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Intestinal permeabilization is central to the pathophysiology of chronic gut inflammation. This study investigated the efficacy of glucoraphanin (GR), prevalent in cruciferous vegetables, particularly broccoli, and its derivative sulforaphane (SF), in inhibiting tumor necrosis factor alpha (TNFα)-induced Caco-2 cell monolayers inflammation and permeabilization through the regulation of redox-sensitive events. TNFα binding to its receptor led to a rapid increase in oxidant production and subsequent elevation in the mRNA levels of NOX1, NOX4, and Duox2. GR and SF dose-dependently mitigated both these short- and long-term alterations in redox homeostasis. Downstream, GR and SF inhibited the activation of the redox-sensitive signaling cascades NF-κB (p65 and IKK) and MAPK ERK1/2, which contribute to inflammation and barrier permeabilization. GR (1 μM) and SF (0.5-1 μM) prevented TNFα-induced monolayer permeabilization and the associated reduction in the levels of the tight junction (TJ) proteins occludin and ZO-1. Both GR and SF also mitigated TNFα-induced increased mRNA levels of the myosin light chain kinase, which promotes TJ opening. Molecular docking suggests that although GR is mostly not absorbed, it could interact with extracellular and membrane sites in NOX1. Inhibition of NOX1 activity by GR would mitigate TNFα receptor downstream signaling and associated events. These findings support the concept that not only SF, but also GR, could exert systemic health benefits by protecting the intestinal barrier against inflammation-induced permeabilization, in part by regulating redox-sensitive pathways. GR has heretofore not been viewed as a biologically active molecule, but rather, the benign precursor of highly active SF. The consumption of GR and/or SF-rich vegetables or supplements in the diet may offer a means to mitigate the detrimental consequences of intestinal permeabilization, not only in disease states but also in conditions characterized by chronic inflammation of dietary and lifestyle origin.

BACKGROUND: Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC. METHODS: KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1. RESULTS: One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2-14.3) and 10.3 months (2.7-13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2-44.1] and sunitinib/pazopanib (29.2% [18.6-41.8]). Grade 3-5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects. CONCLUSIONS: ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT03260894 .

AbstractImidazole, a five-membered heterocyclic compound, has multipurpose applications for its bioactivity, uses in charge transport materials, and NLO materials. The review provides a comprehensive survey of the synthetic strategies of imidazole from various starting materials, highlighting their percentage yield and mechanistic insights. The most popular starting materials for the syntheses of imidazole include diketones, cyanides, imines, amidines, imidamides, di-amines, and oximes. Although the selection of a particular synthetic strategy will depend largely on the desired imidazole derivative, the survey consists of more than a century of research on imidazole synthetic procedures, starting with Heinrich Debus synthesis in 1858 till the present day. Most recent advancements and future perspectives in the field have been explored. The study will help researchers choose the most suitable starting material, catalyst, solvent, or reaction conditions for the synthesis of various imidazole derivatives. [ABSTRACT FROM AUTHOR]

3‐Hydroxypyridines are attractive owing to their potential applications in medicinal chemistry. However, only a few reports on the synthesis of 2,4,6‐trisubstituted 3‐hydroxypyridines have been published to date. Herein, we describe a novel method for synthesizing 2,4,6‐trisubstituted 3‐hydroxypyridines. Au(III)‐catalyzed reactions using C‐alkynyl‐O‐vinyl oximes via intramolecular nucleophilic addition, followed by skeletal rearrangement, including N−O bond cleavage. This protocol provides unprecedented 25 examples of 2,4,6‐trisubstituted 3‐hydroxypyridines with good functional and bulky‐group tolerances. Mechanistic studies suggest that the reaction proceeds through the generation of isoxazolium and nitrene species. [ABSTRACT FROM AUTHOR]

The reduction of oximes was recently identified as a promiscuous activity of Old Yellow Enzymes (OYEs). This reaction involves a two‐step reduction of α‐oxime‐ß‐ketoesters to the corresponding amines, which spontaneously dimerise to yield pyrazine derivatives. This biotransformation is currently limited to substrates with small substituents like methyl/ethyl on the keto moiety. We used a structure‐based approach to engineer 12‐oxophytodienoate reductase 3 (OPR3) from Solanum lycopersicum as a prototypical OYE to accept oximes with bulkier substituents. To this end, three single and two double variants were prepared and tested on six oxime substrates. The engineered variants indeed showed activity on some of the bulkier substrates, which had not been converted at all by the wild‐type enzyme, including the diester compound diethyl‐2‐(hydroximino) malonate. While we were unable to identify variants capable of converting substrates with branched and aromatic substituents, the results demonstrate the validity of our engineering approach, suggesting potential pathways for expanding the substrate scope of OYEs. [ABSTRACT FROM AUTHOR]

A cobalt-catalyzed three-component assembly of substituted aryl oximes with dienes and formaldehyde via C–H bond activation is described. This protocol affords highly regio- and chemoselective substituted homoallylic alcohols with moderate-to-excellent yields. The scope of this protocol has been extensively explored with various substituted aryl ketoximes and aldoximes. Butadiene and internally substituted dienes are also well compatible for this transformation. A plausible reaction mechanism is proposed to account for the present reaction and is supported by deuterium labeling studies. [ABSTRACT FROM AUTHOR]

Electrocatalytic nitrate reduction reaction (NO3RR) coupled with organic compounds to synthesize oximes for value-added conversion of waste pollutants has very promising prospects. However, due to the susceptibility of the feedstock to hydrogenation, the relatively low reaction efficiency, and the poor stability of oximes, the reaction in acidic electrolytes remains a formidable challenge. Herein, we report a novel strategy for the one-step synthesis of oximes from nitrite and aldehydes/ketones in acidic electrolytes using a Zn-based catalyst (multilayered Zn nanosheet catalyst, M-ZnNSs). 99% yield and 99% selectivity of phenylacetaldehyde oxime were achieved at a constant current of -12 mA cm-2. Moreover, various aldehydes/ketones were efficiently converted to oximes with yield and selectivity up to >90%, demonstrating the high versatility of this method. Furthermore, the catalyst exhibited remarkable long-term stability (>100 h). This work proposes a green strategy to promote the recycling of nitrogen resources, enhance the value of NO3- conversion products, and develop new ideas for electrochemical C-N coupling. [ABSTRACT FROM AUTHOR]

