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K-Ras is the most commonly mutated oncogene in human cancer. The recently approved non-small cell lung cancer drugs sotorasib and adagrasib covalently capture an acquired cysteine in K-Ras-G12C mutation and lock it in a signaling-incompetent state. However, covalent inhibition of G12D, the most frequent K-Ras mutation particularly prevalent in pancreatic ductal adenocarcinoma, has remained elusive due to the lack of aspartate-targeting chemistry. Here we present a set of malolactone-based electrophiles that exploit ring strain to crosslink K-Ras-G12D at the mutant aspartate to form stable covalent complexes. Structural insights from X-ray crystallography and exploitation of the stereoelectronic requirements for attack of the electrophile allowed development of a substituted malolactone that resisted attack by aqueous buffer but rapidly crosslinked with the aspartate-12 of K-Ras in both GDP and GTP state. The GTP-state targeting allowed effective suppression of downstream signaling, and selective inhibition of K-Ras-G12D-driven cancer cell proliferation in vitro and xenograft growth in mice.

Herein, we report concise total syntheses of diterpene natural products (-)-crinipellins A and B with a tetraquinane skeleton, three adjacent all-carbon quaternary centers, and multiple oxygenated and labile functional groups. Our synthesis features a convergent Kozikowski β-alkylation to unite two readily available building blocks with all the required carbon atoms, an intramolecular photochemical [2 + 2] cycloaddition to install three challenging and adjacent all-carbon quaternary centers and a 5-6-4-5 tetracyclic skeleton, and a controlled Cargill rearrangement to rearrange the 5-6-4-5 tetracyclic skeleton to the desired tetraquinane skeleton. These strategically enabling transformations allowed us to complete total syntheses of (-)-crinipellins A and B in 12 and 13 steps, respectively. The results of quantum chemical computations revealed that the Bronsted acid-catalyzed Cargill rearrangements likely involve stepwise paths to products and the AlR3-catalyzed Cargill rearrangements likely involve a concerted path with asynchronous alkyl shifting events to form the desired product.

Application of the [1,2]-Wittig rearrangement and cyclisation approach to 3-arylphthalides has been evaluated for the synthesis of three bioactive natural products. While this is successful in the case of crycolide, providing the second synthesis of this compound, the more sterically demanding targets isopestacin and cryphonectric acid prove not to be amenable to this approach, with the 2,6-disubstituted aryl groups causing the failure of the rearrangement and alkylation steps, respectively. Direct oxidation of the substituted benzhydrols resulting from [1,2]-Wittig rearrangement using MnO2 provides a new route to 3-aryl-3-hydroxyisoindolinones, and this method has been used in the synthesis of two 3-aryl-3-benzyloxyisoindolinone anticancer agents. [ABSTRACT FROM AUTHOR]

Anti-wear and anti-oxidation abilities are two key properties of lubricants that play a crucial role in ensuring long-term stable equipment operation. In this study, we aimed to develop a base oil with good anti-oxidation and anti-wear properties for use under extreme pressure. The as-prepared metallocene polyalphaolefin (mPAO) was chemically modified using the trifluoromethanesulfonic acid (TfOH) catalysis through an alkylating reaction with triphenyl phosphorothioate (TPPT). During the experiments, when the reaction temperature exceeded 70 °C or the concentration of TfOH exceeded 2.67%, the β -scission reaction in the alkylation process became significantly more pronounced. The physical and chemical properties of TPPT-modified mPAO (T-mPAO) were evaluated by nuclear magnetic resonance spectroscopy, Fourier trans-form infrared spectroscopy, gel–permeation chromatography, and ASTM standards. T-mPAO showed significantly improved antioxidant capacity, with the initial oxidation temperature increasing by 32 °C compared to the base oil, and it exhibited the slowest increase in acid number in the 96-h oven oxidation test. The tribological tests showed that T-mPAO had the lowest friction coefficient, wear track, and wear rate (72.7% lower than that of mPAO) as well as the highest PB (238 kg) and PD (250 kg) among all tested samples. Compared to mPAO, the average friction coefficient of TPPT-modified mPAO in the four-ball friction test was reduced by 30.5%, and by 16.4% in the TE77 reciprocating friction test. Based on the experimental results, T-mPAO had strong anti-oxidation ability and excellent lubricating performance.The successful synthesis of multifunctional mPAO has enabled lubricant base oil additization, making it possible to use it in more demanding work scenarios, greatly broadening its application scope and making lubricant formulation blending more flexible. [ABSTRACT FROM AUTHOR]

Among the natural tetramic acids with a decalinoyl part, signermycin B is unique because it contains a cis‐decalin. In this paper, we demonstrate that the cis‐decalin section of signermycin B can be accessed by an anionic oxy‐Cope rearrangement. The substrate, a tricyclic dienol was prepared by an intramolecular Diels‐Alder reaction of a masked ortho‐benzoquinone, generated by oxidation of an α‐methoxyphenol in presence of cis‐2‐hexenol. After a superfluous bromine on the cycloadduct was removed, reaction of the tricyclic ketone with isopropenylmagnesium bromide led to the tricyclic trienol that underwent the oxy‐Cope rearrangement to a cis‐decalinone. While we could show, that introduction of the 4‐ethyl substituent (signermycin B numbering) is possible by enolate alkylation, the 4‐epi‐isomer was formed. [ABSTRACT FROM AUTHOR]

