derivative of spliceostatin A. The synthesis involved a cross-metathesis or a Suzuki cross-coupling reaction as the key step. The functionalized epoxy alcohol ring was constructed from commercially available optically active tri- O-acetyl-d-glucal. The biological properties of the cyclopropyl derivative revealed that it is active in human cells and inhibits splicing in vitro comparable to spliceostatin A.

C(sp3)-H bond functionalization has emerged as a robust tool enabling rapid construction of molecular complexity from simple building blocks, and the development of asymmetric versions of this reaction creates a powerful methodology to access enantiopure sp3-rich materials. Herein, we report the stereoselective functionalization of C(sp3)-H bonds of cyclic ethers employing a photochemically active diaryliodonium salt in combination with an anionic phase-transfer catalyst. The synthetic strategy outlined herein allows for regio- and stereochemical control in the α-C-H acetalization of furans and pyrans using alcohol nucleophiles, thus providing the ability to control the configuration at the stereogenic exocyclic acetal carbon.

Thailanstatin A has been isolated recently from the fermentation broth of B. thailandensis MSMB43. We describe here an enantioselective convergent synthesis of thailanstatin A methyl ester and evaluation of its splicing activity. Synthesis of both highly functionalized tetrahydropyran rings were carried out from commercially available tri- O-acetyl-d-glucal as the key starting material. Our convergent synthesis involved the synthesis of both tetrahydropyran fragments in a highly stereoselective manner. The fragments were then coupled using cross-metathesis as the key step. The synthesis of the diene subunit included a highly stereoselective Claisen rearrangement, a Cu(I)-mediated conjugate addition of MeLi to set the C-14 methyl stereochemistry, a reductive amination reaction to install the C16-amine functionality, and a Wittig olefination reaction to incorporate the diene unit. The epoxy alcohol subunit was synthesized by a highly selective anomeric allylation, a Peterson olefination, and a vanadium catalyzed epoxidation that installed the epoxide stereoselectively. Cross-metathesis of the olefins provided the methyl ester derivative of thailanstatin A. We have carried out in vitro splicing studies of the methyl ester derivative, which proved to be a potent inhibitor of the spliceosome.

Mass spectrometry of intact proteins and protein complexes has the potential to provide a transformative level of information on biological systems, ranging from sequence and post-translational modification analysis to the structures of whole protein assemblies. This ambitious goal requires the efficient fragmentation of both intact proteins and the macromolecular, multicomponent machines they collaborate to create through noncovalent interactions. Improving technologies in an effort to achieve such fragmentation remains perhaps the greatest challenge facing current efforts to comprehensively analyze cellular protein composition and is essential to realizing the full potential of proteomics. In this work, we describe the use of a trimethyl pyrylium (TMP) fixed-charge covalent labeling strategy aimed at enhancing fragmentation for challenging intact proteins and intact protein complexes. Combining analysis of TMP-modified and unmodified protein complexes results in a greater diversity of regions within the protein that give rise to fragments, and results in an up to 2.5-fold increase in sequence coverage when compared to unmodified protein alone, for protein complexes up to 148 kDa. TMP modification offers a simple and powerful platform to expand the capabilities of existing mass spectrometric instrumentation for the complete characterization of intact protein assemblies.

Pyrans are one of the most significant skeletons of oxygen-containing heterocyclic molecules, which exhibit a broad spectrum of medicinal applications and are constituents of diverse natural product analogues. Various biological applications of these pyran analogues contributed to the growth advances in these oxygen-containing molecules. Green one-pot methodologies for synthesising these heterocyclic molecules have received significant attention. This review focuses on the recent developments in synthesising pyran ring derivatives using reusable catalysts and emphasises the multicomponent reaction strategies using green protocols. The advantages of the catalysts in terms of yields, reaction conditions, and recyclability are discussed. [ABSTRACT FROM AUTHOR]