NMR signals can be greatly enhanced, or hyperpolarised, by interactions with para-hydrogen. We demonstrate here that oximes can be reversibly hyperpolarised by coordination to an iridium complex, that oxime E/Z geometry is significant for activity, and that hyperpolarised oximes can subsequently transfer these enhanced signals through proton exchange. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: In this paper, the difunctionalizative perfluoroalkyloximation of alkenes has been developed for the first time. This photochemical method allows for the synthesis of various perfluoroalkyl ethanone oximes with excellent regioselectivity and good functional group tolerance. Our method employs the most common perfluoroalkyl source, perfluoroalkyl iodides, as Rf reagents. Besides long‐chain perfluoroalkyl groups, this approach could be extended to incorporating additional groups, including trifluoromethyl, difluoromethyl, sulfonyl, and malonate, selectively into olefins, resulting in a range of β‐substituted ethanone oximes. Notably, the potential of this method in the Fukuyama indole synthesis, generating novel 2‐perfluoroalkylated 3‐(α‐oximidobenzyl)indoles via a radical cascade mechanism with 2‐vinylphenylacryloyl isocyanate as the radical acceptor, presents a compelling avenue for drug synthesis. The protocol is efficient, scalable, and useful for late‐stage modification of bioactive molecules. [ABSTRACT FROM AUTHOR]

Combining chemical reactivities of allenes and oximes created a methodology for the preparation of heterocyclic triquinane‐type skeletons via a cascade process constructing four bonds in a single step. The initial reaction of allene moiety promoted by Pd‐catalysis, affording π‐allyl Pd‐species, was followed by two additional transformations ‐ nucleophilic displacement and dipolar cycloaddition ‐ to furnish the product highly stereoselectively in moderate to good yields. For the process to be efficient, it was necessary to use a dipolarophilic component as a solvent. Intriguingly, while the reaction with cyclopentanone derived oxime progressed through the whole cascade, with cyclohexanone analogue it stopped at the nitrone stage, requiring an additional step to yield similar type of products. Some aspects of the studied cascade were examined by DFT. [ABSTRACT FROM AUTHOR]

Six novel brominated bis-pyridinium oximes were designed and synthesized to increase their nucleophilicity and reactivation ability of phosphorylated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Their pKa was valuably found lower to parent non-halogenated oximes. Stability tests showed that novel brominated oximes were stable in water, but the stability of di-brominated oximes was decreased in buffer solution and their degradation products were prepared and characterized. The reactivation screening of brominated oximes was tested on AChE and BChE inhibited by organophosphorus surrogates. Two mono-brominated oximes reactivated AChE comparably to non-halogenated analogues, which was further confirmed by reactivation kinetics. The acute toxicity of two selected brominated oximes was similar to commercially available oxime reactivators and the most promising brominated oxime was tested in vivo on sarin- and VX-poisoned rats. This brominated oxime showed interesting CNS distribution and significant reactivation effectiveness in blood. The same oxime resulted with the best protective index for VX-poisoned rats. [ABSTRACT FROM AUTHOR]

An overview is given on the significance of the oxime moiety in crop protection chemistry. This review focuses on the two most important aspects of agrochemical oximes, which are the occurrence and role of oxime groups in compounds with herbicidal, fungicidal and insecticidal activity, as well as the application of oxime derivatives as intermediates in the synthesis of crop protection agents not bearing any oxime function. Especially noteworthy is the fact, that in the synthesis of agrochemicals, oximes can be cyclized to isooxazoline, isoxazole, oxadiazole, oxazine, pyrrole, isothiazole and imidazole rings. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

In this paper, an iron-catalyzed deboronation/cyanoalkylation of vinyl boronic acids for the preparation of distal cyanoalkyl alkenes with vinyl boronic acids as radical acceptor and activator is reported. In this reaction, various cyclobutanone oximes and substituted vinyl boronic acids can be transformed into the corresponding cyanoalkylated alkenes in moderate to good yields under these conditions. Mechanistic studies indicated that a single-electron transfer process may be involved in this transformation. [ABSTRACT FROM AUTHOR]

The widely used insecticide chlorpyrifos (CP) is known to inhibit acetylcholinesterase (AChE) activity attributed to result in various neurological disorders and acetylcholine-dependent organ functions including heart, skeletal muscle, lung, gastrointestinal tract, and central nervous systems. Enzyme reactivators, such as oximes, are known to restore AChE activity and mitigate adverse effects. The identification of compounds that reactivate AChE constitute agents with important therapeutic beneficial effects in cases of pesticide poisoning. However, the screening of novel drugs using traditional models may raise ethical concerns. This study aimed to investigate the potential of Drosophila melanogaster as a model organism for screening AChE reactivators, with a focus on organophosphate poisoning. The efficacy of several oximes, including pralidoxime, trimedoxime, obidoxime, methoxime, HI-6, K027, and K048, against CP-induced AChE activity inhibition in D. melanogaster was determined in silico, in vitro, and in vivo experiments. Molecular docking studies indicated a strong interaction between studied oximes and the active-site gorge of AChE. Data showed that selected oximes (100 μM) are effective in the reactivation of AChE inhibited by CP (10 μM) in vitro. Finally, in vivo investigations demonstrated that selected oximes, pralidoxime and K048 (1.5 ppm), reversed the locomotor deficits, inhibition of AChE activity as well as lowered the mortality rates induced by CP (0.75 ppm). Our findings contribute to utilization of D. melanogaster as a robust model for determination of actions of identified new AChE inhibitory agents with more effective therapeutic properties that those currently in use in the clinical practice in treatment of AChE associated disorders. [ABSTRACT FROM AUTHOR]