Background: Clinical data on patients infected with influenza B Victoria (BV) after the approval of baloxavir is lacking., Methods: This observational study of the Japanese 2023-2024 influenza season analyzed data from 25 outpatients with A(H1N1)pdm09, 36 with A(H3N2), and 65 with BV. Viral samples were collected before and after administering an antiviral (70 patients received baloxavir and 56 received a neuraminidase inhibitor), on days 1, 5, and 10. Isolated viruses after culturing were amplified using RT-PCR and sequenced to detect mutations of concern, including acidic protein (PA)-amino acid (AA) E23X/I38X for influenza A and M34X/I38X for BV. Fever and symptoms were tracked via self-reporting diaries., Results: No PA-AA-substituted virus was detected from 126 pre-treatment samples. In the baloxavir cohort, one (7.1%, 1/14) PA I38F-substituted A(H1N1)pdm09 and two (11.1%, 2/18) PA I38T-substituted A(H3N2) viruses were isolated on day 5 but not on day 10. No (0%, 0/37) PA-AA-substituted BV was detected on day 5 or after. The virus isolation rate on day 5 was higher among patients with BV than with influenza A in both baloxavir (35.1% vs. 14.3% for A(H1N1)pdm09 and 16.7% for A(H3N2)) and oseltamivir-treated patients (44.4% vs. 0% for A(H1N1)pdm09 and 33.3% for A(H3N2)). Patients with PA-AA-substituted influenza A after baloxavir administration did not have longer fever duration than those without virus isolation or with wild-type virus on day 5, for both A(H1N1)pdm09 and A(H3N2)., Conclusions: Baloxavir-resistant variants were not detected in influenza BV before treatment, as with A. The emergence of PA-AA-substituted influenza A after baloxavir administration was temporal and did not cause prolonged symptoms. No baloxavir-resistant BV variants were observed after baloxavir administration., (© 2024 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

The health and productivity of broilers may be improved by optimizing the availability and levels of trace minerals (TM) in their feed, especially in the presence of parasites. This study investigated the effects of replacing inorganic TM (ITM) with an advanced chelate technology-based 7 TM (ACTM) on performance, hematology, lesion score, oocyst shedding, gut morphology, and tight junction structure in broilers challenged with mixed Eimeria species. There were 480 1-day-old broiler chickens divided into 5 groups: uninfected negative control and recommended levels of ITM (NC); infected positive control and recommended levels of ITM (PC); or PC supplemented with salinomycin (SAL); PC diet with 50 % ACTM instead of ITM (ACTM50); or PC diet with 100 % ACTM instead of ITM (ACTM100). All groups, except NC, were orally challenged with mixed Eimeria spp. oocysts on day 14. Each group had 6 replicate cages, with 16 birds per replicate. The results showed that the NC, SAL, and ACTM100 groups had higher (P < 0.05) body weight, average daily gain (ADG), and European production efficiency index (EPEI), as well as a lower (P < 0.05) feed conversion, mortality rate, and heterophile to lymphocyte ratio compared to the PC group, with the NC group having the highest ADG and EPEI throughout the experiment. The SAL and ACTM100 groups had lower (P < 0.05) intestinal lesion scores and oocyst numbers compared to the PC group, although all coccidiosis-challenged groups had higher oocyst shedding compared to the NC group. On day 24, the challenged birds in the SAL and ACTM100 groups had higher (P < 0.05) villus height and surface area in the duodenum and ileum, as well as a higher (P < 0.05) villus height to crypt depth ratio in the jejunum. The expression levels of jejunal CLDN1 and ZO-1 were also higher (P < 0.05) in the ACTM100 and SAL groups compared to the PC and ACTM50 groups at 24 days of age. In conclusion, while using ACTM in broiler diets at 50 % of the commercial recommended levels maintained performance and physiological responses, complete replacement with ACTM improved growth performance and intestinal health characteristics, similar to salinomycin under Eimeria challenge conditions., Competing Interests: Declaration of Competing Interest Bonzachicken is designed and synthesized using the Advanced Chelate Compounds Technology, invented by Mr. Mohammad Hassan Nazaran and patented in the United States Patent and Trademark Office (US8288587B2). The authors of this research have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Paederus contact dermatitis is a skin disease caused by beetles of the genus Paederus and the release of a vesicant substance called paederin. It is worldwide distributed; However, it is more common in rainy seasons and hot climates. The clinical manifestations are vesicle-pustules that settle on erythematous skin. Treatment is based on washing with soap and water to neutralize the action of the toxin and the administration of topical steroids in short cycles. We report the case of a 28-year-old male patient who came to the dermatology clinic with a 48-hour history of two erythematous plaques with central blisters plus superficial ulceration located on the flexor aspect of the arm and right forearm, accompanied by a sensation of burning and itching at the site of the lesions, without other accompanying symptoms. As background, he states that he was on vacation in the coastal region of Ecuador when the lesions appeared. An incisional biopsy was performed and due to the clinical characteristics and the history of travel to a tropical region, it was diagnosed as Paederus dermatitis and treatment with antihistamines, topical steroids and cold compresses was indicated. After 8 days of treatment, the lesions subsided, leaving post-inflammatory hyperpigmentation., (Universidad Nacional de Córdoba)