In this work, six benzothioxanthene‐based oxime esters were employed as photoinitiators for photopolymerization under visible light (LED) and sunlight. Their abilities to behave as Type I photoinitiators by mean of a photocleavage mechanism of oxime esters but also in multicomponent photoinitiating systems with an iodonium salt (through an electron transfer mechanism) were both explored with the different structures. Due to their broad absorption spectra tailing up 600 nm, photoinitiating properties of the benzothioxanthene‐based oxime esters were systematically tested under excitation with low‐intensity LED light at wavelengths of 405 nm and 450 nm. Additionally, parallel to the polymerization tests done under artificial light, the different benzothioxanthene‐based oxime esters were also investigated as solar photoinitiators and displayed a high reactivity in France (Western Europe) even in winter conditions. For the best candidates i.e. the most reactive structures, direct laser write experiments were carried out, evidencing the interest of these structures. [ABSTRACT FROM AUTHOR]

Primary amines and nitriles play a central role in almost every branch of the chemical industry, and many synthetic strategies exist to obtain them. The major drawbacks of these existing approaches are low selectivities and highly toxic reagents like hydrogen cyanide. This article presents alternative catalytic routes based on aldoximes to address those challenges and outlines what needs to be done to implement aldoximes into a greener amine and nitrile production. [ABSTRACT FROM AUTHOR]

Nitrogen oxide (NOx) is an attractive nitrogen source. Electrocatalytic NOx reduction coupled with the conversion of carbon source molecules offers a potential route for sustainable synthesis of valuable nitrogenous organics. This review discusses recent progress on the synthesis of electrocatalytic organonitrogen compounds (such as oximes, amino acids, amines, amides and urea) via C−N coupling from NOx and carbon source. The electrocatalytic performance, catalyst structure and especially reaction mechanism are discussed. Current challenges, catalyst design principles, the understanding on reaction mechanisms, as well as possible strategies for improving reaction selectivity and activity are proposed, which will guide future researches in the electrocatalytic conversion of NOx and carbon source. [ABSTRACT FROM AUTHOR]

Oximes, belonging to imines with the general formula of RR'C=NOH, are produced by the nucleophilic addition reaction between hydroxylamine with ketones or aldehydes, yielding corresponding aldoxime and ketoxime. The presence of hydrogen bond acceptor and donor is the classical feature of oxime‐containing structural framework. This review presents a summary of the role of oximes and its structure activity relationships including antimicrobial, anticancer, anti‐inflammatory, antihyperglycemic, insecticidal agents, along with their involvement in the treatment of organophosphorus poisoning. The review also focused on the pharmacological profile of lead molecules of several classes of oxime‐containing compounds. [ABSTRACT FROM AUTHOR]

Sustainable carbon dots comprising surficial oxime ester groups following homolytic bond cleavage exhibit potential as photoinitiators for traditional free radical photopolymerization. Carbon dots were made following a solvothermal procedure from sustainable furfural available from lignocellulose. Surficial aldehyde moieties reacted with hydroxylamine to the respective oxime while reaction with benzoyl chloride resulted in a biobased Type I photoinitiator comprising sustainable carbon dot (CD‐PI). Photoinitiating ability was compared with the traditional photoinitiator (PI) ethyl (2,4,6‐trimethyl benzoyl) phenyl phosphinate (TPO‐L) by real‐time FTIR with UV exposure at 365 nm. Photopolymer composition based on a mixture of urethane dimethacrylate (UDMA) and tripropylene glycol diacrylate (TPGDA) resulted in a similar final conversion of about 70 % using either CD‐PI or TPO‐L. Nevertheless, it appeared homogeneous in the case of compositions processed with CD‐PI, while those made with TPO‐L were heterogeneous as shown by two glass transition temperatures. Moreover, the migration rate of CD‐PI in the cured samples was lower in comparison with those samples using TPO‐L as PI. [ABSTRACT FROM AUTHOR]

Research on the chemoselective metal‐catalyzed hydrogenation of conjugated π‐systems has mostly been focussed on enones. Herein, we communicate the understudied asymmetric hydrogenation of enimines catalyzed by N,P‐iridium complexes and chemoselective toward the alkene. A number of enoxime ethers underwent hydrogenation smoothly to yield the desired products in high yield and stereopurity (up to 99 % yield, up to 99 % ee). No hydrogenation of the C=N π‐bond was observed under the applied reaction conditions (20 bar H2, rt, DCM). It was demonstrated that the chiral oxime ether could be hydrolyzed into the ketone with complete preservation of the installed stereogenity at the α‐carbon. At last, a binding mode of the substrate to the active iridium catalyst and the consequence for the stereoselective outcome was proposed. [ABSTRACT FROM AUTHOR]

The treatment of organophosphate (OP) anticholinesterases currently lacks an effective oxime reactivator of OP‐inhibited acetylcholinesterase (AChE) which can penetrate the blood‐brain barrier (BBB). Our laboratories have synthesized novel substituted phenoxyalkyl pyridinium oximes and tested them for their ability to promote survival of rats challenged with lethal doses of nerve agent surrogates. These previous studies demonstrated the ability of some of these oximes to promote 24‐h survival to rats challenged with a lethal level of highly relevant surrogates for sarin and VX. The reactivation of OP‐inhibited AChE in peripheral tissues was likely to be a major contributor to their efficacy in survival of lethal OP challenges. In the present study, twenty of these novel oximes were screened in vitro for reactivation ability for AChE in rat skeletal muscle and serum using two nerve agent surrogates: phthalimidyl isopropyl methylphosphonate (PIMP, a sarin surrogate) and 4‐nitrophenyl ethyl methylphosphonate (NEMP, a VX surrogate). The oximes demonstrated a range of 23%–102% reactivation of AChE in vitro across both tissue types. Some of the novel oximes tested in the present study demonstrated the ability to more effectively reactivate AChE in serum than the currently approved oxime, 2‐PAM. Therefore, some of these novel oximes have the potential to reverse AChE inhibition in peripheral target tissues and contribute to survival efficacy. [ABSTRACT FROM AUTHOR]