Influenza viruses remain a major threat to human health. Four classes of drugs have been approved for the prevention and treatment of influenza infections. Oseltamivir, a neuraminidase inhibitor, is a first-line anti-influenza drug, and baloxavir is part of the newest generation of anti-influenza drugs that targets the viral polymerase. The emergence of drug resistance has reduced the efficacy of established antiviral drugs. Combination therapy is one of the options for controlling drug resistance and enhancing therapeutical efficacies. Here, we evaluate the antiviral effects of baloxavir combined with neuraminidase inhibitors (NAIs) against wild-type influenza viruses, as well as influenza viruses with drug-resistance mutations. The combination of baloxavir with NAIs led to significant synergistic effects; however, the combination of baloxavir with laninamivir failed to result in a synergistic effect on influenza B viruses. Considering the rapid emergence of drug resistance to baloxavir, we believe that these results will be beneficial for combined drug use against influenza.

A simple pot, atom and step economic (PASE) synthesis of 2-amino-3-aroyl-4-aryl-tetrahydro-5H-chromen-5-one and hitherto unreported 2-amino-3-aroyl-4-aryl-dihydro-pyrano[3,2-c]chromen-5-one, 2-amino-3-aroyl-dihydrospiro[chromene-4,3'-indoline]-2',5(6H)-dione, 2-amino-3-aroyl-dihydro-5H-spiro[cyclopenta[b]pyran-4,3'-indoline]-2',5-dione, and 2'-amino-3'-aroyl-dihydro-2H-spiro[acenaphthylene-1,4'-chromene]-2,5'(6'H)-dione has been developed using LUDOX HS-40, a commercially available innocuous and inexpensive catalyst via direct annulations of benzoylacetonitrile, aldehyde/isatin/acenaphthoquinone and dimedone/cyclicdiketone/4-hydroxycoumarins in ethanol. This protocol offers advantages such as wide range of substrate scope, operational simplicity, higher yields, and cost-effectiveness. [ABSTRACT FROM AUTHOR]

Pericyclic reactions-which proceed in a concerted fashion through a cyclic transition state-are among the most powerful synthetic transformations used to make multiple regioselective and stereoselective carbon-carbon bonds. They have been widely applied to the synthesis of biologically active complex natural products containing contiguous stereogenic carbon centres. Despite the prominence of pericyclic reactions in total synthesis, only three naturally existing enzymatic examples (the intramolecular Diels-Alder reaction, and the Cope and the Claisen rearrangements) have been characterized. Here we report a versatile S-adenosyl-l-methionine (SAM)-dependent enzyme, LepI, that can catalyse stereoselective dehydration followed by three pericyclic transformations: intramolecular Diels-Alder and hetero-Diels-Alder reactions via a single ambimodal transition state, and a retro-Claisen rearrangement. Together, these transformations lead to the formation of the dihydropyran core of the fungal natural product, leporin. Combined in vitro enzymatic characterization and computational studies provide insight into how LepI regulates these bifurcating biosynthetic reaction pathways by using SAM as the cofactor. These pathways converge to the desired biosynthetic end product via the (SAM-dependent) retro-Claisen rearrangement catalysed by LepI. We expect that more pericyclic biosynthetic enzymatic transformations remain to be discovered in naturally occurring enzyme 'toolboxes'. The new role of the versatile cofactor SAM is likely to be found in other examples of enzyme catalysis.

A direct access to O-heterocycles by Bi(OTf)3-catalyzed intermolecular cyclization of phenols with diols is described. Catalytic dehydrative tandem formation of C–O and C–C bonds was achieved by using a Bi(OTf)3 catalyst without any additives. The catalytic intermolecular cyclization of phenols with various diols proceeded to give the corresponding chromanes in up to 91% yield and/or pyran derivatives in up to 66% yield. [ABSTRACT FROM AUTHOR]

No disease-modifying treatment exists for the fatal neurodegenerative polyglutamine disease known both as Machado-Joseph disease and spinocerebellar ataxia type 3. As a potential route to therapy, we identified small molecules that reduce levels of the mutant disease protein, ATXN3. Screens of a small molecule collection, including 1250 Food and Drug Administration-approved drugs, in a novel cell-based assay, followed by secondary screens in brain slice cultures from transgenic mice expressing the human disease gene, identified the atypical antipsychotic aripiprazole as one of the hits. Aripiprazole increased longevity in a Drosophila model of Machado-Joseph disease and effectively reduced aggregated ATXN3 species in flies and in brains of transgenic mice treated for 10 days. The aripiprazole-mediated decrease in ATXN3 abundance may reflect a complex response culminating in the modulation of specific components of cellular protein homeostasis. Aripiprazole represents a potentially promising therapeutic drug for Machado-Joseph disease and possibly other neurological proteinopathies.

O-GlcNAcylation is a dynamic post-translational modification consisting of the addition of a single N-acetylglucosamine sugar to serine and threonine residues in proteins by the enzyme O-linked β-N-acetylglucosamine transferase (OGT), whereas the enzyme O-GlcNAcase (OGA) removes the modification. In cancer, tumor samples present with altered O-GlcNAcylation; however, changes in O-GlcNAcylation are not consistent between tumor types. Interestingly, the tumor suppressor p53 is modified by O-GlcNAc, and most solid tumors contain mutations in p53 leading to the loss of p53 function. Because ovarian cancer has a high frequency of p53 mutation rates, we decided to investigate the relationship between O-GlcNAcylation and p53 function in ovarian cancer. We measured a significant decrease in O-GlcNAcylation of tumor tissue in an ovarian tumor microarray. Furthermore, O-GlcNAcylation was increased, and OGA protein and mRNA levels were decreased in ovarian tumor cell lines not expressing the protein p53. Treatment with the OGA inhibitor Thiamet-G (TMG), silencing of OGA, or overexpression of OGA and OGT led to p53 stabilization, increased nuclear localization, and increased protein and mRNA levels of p53 target genes. These data suggest that changes in O-GlcNAc homeostasis activate the p53 pathway. Combination treatment of the chemotherapeutic cisplatin with TMG decreased tumor cell growth and enhanced cell cycle arrest without impairing cytotoxicity. The effects of TMG on tumor cell growth were partially dependent on wild type p53 activation. In conclusion, changes in O-GlcNAc homeostasis activate the wild type p53 pathway in ovarian cancer cells, and OGA inhibition has the potential as an adjuvant treatment for ovarian carcinoma.

Herboxidiene is a potent inhibitor of spliceosomes. It exhibits excellent anticancer activity against multiple human cancer cell lines. Herein, we describe an enantioselective synthesis of a desmethyl derivative and the corresponding carba-derivatives of herboxidiene. The synthesis involved Suzuki coupling of a vinyl iodide with boronate as the key reaction. For the synthesis of carba-derivatives, the corresponding optically active cyclohexane-1,3-dicarbonyl derivatives were synthesized using an enantioselective desymmetrization of meso-anhydride. The biological properties of these derivatives were evaluated in an in vitro splicing assay.

The Escherichia coli AcrAB-TolC efflux pump is the archetype of the resistance nodulation cell division (RND) exporters from Gram-negative bacteria. Overexpression of RND-type efflux pumps is a major factor in multidrug resistance (MDR), which makes these pumps important antibacterial drug discovery targets. We have recently developed novel pyranopyridine-based inhibitors of AcrB, which are orders of magnitude more powerful than the previously known inhibitors. However, further development of such inhibitors has been hindered by the lack of structural information for rational drug design. Although only the soluble, periplasmic part of AcrB binds and exports the ligands, the presence of the membrane-embedded domain in AcrB and its polyspecific binding behavior have made cocrystallization with drugs challenging. To overcome this obstacle, we have engineered and produced a soluble version of AcrB [AcrB periplasmic domain (AcrBper)], which is highly congruent in structure with the periplasmic part of the full-length protein, and is capable of binding substrates and potent inhibitors. Here, we describe the molecular basis for pyranopyridine-based inhibition of AcrB using a combination of cellular, X-ray crystallographic, and molecular dynamics (MD) simulations studies. The pyranopyridines bind within a phenylalanine-rich cage that branches from the deep binding pocket of AcrB, where they form extensive hydrophobic interactions. Moreover, the increasing potency of improved inhibitors correlates with the formation of a delicate protein- and water-mediated hydrogen bond network. These detailed insights provide a molecular platform for the development of novel combinational therapies using efflux pump inhibitors for combating multidrug resistant Gram-negative pathogens.