Oxime ethers are attractive compounds in medicinal scaffolds due to the biological and pharmaceutical properties, however, the crucial and widespread step of industrial oxime formation using explosive hydroxylamine (NH2OH) is insecure and troublesome. Herein, we present a convenient method of oxime ether synthesis in a one‐pot tandem electrochemical system using magnesium based metal‐organic framework‐derived magnesium oxide anchoring in self‐supporting carbon nanofiber membrane catalyst (MgO‐SCM), the in situ produced NH2OH from nitrogen oxides electrocatalytic reduction coupled with aldehyde to produce 4‐cyanobenzaldoxime with a selectivity of 93 % and Faraday efficiency up to 65.1 %, which further reacted with benzyl bromide to directly give oxime ether precipitate with a purity of 97 % by convenient filtering separation. The high efficiency was attributed to the ultrafine MgO nanoparticles in MgO‐SCM, effectively inhibiting hydrogen evolution reaction and accelerating the production of NH2OH, which rapidly attacked carbonyl of aldehydes to form oximes, but hardly crossed the hydrogenation barrier of forming amines, thus leading to a high yield of oxime ether when coupling benzyl bromide nucleophilic reaction. This work highlights the importance of kinetic control in complex electrosynthetic organonitrogen system and demonstrates a green and safe alternative method for synthesis of organic nitrogen drug molecules. [ABSTRACT FROM AUTHOR]

An intermolecular copper catalyzed heteroannelation reaction using Csp3‐Csp3 radical coupling approach has been accomplished to synthesize 2,5‐diphenyl‐3‐(pyrimidin‐2‐yl)‐3,4‐dihydro‐2H‐pyrrolo[2,3‐d]thiazole. C−C coupling between 4‐thiazolidinones and O‐acetyl oximes under Cu catalyst further cyclizes to get the target molecule thiazolidine‐fused nucleus. This unified method offers access to novel fused heterocycles with pyrimidines bearing 4‐thiazolidinone in moderate to higher yields. The optimization study includes various copper catalysts, oxidants, bases and solvents at different temperatures. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) remains a global health threat. Ribonuclease H (RNase H), part of the virus polymerase protein, cleaves the pgRNA template during viral genome replication. Inhibition of RNase H activity prevents (+) DNA strand synthesis and results in the accumulation of non-functional genomes, terminating the viral replication cycle. RNase H, though promising, remains an under-explored drug target against HBV. We previously reported the identification of a series of N-hydroxypyridinedione (HPD) imines that effectively inhibit the HBV RNase H. In our effort to further explore the HPD scaffold, we designed, synthesized, and evaluated 18 novel HPD oximes, as well as 4 structurally related minoxidil derivatives and 2 barbituric acid counterparts. The new analogs were docked on the RNase H active site and all proved able to coordinate the two Mg2+ ions in the catalytic site. All of the new HPDs effectively inhibited the viral replication in cell assays exhibiting EC50 values in the low μM range (1.1–7.7 μM) with low cytotoxicity, resulting in selectivity indexes (SI) of up to 92, one of the highest reported to date among HBV RNase H inhibitors. Our findings expand the structure–activity relationships on the HPD scaffold, facilitating the development of even more potent anti-HBV agents. [ABSTRACT FROM AUTHOR]

In this research, with an aim to develop novel pyrazole oxime ether derivatives possessing potential biological activity, thirty-two pyrazole oxime ethers, including a substituted pyridine ring, have been synthesized and structurally identified through 1H NMR, 13C NMR, and HRMS. Bioassay data indicated that most of these compounds owned strong insecticidal properties against Mythimna separata, Tetranychus cinnabarinus, Plutella xylostella, and Aphis medicaginis at a dosage of 500 μg/mL, and some title compounds were active towards Nilaparvata lugens at 500 μg/mL. Furthermore, some of the designed compounds had potent insecticidal effects against M. separata, T. cinnabarinus, or A. medicaginis at 100 μg/mL, with the mortalities of compounds 8a, 8c, 8d, 8e, 8f, 8g, 8o, 8s, 8v, 8x, and 8z against A. medicaginis, in particular, all reaching 100%. Even when the dosage was lowered to 20 μg/mL, compound 8s also expressed 50% insecticidal activity against M. separata, and compounds 8a, 8e, 8f, 8o, 8v, and 8x displayed more than 60% inhibition rates against A. medicaginis. The current results provided a significant basis for the rational design of biologically active pyrazole oxime ethers in future. [ABSTRACT FROM AUTHOR]

Nowadays, photopolymerization has spanned across all academic and industrial applications due to its appealing features such as energy saving, environmentally‐friendly polymerization conditions, high monomer conversions, rapid polymerization kinetics and so on. Photoinitiator (PI), as a crucial component of the photoinitiating system (PIS) are capable of interacting with light efficiently, enabling to generate initiating species in mono or multicomponent systems. In this work, 13 phenothiazine‐based oxime esters (OXEs) (never reported before) were synthesized and their photoinitiation abilities for the free radical photopolymerization (FRP) of acrylates were examined upon irradiation with LED@405 nm. Parallel to their photochemical reactivities, their abilities to initiate thermal polymerization processes were also investigated. Finally, these OXEs exhibited excellent photo/thermal initiation performances, demonstrating their dual initiation properties. Phenothiazine‐based oxime esters can be used as PIs in 3D printing as well as thermal initiator in the manufacturing of carbon fiber composites. [ABSTRACT FROM AUTHOR]

New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain–blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents–sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. In silico analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer's and Parkinson's. [ABSTRACT FROM AUTHOR]