When humans consume seafood contaminated by lipophilic polyether phycotoxins, such as azaspiracids (AZAs), the toxins are mainly leached and absorbed in the small intestine, potentially causing intestinal damage. In this study, human intestinal epithelial Caco-2 cells were used to investigate the adverse effects of azaspiracid-2 (AZA-2) on human intestinal epithelial cells. Cell viability, apoptosis, oxidative damage and mitochondrial ultrastructure were investigated, and ribonucleic acid sequence (RNA-seq) analysis was applied to explore the potential mechanisms of AZA-2 toxicity to Caco-2 cells. Results showed that AZA-2 significantly reduced the proliferation of Caco-2 cells in a concentration-dependent response, and the 48 h EC 50 of AZA-2 was 12.65 nmol L -1 . AZA-2 can induce apoptosis in Caco-2 cells in a dose-dependent manner. Visible mitochondrial swelling, cristae disintegration, membrane rupture and autophagy were observed in Caco-2 cells exposed to AZA-2. Reactive oxygen species (ROS) and malondialdehyde (MDA) content were significantly increased in Caco-2 cells after 48 h of exposure to 1 and 10 nmol L -1 of AZA-2. Transcriptome analysis showed that KEGG pathways related to cellular oxidative damage and lipid metabolism were affected, mainly including mitophagy, oxidative phosphorylation, cholesterol metabolism, vitamin digestion and absorption, bile secretion and the peroxisome proliferator-activated receptor signaling pathway. The cytotoxic effects of AZA-2 on Caco-2 cells may be associated with ROS-mediated autophagy and apoptosis in mitochondrial cells. Results of this study improve understanding of the cytotoxicity and molecular mechanisms of AZA-2 on Caco-2 cells, which is significant for protecting human health.

We compared the duration of fever in children infected with A(H1N1)pdm09, A(H3N2), or influenza B viruses following treatment with baloxavir marboxil (baloxavir) or neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, or laninamivir). This observational study was conducted at 10 outpatient clinics across 9 prefectures in Japan during the 2012-2013 and 2019-2020 influenza seasons. Patients with influenza rapid antigen test positive were treated with one of four anti-influenza drugs. The type/subtype of influenza viruses were identified from MDCK or MDCK SIAT1 cell-grown samples using two-step real-time PCR. Daily self-reported body temperature after treatment were used to evaluate the duration of fever by treatment group and various underlying factors. Among 1742 patients <19 years old analyzed, 452 (26.0%) were A(H1N1)pdm09, 827 (48.0%) A(H3N2), and 463 (26.0%) influenza B virus infections. Among fours treatment groups, baloxavir showed a shorter median duration of fever compared to oseltamivir in univariate analysis for A(H1N1)pdm09 virus infections (baloxavir, 22.0 h versus oseltamivir, 26.7 h, P < 0.05; laninamivir, 25.5 h, and zanamivir, 25.0 h). However, this difference was not significant in multivariable analyses. For A(H3N2) virus infections, there were no statistically significant differences observed (20.3, 21.0, 22.0, and 19.0 h) uni- and multivariable analyses. For influenza B, baloxavir shortened the fever duration by approximately 15 h than NAIs (20.3, 35.0, 34.3, and 34.1 h), as supported by uni- and multivariable analyses. Baloxavir seems to have comparable clinical effectiveness with NAIs on influenza A but can be more effective for treating pediatric influenza B virus infections than NAIs., 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 Author(s). Published by Elsevier B.V. All rights reserved.)

Several processes have been developed in the past to selectively extract oleuropein and its aglycones from olive derived materials. In the present manuscript, we outline a novel approach for processing olive leaves aqueous extracts. This allowed first to select microwave irradiation as the methodology able to provide a large enrichment in oleuropein. Subsequently, the use of lamellar solids led to the selective and high yield concentration of the same. Adsorption on solids also largely contributed to the long term chemical stability of oleuropein. Finally, an eco-friendly, readily available, and reusable catalyst like H 2 SO 4 supported on silica was applied for the hydrolysis of oleuropein into hydroxytyrosol and elenolic acid. This latter was in turn selectively isolated by an acid-base work-up providing its monoaldehydic dihydropyran form (7.8 % extractive yield), that was unequivocally characterized by GC-MS. The isolation of elenolic acid in pure form is described herein for the first time., 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 Author(s). Published by Elsevier Ltd.. All rights reserved.)

A method for the simultaneous determination of the four stereoisomers of the chiral herbicide profoxydim in rice and husk was developed using the QuEChERS method and LC-tandem mass spectrometry. Four polysaccharide-based chiral stationary phase columns were evaluated. All four stereoisomers were successfully separated on a Chiracel OJ-3R column. The effects of mobile phase, modifiers, mobile phase flow rate and temperature on the separation were also investigated. Different QuEChERS methods were compared for the development of an optimized sample preparation procedure. The method, following SANTE guidelines, showed excellent linearity (R 2  ≥ 0.99), the LODs were below 4.0 µg kg -1 , and the LOQs did not exceed 12.5 µg kg -1 . The overall average recoveries at three levels (12.5, 25.0 and 250 µg kg -1 ) ranged from 76.77 % to 106.53 %, with RSD values less than 7 %. The method is demonstrated to be convenient and reliable for the routine monitoring of profoxydim stereoisomers in rice and husk., 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 Author(s). Published by Elsevier Ltd.. All rights reserved.)

Alzheimer's disease (AD) and other taupathies are neurodegenerative disorders associated with the amyloid deposition of the Tau protein in the brain. This amyloid formation may be inhibited by small molecules, which is recognized as one of the best therapeutic strategies to stop the progression of the disease. This work focuses on the small nucleating segment, hexapeptide-paired helical filament 6 (PHF6), responsible for Tau aggregation. Using computational modeling and classical molecular dynamics simulations, we show that PHF6 monomers collapse in water to form β-sheet rich structures, and the main olive oil polyphenol oleuropein aglycone (OleA) prevents peptide aggregation significantly. We gradually increase the ratio of the PHF6-OleA from 1:1 to 1:3 and find that for the 1:1 ratio, the peptide monomers are prone to form aggregated structures, while for the 1:2 ratio, the formation of the extended β-sheet structure is significantly less. For a 1:3 ratio of protein/OleA, the peptide residues are sufficiently crowded by OleA molecules through hydrogen bonding, hydrophobic interactions, and π-π stacking; hence, the peptide chains prefer to exist in a monomeric random coil conformation.

Reactive oxygen species (ROS) are normally produced in skeletal muscle. However, an imbalance in their regulatory systems can lead to their accumulation and ultimately to oxidative stress, which is one of the causes of the ageing process. Companion dogs share the same environment and lifestyle as humans, making them an excellent comparative model for the study of ageing, as well as they constitute a growing market for bioactive molecules that improve the quality of life of pets. The anti-ageing properties of oleuropein aglycone (OLE), a bioactive compound from olive leaves known for its antioxidant properties, were investigated in Myok9 canine muscle cell model. After incubation with OLE, senescence was induced in the canine cellular model by hydrogen peroxide (H 2 O 2 ). Analyses were performed on cells after seven days of differentiation. The oxidative stress induced by H 2 O 2 treatment on differentiated canine muscle cells led to a significant increase in ROS formation, which was reduced by OLE pretreatment alone or in combination with H 2 O 2 by about 34% and 32%, respectively. Cells treated with H 2 O 2 showed a 48% increase the area of senescent cells stained by SA-β-gal, while OLE significantly reduced the coloured area by 52%. OLE, alone or in combination with H 2 O 2 , showed a significant antioxidant activity, possibly through autophagy activation, as indicated by the expression of autophagic markers., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In the present work, the reaction of the acetoactanilide derivatives with either benzenediazonium chloride, 4‐chlorobenzenediazonium chloride, or 4‐methoxybenzenediazonium, gave arylhydrazone derivatives. Heterocyclizations of the latter compounds were carried out to afford new thiophene, pyran and pyridine derivatives. The cyctotoxicity of the synthesized compounds against the selected six cancer cell lines was determined where eleven compounds exhibited the highest inhibitions. Through out this work, the produced pyridazine derivatives were selected for evaluation against cancer cell lines categorized according to the disease and the compounds showed high inhibitions. The results obtained in this work encourage further work in the future. [ABSTRACT FROM AUTHOR]