Investigating the reactivity of small nucleophilic scaffolds is a strategic approach for the design of new catalysts aiming at effective detoxification processes of organophosphorus compounds. The drug methimazole (MMZ) is an interesting candidate featuring two non‐equivalent nucleophilic centers. Herein, phosphoryl transfer reactions mediated by MMZ were assessed by means of spectrophotometric kinetic studies, mass spectrometry (MS) analyses, and density functional theory (DFT) calculations using the multi‐electrophilic compound O,O‐diethyl 2,4‐dinitrophenyl phosphate (DEDNPP). MMZ anion acts primarily as an S‐nucleophile, exhibiting a nucleophilic activity comparable to that of certain oximes featuring alpha‐effect. Selective nucleophilic aromatic substitution was observed, consistent with the DFT prediction of a low energy barrier. Overall, the results bring important advances regarding the mechanistic understanding of nucleophilic dephosphorylation reactions, which comprises a strategic tool for neutralizing toxic organophosphates, hence promoting chemical security. [ABSTRACT FROM AUTHOR]

Organophosphate pesticide poisoning challenges health care systems worldwide. Furthermore, nerve agents remain a continuous threat. The treatment options for organophosphate poisoning have virtually been unchanged for decades, relying on symptomatic treatment and the use of oximes to indirectly restore neuromuscular function. Hence, compounds targeting directly nicotinic acetylcholine receptors (nAChRs) might substantially improve treatment options. The current study investigated a series of bispyridinium analogues with a trimethylene or 2,2′-diethyloxy linker in a rat hemidiaphragm model, using indirect field stimulation. Methyl- and ethyl-substituted bispyridinium analogues restored neuromuscular function up to 37 ± 17% (MB419, a 3-methyl analogue) at a stimulation frequency of 20 Hz. The bispyridinium analogues with a 2- or 3-methyl group, or a 2- or 3-ethyl group, tended towards a higher restoration of neuromuscular function than those with a 4-methyl or 4-ethyl group, respectively. The current data can be used for future studies to optimize structure-based molecular modeling of compounds targeting the nAChR. [Display omitted] • Bispyridinium non-oximes analogues with a trimethylene or 2,2′-diethyloxy linker and various substituents were studied. • Methyl- and ethyl- substituted compounds with a trimethylene linker were able to partially restore muscle force. • The investigated bispyridinium analogues can be used for future studies to optimize structure-based molecular modeling. [ABSTRACT FROM AUTHOR]

The Hippo signaling pathway plays an essential role in organ size control and tumorigenesis. Loss of Hippo signal and hyper-activation of the downstream oncogenic YAP signaling are commonly observed in various types of cancers. We previously identified STRN3-containing PP2A phosphatase as a negative regulator of MST1/2 kinases (i.e., Hippo) in gastric cancer (GC), opening the possibility of selectively targeting the PP2Aa–STRN3–MST1/2 axis to recover Hippo signaling against cancer. Here, we further discovered 1) disulfiram (DSF), an FDA-approved drug, which can similarly block the binding of STRN3 to PP2A core enzyme and 2) CX-6258 (CX), a chemical inhibitor, that can disrupt the interaction between STRN3 and MST1/2, both allowing reactivation of Hippo activity to inhibit GC. More importantly, we found these two compounds, via an MST1/2 kinase-dependent manner, inhibit DNA repair to sensitize GC towards chemotherapy. In addition, we identified thiram, a structural analog of DSF, can function similarly to inhibit cancer cell proliferation or enhance chemotherapy sensitivity. Interestingly, inclusion of copper ion enhanced such effects of DSF and thiram on GC treatment. Overall, this work demonstrated that pharmacological targeting of the PP2Aa–STRN3–MST1/2 axis by drug compounds can potently recover Hippo signal for tumor treatment. [ABSTRACT FROM AUTHOR]

PURPOSE: This study aimed to identify baseline clinical features associated with the outcomes of patients enrolled in the COMBI-MB phase II study of dabrafenib and trametinib treatment in patients with V600 BRAF-mutant metastatic melanoma with melanoma brain metastases (MBM). Exploratory biomarker analysis was also conducted as part of the synergistic COMBI-BRV trial (BRV116521), to identify molecular and immunologic changes associated with dabrafenib in MBMs and extracranial metastases (ECM). PATIENTS AND METHODS: Post hoc analysis was performed for baseline features of patients (n = 125) enrolled in COMBI-MB. Analyses were performed to identify baseline clinical features associated with intracranial response rate (ICRR), progression-free survival (PFS), and overall survival (OS). UNLABELLED: Exploratory biomarker analysis was performed on biospecimen collected in the COMBI-BRV trial in which patients with BRAF-mutant, resectable MBM were treated with dabrafenib for 10 to 14 days prior to craniotomy. Accessible ECM were resected or biopsied at the time of craniotomy. Biospecimens underwent molecular and immunologic profiling for comparative analyses. RESULTS: In COMBI-MB baseline treatment with corticosteroids was independently associated with lower ICRR [39% vs. 63%; OR, 0.323; 95 % confidence interval (CI), 0.105-0.996; P = 0.049] and shorter PFS (HR, 1.93; 95% CI, 1.06-3.51; P = 0.031). Additional significant associations identified in the multivariate analysis were improved PFS in patients with a BRAFV600E genotype (HR, 0.565; 95% CI, 0.321-0.996; P = 0.048) and improved OS in patients with Eastern Cooperative Oncology Group 0 (HR, 0.44; 95% CI, 0.25-0.78; P = 0.005). CONCLUSIONS: Corticosteroid treatment was associated with reduced ICRR and PFS in COMBI-MB, similar to results with immunotherapy for MBMs. Baseline corticosteroid treatment is a key factor to consider in MBM patient management and clinical trial design/interpretation.