Recently we described a novel pyranopyridine inhibitor (MBX2319) of RND-type efflux pumps of the Enterobacteriaceae. MBX2319 (3,3-dimethyl-5-cyano-8-morpholino-6-(phenethylthio)-3,4-dihydro-1H-pyrano[3,4-c]pyridine) is structurally distinct from other known Gram-negative efflux pump inhibitors (EPIs), such as 1-(1-naphthylmethyl)-piperazine (NMP), phenylalanylarginine-β-naphthylamide (PAβN), D13-9001, and the pyridopyrimidine derivatives. Here, we report the synthesis and biological evaluation of 60 new analogs of MBX2319 that were designed to probe the structure activity relationships (SARs) of the pyranopyridine scaffold. The results of these studies produced a molecular activity map of the scaffold, which identifies regions that are critical to efflux inhibitory activities and those that can be modified to improve potency, metabolic stability and solubility. Several compounds, such as 22d-f, 22i and 22k, are significantly more effective than MBX2319 at potentiating the antibacterial activity of levofloxacin and piperacillin against Escherichia coli.

An enantioselective total synthesis of spliceostatin E has been accomplished. The δ-lactone unit A was constructed from readily available (R)-glycidyl alcohol using a ring-closing olefin metathesis as the key reaction. A cross-metathesis of ring A containing δ-lactone and the functionalized tetrahydropyran B-ring provided spliceostatin E. Our biological evaluation of synthetic spliceostatin E revealed that it does not inhibit splicing in vitro and does not impact speckle morphology in cells. Spliceostatin E was reported to possess potent antitumor activity.

Pyrans are one of the most significant skeletons of oxygen-containing heterocyclic molecules, which exhibit a broad spectrum of medicinal applications and are constituents of diverse natural product analogues. Various biological applications of these pyran analogues contributed to the growth advances in these oxygen-containing molecules. Green one-pot methodologies for synthesising these heterocyclic molecules have received significant attention. This review focuses on the recent developments in synthesising pyran ring derivatives using reusable catalysts and emphasises the multicomponent reaction strategies using green protocols. The advantages of the catalysts in terms of yields, reaction conditions, and recyclability are discussed.

The stereospecific ring-opening of O-heterocycles to provide acyclic alcohols and carboxylic acids with controlled formation of a new C-C bond is reported. These reactions provide new methods for synthesis of acyclic polyketide analogs with complex stereochemical arrays. Stereoselective synthesis of the cyclic template is utilized to control relative configuration; subsequent stereospecific nickel-catalyzed ring-opening affords the acyclic product. Aryl-substituted tetrahydrofurans and tetrahydropyrans undergo nickel-catalyzed Kumada-type coupling with a range of Grignard reagents to furnish acyclic alcohols with high diastereoselectivity. Enantioenriched lactones undergo Negishi-type cross-coupling with dimethylzinc to afford enantioenriched carboxylic acids. Application in a two-step enantioselective synthesis of an anti-dyslipidemia agent is demonstrated.

Efflux pumps of the resistance nodulation division (RND) superfamily, such as AcrB, make a major contribution to multidrug resistance in Gram-negative bacteria. The development of inhibitors of the RND pumps would improve the efficacy of current and next-generation antibiotics. To date, however, only one inhibitor has been cocrystallized with AcrB. Thus, in silico structure-based analysis is essential for elucidating the interaction between other inhibitors and the efflux pumps. In this work, we used computer docking and molecular dynamics simulations to study the interaction between AcrB and the compound MBX2319, a novel pyranopyridine efflux pump inhibitor with potent activity against RND efflux pumps of Enterobacteriaceae species, as well as other known inhibitors (D13-9001, 1-[1-naphthylmethyl]-piperazine, and phenylalanylarginine-β-naphthylamide) and the binding of doxorubicin to the efflux-defective F610A variant of AcrB. We also analyzed the binding of a substrate, minocycline, for comparison. Our results show that MBX2319 binds very tightly to the lower part of the distal pocket in the B protomer of AcrB, strongly interacting with the phenylalanines lining the hydrophobic trap, where the hydrophobic portion of D13-9001 was found to bind by X-ray crystallography. Additionally, MBX2319 binds to AcrB in a manner that is similar to the way in which doxorubicin binds to the F610A variant of AcrB. In contrast, 1-(1-naphthylmethyl)-piperazine and phenylalanylarginine-β-naphthylamide appear to bind to somewhat different areas of the distal pocket in the B protomer of AcrB than does MBX2319. However, all inhibitors (except D13-9001) appear to distort the structure of the distal pocket, impairing the proper binding of substrates.