PurposeCombination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4-blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600-mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy.Patients and methodsIn a phase III trial, patients with treatment-naive BRAFV600-mutant metastatic melanoma were randomly assigned to receive either combination nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary end point was 2-year overall survival (OS). Secondary end points were 3-year OS, objective response rate, response duration, progression-free survival, crossover feasibility, and safety.ResultsA total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rank P = .010). Step 1 progression-free survival favored arm A (P = .054). Objective response rates were arm A: 46.0%; arm B: 43.0%; arm C: 47.8%; and arm D: 29.6%. Median duration of response was not reached for arm A and 12.7 months for arm B (P < .001). Crossover occurred in 52% of patients with documented disease progression. Grade ≥ 3 toxicities occurred with similar frequency between arms, and regimen toxicity profiles were as anticipated.ConclusionCombination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

BackgroundTargeting programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase (IDO1) pathways is an appealing option for cancer treatment.MethodsThe open-label, phase 1/2 ECHO-203 study evaluated the safety, tolerability, and efficacy of the IDO1 inhibitor epacadostat in combination with durvalumab, a human anti-PD-L1 monoclonal antibody in adult patients with advanced solid tumors.ResultsThe most common treatment-related adverse events were fatigue (30.7%), nausea (21.0%), decreased appetite (13.1%), pruritus (12.5%), maculopapular rash (10.8%), and diarrhea (10.2%). Objective response rate (ORR) in the overall phase 2 population was 12.0%. Higher ORR was observed in immune checkpoint inhibitor (CPI)-naïve patients (16.1%) compared with patients who had received previous CPI (4.1%). Epacadostat pharmacodynamics were evaluated by comparing baseline kynurenine levels with those on therapy at various time points. Only the 300-mg epacadostat dose showed evidence of kynurenine modulation, albeit unsustained.ConclusionsEpacadostat plus durvalumab was generally well tolerated in patients with advanced solid tumors. ORR was low, and evaluation of kynurenine concentration from baseline to cycle 2, day 1, and cycle 5, day 1, suggested >300 mg epacadostat twice daily is needed to ensure sufficient drug effect.Clinical trial informationA study of epacadostat (INCB024360) in combination with durvalumab (MEDI4736) in subjects with selected advanced solid tumors (ECHO-203) (NCT02318277).

Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10–30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes. [ABSTRACT FROM AUTHOR]

The synthesis of stereochemically pure oximes, amines, saturated and unsaturated cyanomethyl compounds, and methylaminomethyl compounds at the C9 position in 3-hydroxy-N-phenethyl-5-phenylmorphans provided μ-opioid receptor (MOR) agonists with varied efficacy and potency. One of the most interesting compounds, (2-((1S,5R,9R)-5-(3-hydroxyphenyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-9-yl)acetonitrile), was found to be a potent partial MOR agonist (EC50 = 2.5 nM, %Emax = 89.6%), as determined in the forskolin-induced cAMP accumulation assay. Others ranged in potency and efficacy at the MOR, from nanomolar potency with a C9 cyanomethyl compound (EC50 = 0.85 nM) to its totally inactive diastereomer, and three compounds exhibited weak MOR antagonist activity (the primary amine 3, the secondary amine 8, and the cyanomethyl compound 41). Many of the compounds were fully efficacious; their efficacy and potency were affected by both the stereochemistry of the molecule and the specific C9 substituent. Most of the MOR agonists were selective in their receptor interactions, and only a few had δ-opioid receptor (DOR) or κ-opioid receptor (KOR) agonist activity. Only one compound, a C9-methylaminomethyl-substituted phenylmorphan, was moderately potent and fully efficacious as a KOR agonist (KOR EC50 = 18 nM (% Emax = 103%)). [ABSTRACT FROM AUTHOR]

A new application involving a water–stable amido–functionalized allylboronate has been developed for 1,2‐addition to carbon–nitrogen double bonds. The process achieves highly enantioselective allylation of aldoxime derivatives in water, by employing O‐Boc oximes as substrates under Zn(OH)2–chiral aminophenol catalysis. This process affords the corresponding homoallylic amines with 91–96 % ee. The products could be transformed into N‐hydroxy‐γ‐lactam or 1,2‐oxazinan‐6‐one, through an acidic or a protection‐acidic treatment sequence, respectively, almost without enantiopurity loss. [ABSTRACT FROM AUTHOR]

This review presents recent studies of the chemical and molecular regulators of acetylcholine (ACh) signaling and the complexity of the small molecule and RNA regulators of those mechanisms that control cholinergic functioning in health and disease. The underlying structural, neurochemical, and transcriptomic concepts, including basic and translational research and clinical studies, shed new light on how these processes inter‐change under acute states, age, sex, and COVID‐19 infection; all of which modulate ACh‐mediated processes and inflammation in women and men and under diverse stresses. The aspect of organophosphorus (OP) compound toxicity is discussed based on the view that despite numerous studies, acetylcholinesterase (AChE) is still a vulnerable target in OP poisoning because of a lack of efficient treatment and the limitations of oxime‐assisted reactivation of inhibited AChE. The over‐arching purpose of this review is thus to discuss mechanisms of cholinergic signaling dysfunction caused by OP pesticides, OP nerve agents, and anti‐cholinergic medications; and to highlight new therapeutic strategies to combat both the acute and chronic effects of these chemicals on the cholinergic and neuroimmune systems. Furthermore, OP toxicity was examined in view of cholinesterase inhibition and beyond in order to highlight improved small molecules and RNA therapeutic strategies and assess their predicted pitfalls to reverse the acute toxicity and long‐term deleterious effects of OPs. [ABSTRACT FROM AUTHOR]

Millions of individuals globally suffer from inadvertent, occupational or self‐harm exposures from organophosphate (OP) insecticides, significantly impacting human health. Similar to nerve agents, insecticides are neurotoxins that target and inhibit acetylcholinesterase (AChE) in central and peripheral synapses in the cholinergic nervous system. Post‐exposure therapeutic countermeasures generally include administration of atropine with an oxime to reactivate the OP‐inhibited AChE. However, animal model studies and recent clinical trials using insecticide‐poisoned individuals have shown minimal clinical benefits of the currently approved oximes and their efficacy as antidotes has been debated. Currently used oximes either reactivate poorly, do not readily cross the blood–brain barrier (BBB), or are rapidly cleared from the circulation and must be repeatedly administered. Zwitterionic oximes of unbranched and simplified structure, for example RS194B, have been developed that efficiently cross the BBB resulting in reactivation of OP‐inhibited AChE and dramatic reversal of severe clinical symptoms in mice and macaques exposed to OP insecticides or nerve agents. Thus, a single IM injection of RS194B has been shown to rapidly restore blood AChE and butyrylcholinesterase (BChE) activity, reverse cholinergic symptoms, and prevent death in macaques following lethal inhaled sarin and paraoxon exposure. The present macaque studies extend these findings and assess the ability of post‐exposure RS194B treatment to counteract oral poisoning by highly toxic diethylphosphorothioate insecticides such as parathion and chlorpyrifos. These OPs require conversion by P450 in the liver of the inactive thions to the active toxic oxon forms, and once again demonstrated RS194B efficacy to reactivate and alleviate clinical symptoms within 60 mins of a single IM administration. Furthermore, when delivered orally, the Tmax of RS194B at 1–2 h was in the same range as those administered IM but were maintained in the circulation for longer periods greatly facilitating the use of RS194B as a non‐invasive treatment, especially in isolated rural settings. [ABSTRACT FROM AUTHOR]

A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC50 = 0.101 ± 0.003 µM and HssBChE IC50 = 0.036 ± 0.002 µM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound. [ABSTRACT FROM AUTHOR]

An efficient TBHP/TBAI mediated strategy has been developed for the synthesis of 2,4,6‐trisubstitued pyridines from ketoxime acetates and benzylamines under metal‐free conditions for the first time. In this protocol benzylamine acts as an effective ArCO surrogate. This methodology features use of inexpensive catalysts, avert of additional ligands and additives and high functional group tolerance. Moreover, 5‐Lipoxygenase enzyme inhibitory activities were performed for all synthesised compounds. Among all 2,4,6‐trisubstituted pyridines 3fg, 3fa and 3eg showed good activity. [ABSTRACT FROM AUTHOR]

We report herein the development of palladium‐catalyzed deacylative deuteration of arylketone oxime ethers. This protocol features excellent functional group tolerance, heterocyclic compatibility, and high deuterium incorporation levels. Regioselective deuteration of some biologically important drugs and natural products are showcased via Friedel–Crafts acylation and subsequent deacylative deuteration. Vicinal meta‐C−H bond functionalization (including fluorination, arylation, and alkylation) and para‐C−H bond deuteration of electro‐rich arenes are realized by using the ketone as both directing group and leaving group, which is distinct from aryl halide in conventional dehalogenative deuteration. [ABSTRACT FROM AUTHOR]

This article, published in the journal Synlett, explores the use of biomimetic dimerization in the synthesis of natural products. The authors discuss the efficiency and elegance of this approach and its popularity in the field. They present two case studies, focusing on the synthesis of linderaspirone A and bi-linderone, as well as parvistemin A and (±)-diperezone. The authors propose biosynthetic pathways and synthetic approaches for these compounds. They also discuss the use of biomimetic dimerization in the total synthesis of other natural products, such as scabellone B and spiroxins A/C/D. The article acknowledges the contributions of the research group members and provides brief biographies of the authors. [Extracted from the article]

Method for the synthesis of previously unknown imidazole N-oxides bearing allomaltol unit has been elaborated. The presented approach is based on multicomponent condensation of corresponding oximes containing aroyl and 3-hydroxypyran-4-one fragments with various aldehydes and amines. The advantages of considered method are easily available starting compounds, atom economy, simple experimental procedure including isolation of the final products without column chromatography. The synthetic utility of prepared N-oxides was demonstrated by its further conversion to corresponding 2-chloroimidazole and 2-phenylaminoimidazole derivatives. [ABSTRACT FROM AUTHOR]

Ligands are at the heart of coordination chemistry. They conjure the magic of transition metals expressed in organometallic catalysis. Phosphine or P-ligands have found vast utility in transition metal chemistry, though demanding tedious synthesis. Several N, S-based ligands also find application in organometallic chemistry. Oximes are easily derived from aldehydes and ketones by simple reactions with hydroxylamine. Thus, an extensive library of oximes is available with different structural and electronic variations essential for coordination chemistry and catalysis. Several compounds with complex structural features, unavailable for phosphorous ligands, can be readily converted into active oxime ligands in a single derivatization step. Oxime ligands and metal complexes are applied in synthesizing diverse organic molecules and thus versatile ligands in organotransition metal chemistry. [ABSTRACT FROM AUTHOR]

A series of novel Di‑tert‑butyl(E)-4‑hydroxy-6-(hydroxyimino)-4-methyl-2-arylcyclohexane-1,3-dicarboxylate derivatives were synthesized in two steps with excellent yields. In the First step, tert‑butylacetoacetate and substituted benzaldehyde were directly condensed using methylamine catalyst in ethanol as a solvent to create substituted 1,3-bis(tert‑butoxycarbonyl)-cyclohexanone. A second stage involved synthesizing BHMAC (Ar = pH and Ar = p-OCH3C6H4) by treating the respective ketones in an ethanol medium with hydroxylamine hydrochloride and sodium acetate trihydrate. NMR, IR, and mass spectroscopy were used to confirm the oxime derivatives. Density functional theory calculations at the DFT/B3LYP level using 6–31G++ (d, p) have been performed to reproduce the structure and geometry in order to understand the electrical behavior of synthesized compounds. Using bovine serum albumin, a protein denaturation test is used to assess anti-inflammatory efficacy. BHMAC demonstrates conventional pharmacological molecules in its notable anti-inflammatory action and has effects that are dependent on concentration. Utilizing the phosphomolybdenum technique, the total antioxidant activity of the 2,4-bis(tert‑butoxycarbonyl)-cyclohexanone oxime (2 a and 2 b) was assessed standard Vitamin C medications .The results revealed that 2 a & 2 b possess significant antioxidant activity Molecular docking experiments indicate that the chemical may interact with anti-inflammatory and antioxidant causing enzymes. Strong binding energies and inhibition constants with cyclooxygenase (PDB: 1PGG) are demonstrated by BHMAC, suggesting that it is a suitable material for investigations pertaining to anti-inflammatory. BHMAC's remarkable anti-inflammatory and antioxidant properties, together with its synthesis and characterization, highlight its potential as a viable candidate for more biomedical research and therapeutic development.