A diastereoselective synthesis of cis-2,6-disubstituted tetrahydropyran-4-ones was developed. The key step of this methodology, a silyl enol ether Prins cyclization, was promoted by a condensation reaction between a hydroxy silyl enol ether and an aldehyde to afford substituted tetrahydropyran-4-ones. The cyclization was tolerant of many functional groups, and the modular synthesis of the hydroxy silyl enol ether allowed for the formation of more than 30 new tetrahydropyran-4-ones with up to 97% yield and >95:5 dr. The cyclization step forms new carbon-carbon and carbon-oxygen bonds, as well as a quaternary center with good diastereoselectivity. The method provides a versatile route for the synthesis of substituted tetrahydropyrans.

FR901464 (1) and spliceostatin A (2) are potent inhibitors of spliceosomes. These compounds have shown remarkable anticancer activity against multiple human cancer cell lines. Herein, we describe efficient, enantioselective syntheses of FR901464, spliceostatin A, six corresponding diastereomers and an evaluation of their splicing activity. Syntheses of spliceostatin A and FR901464 were carried out in the longest linear sequence of 9 and 10 steps, respectively. To construct the highly functionalized tetrahydropyran A-ring, we utilized CBS reduction, Achmatowicz rearrangement, Michael addition, and reductive amination as key steps. The remarkable diastereoselectivity of the Michael addition was specifically demonstrated with different substrates under various reaction conditions. The side chain B was prepared from an optically active alcohol, followed by acetylation and hydrogenation over Lindlar's catalyst. The other densely functionalized tetrahydropyran C-ring was derived from readily available (R)-isopropylidene glyceraldehyde through a route featuring 1,2-addition, cyclic ketalization, and regioselective epoxidation. These fragments were coupled together at a late stage through amidation and cross-metathesis in a convergent manner. Six key diastereomers were then synthesized to probe the importance of specific stereochemical features of FR901464 and spliceostatin A, with respect to their in vitro splicing activity.

An enantioselective total synthesis of GEX1Q1 has been accomplished in a convergent manner. The C-5 asymmetric center has now been assigned through synthesis. GEX1Q1 displayed slightly better spliceosome inhibitory activity over its C-5 epimer. The salient features of this synthesis include an asymmetric hetero-Diels-Alder reaction to construct the tetrahydropyran ring and a Suzuki cross-coupling to assemble the key segments.

Pladienolide B (PB) is a potent cancer cell growth inhibitor that targets the SF3B1 subunit of the spliceosome. There is considerable interest in the compound as a potential chemotherapeutic, as well as a tool to study SF3B1 function in splicing and cancer development. The molecular structure of PB, a bacterial natural product, contains a 12-member macrolide ring with an extended epoxide-containing side chain. Using a novel concise enantioselective synthesis, we created a series of PB structural analogs and the structurally related compound herboxidiene. We show that two methyl groups in the PB side chain, as well as a feature of the macrolide ring shared with herboxidiene, are required for splicing inhibition in vitro. Unexpectedly, we find that the epoxy group contributes only modestly to PB potency and is not absolutely necessary for activity. The orientations of at least two chiral centers off the macrolide ring have no effect on PB activity. Importantly, the ability of analogs to inhibit splicing in vitro directly correlated with their effects in a series of cellular assays. Those effects likely arise from inhibition of some, but not all, endogenous splicing events in cells, as previously reported for the structurally distinct SF3B1 inhibitor spliceostatin A. Together, our data support the idea that the impact of PB on cells is derived from its ability to impair the function of SF3B1 in splicing and also demonstrate that simplification of the PB scaffold is feasible.

Most of the common and novel synthesized active methylene compounds as well as heterocycles bearing active methyl or having methine site were used in the syntheses of wide variety of five-, six- and seven-membered azaheterocyclic systems having oxygen or sulfur atom in their structures in addition to some oxygenated heterocycles such as pyrans. Many synthetic approaches were used for the preparation of target heterocyclic systems such as cyclocondensation reactions, ring opening-ring closure, cycloaddition, acid-, base-catalyzed reaction, intermolecular cyclization and self-condensation as well as ring–chain tautomerism has been reviewed in this paper.