Siderophores are synthesized by microbes to facilitate iron acquisition required for growth. Catecholate, hydroxamate, and α-hydroxycarboxylate groups comprise well-established ligands coordinating Fe(III) in siderophores. Recently, a C-type diazeniumdiolate ligand in the newly identified amino acid graminine (Gra) was found in the siderophore gramibactin (Gbt) produced by Paraburkholderia graminis DSM 17151. The N-N bond in the diazeniumdiolate is a distinguishing feature of Gra, yet the origin and reactivity of this C-type diazeniumdiolate group has remained elusive until now. Here, we identify l-arginine as the direct precursor to l-Gra through the isotopic labeling of l-Arg, l-ornithine, and l-citrulline. Furthermore, these isotopic labeling studies establish that the N-N bond in Gra must be formed between the Nδ and Nω of the guanidinium group in l-Arg. We also show the diazeniumdiolate groups in apo-Gbt are photoreactive, with loss of nitric oxide (NO) and H+ from each d-Gra yielding E/Z oxime isomers in the photoproduct. With the loss of Gbt's ability to chelate Fe(III) upon exposure to UV light, our results hint at this siderophore playing a larger ecological role. Not only are NO and oximes important in plant biology for communication and defense, but so too are NO-releasing compounds and oximes attractive in medicinal applications.

BackgroundThe randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic BRAF V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram.MethodsIn COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; BRAF V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4+/CD8+ T-cell ratio via immunophenotyping.ResultsExtensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by BRAF V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4+/CD8+ ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4+/CD8+ ratio was strongly predictive (interaction p=0.0131).ConclusionsThese results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4+/CD8+ T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted.Trial registration numberNCT02967692.

20-Hydroxyecdysone and several of its oxidized derivatives exert cytoprotective effect in mammals including humans. Inspired by this bioactivity of ecdysteroids, in the current study it was our aim to prepare a set of sidechain-modified derivatives and to evaluate their potential to protect the blood-brain barrier (BBB) from oxidative stress. Six novel ecdysteroids, including an oxime and five oxime ethers, were obtained through regioselective synthesis from a sidechain-cleaved calonysterone derivative 2 and fully characterized by comprehensive NMR techniques revealing their complete 1H and 13C signal assignments. Surprisingly, several compounds sensitized hCMEC/D3 brain microvascular endothelial cells to tert-butyl hydroperoxide (tBHP)-induced oxidative damage as recorded by impedance measurements. Compound 8, containing a benzyloxime ether moiety in its sidechain, was the only one that exerted a protective effect at a higher, 10 μM concentration, while at lower (10 nM– 1 μM) concentrations it promoted tBHP-induced cellular damage. Brain endothelial cells were protected from tBHP-induced barrier integrity decrease by treatment with 10 μM of compound 8, which also mitigated the intracellular reactive oxygen species production elevated by tBHP. Based on our results, 17-oxime ethers of oxidized ecdysteroids modulate oxidative stress of the BBB in a way that may point towards unexpected toxicity. Further studies are needed to evaluate any possible risk connected to dietary ecdysteroid consumption and CNS pathologies in which BBB damage plays an important role. [ABSTRACT FROM AUTHOR]

Oxime chemicals are the building blocks of many anticancer drugs and widely used in industry and laboratory. A simple but robust hierarchically porous zeolite (HTS‐1) catalyst was prepared by hydrothermal methods and used for the preparation of vanillin oxime from vanillin in NH3 ⋅ H2O/DIO (v/v 1/10) system. The results of the catalyst characterization showed that the larger pore size and more framework Ti were conducive to promote the transformation of the substrates. The conversion of vanillin and the yield of vanillin oxime were both higher than 99 % under optimized reaction conditions. It was found that the reaction proceeded by oxidation of NH3 to hydroxylamine (NH2OH), and oximation of hydroxylamine with vanillin to obtain vanillin oxime, where the rate‐controlling step was the hydroxylamine formation, and the apparent activation energy was 26.22 kJ/mol. The corresponding oximation products could also be obtained by extending this method to other compounds derived from lignin. Furthermore, the catalytic system was used directly to the conversion of birch biomass to obtain oxime products such as vanillin oxime, syringaldehyde oxime, and furfural oxime etc. This work might give insights into the sustainable production of N‐containing high‐value products from lignocellulose. [ABSTRACT FROM AUTHOR]

In this work, we conducted a study of 7‐exo‐trig cyclizations mechanism involving aryl, vinyl, and alkyl radicals on oxime ethers. Initially, the reaction of brominated oxime ether 9 a with (TMS)3SiH and AIBN gave rise to aryl radicals that underwent a 7‐exo‐trig cyclization on the oxime ether, yielding dibenzoxepine 10 a, and the ipso reaction and reduction products were obtained as well. Approximate rate constants at 80 °C for the 7‐exo‐trig (1.0×108 s−1) and the ipso cyclization (4.3×107 s−1) were determined by competition experiments. DFT calculations showed good agreement with the experimental results. The reduction rate constant of the N‐alkoxyaminyl radical with (TMS)3SiH was calculated to be 4.1×10−1 M−1 s−1; while the rate constants for the 7‐exo‐trig cyclizations of vinyl and alkyl radicals on the oxime ether were estimated in the ranges of 106 s−1–108 s−1 and 103 s−1–108 s−1, respectively. The 7‐exo‐trig cyclization reactions involving aryl, vinyl, and alkyl radicals with oxime ethers were found to be an exothermic and irreversible process, with the oximic carbon showing a preference for nucleophilic alkyl radicals. This kinetic study contributes to the deeper understanding of radical‐mediated cyclizations, enabling the efficient design of complex synthetic routes. [ABSTRACT FROM AUTHOR]