Amino acids with unusual types of chirality and their derivatives have recently attracted attention as precursors in the synthesis of chiral catalysts and peptide analogues with unique properties. In this study, we have synthesized a new nido-carborane-based planar-chiral amino acid, in the molecule of which the amino group is directly bonded to the B(3) atom, and the carboxyl group is attached to the B(9) atom through the CH2S+(Me) fragment. 3-Amino-9-dimethylsulfonio-nido-carborane, prepared in three steps from 3-amino-closo-carborane in a high yield, was a key intermediate in the synthesis of the target planar-chiral amino acid. The carboxymethyl group at the sulfur atom was introduced by the demethylation reaction of the dimethylsulfonio derivative, followed by S-alkylation. The structure of new 3,9-disubstituted nido-carboranes was studied for the first time using NMR spectroscopy. The resonances of all boron atoms in the 11B NMR spectrum of 3-amino-9-dimethylsulfonio-nido-carborane were assigned based on the 2D NMR correlation experiments. The nido-carborane-based planar-chiral amino acid and related compounds are of interest as a basis for peptide-like compounds and chiral ligands. [ABSTRACT FROM AUTHOR]

It is not known why the number of proteinogenic amino acids is limited to 20. Since Miller's experiment, many studies have shown that amino acids could have been generated under prebiotic conditions. However, the amino acid compositions obtained from simulated experiments and exogenous origins are different from those of life. We hypothesized that some simple precursor compounds generated by high-energy reactions were selectively combined by organic reactions to afford a limited number of amino acids. To this direction, we propose two scenarios. One is the reaction of HCN with each side-chain precursor (the aminomalononitrile scenario), and the other is alkylation of the "complex glycine precursor", which is the main product of proton irradiation of the primordial atmosphere (the new polyglycine scenario). Here, selective formation of the 20 amino acids is described focusing on the latter scenario. The structural features of proteinogenic amino acids can be described systematically. The scenario consists of three stages: a high-energy reaction stage (Gly, Ala, Asn, and Asp were established); an alkylation stage (Gln, Glu, Ser, Thr, Val, Ile, Leu, and Pro were generated in considerable amounts); and a peptide formation stage (Phe, Tyr, Trp, His, Lys, Arg, Cys, and Met were selected due to their structural advantages). This scenario is a part of the evolution of Garakuta World, in which many prebiotic materials are contained. [ABSTRACT FROM AUTHOR]

Five historical green dyes from the Historische Farbstoffsammlung, Technical University of Dresden, have been analysed by liquid chromatography – mass spectrometry (LC-MS). The dyes were determined to be formed by the alkylation of either crystal violet or rosaniline and contained both doubly and singly charged ions. One sample had a spread of higher molecular weight doubly charged ions reminiscent of the alkylation of a Hofmann violet. Malachite green was the dye present in one sample. [ABSTRACT FROM AUTHOR]

(−)‐Ambrox, a highly prized and commercially significant component of ambergris, finds widespread application in perfumery, cigarettes, cosmetics, and the food industry. Despite considerable attention to this research area over the years, an environmentally friendly and practical method for synthesizing (−)‐ambrox has remained elusive. This study presents a succinct and efficient approach to (−)‐ambrox synthesis, involving two consecutive alkylations at C‐6, followed by an acid‐catalyzed cyclization to give bicyclic ketones starting from (R)‐carvone. Subsequent reduction, Barton Vinyl Iodide synthesis, alkylation, and an acid‐catalyzed cyclization collectively achieved the synthesis of (−)‐ambrox with a satisfactory yield of 26.2 %. [ABSTRACT FROM AUTHOR]

The ability of aquatic mesofauna representatives involved in trophic chains to sorb and accumulate toxicants is important for understanding the functioning of aquatic ecosystems and for fishing industry. This study investigated the capacity of marine amphipod Gammarus oceanicus and freshwater amphipods Eulimnogammarus vittatus and Gammarus lacustris to absorb the DNA-alkylating agent methyl methanesulfonate (MMS). The presence of alkylating agents in the environment and in the tissues of the amphipods was determined using whole-cell lux-biosensor Escherichia coli MG1655 pAlkA-lux, in which the luxCDABE genes from Photorhabdus luminescens, enabling the luminescence of the cell culture, are controlled by the PalkA promoter of DNA glycosylase. It was shown that within one day of incubation in water containing MMS at a concentration above 10 μM, the amphipods absorbed the toxicant and their tissues produce more alkylation damage to biosensor cells than the surrounding water. Concentrations of MMS above 1 mM in the environment caused the death of the amphipods before the toxicant could be significantly concentrated in their tissues. The sensitivity and the capacity to absorb MMS were found to be approximately the same for the marine amphipod G. oceanicus and the freshwater amphipods E. vittatus and G. lacustris. [ABSTRACT FROM AUTHOR]

Abstract In this study, we have synthesized novel 4-acetophenone moiety-bearing functionalized imidazole derivatives containing S-, and N-ethyl substituents and evaluated their anticancer activity. Their anticancer activity was studied against human breast carcinoma (MDA-MB-231), human prostate carcinoma (PPC-1), and human glioblastoma (U-87). Compounds 4, 9, 14, and 22 were identified as the most promising anticancer agents from a series of imidazole derivatives. They showed the highest cytotoxicity by MTT assay against MDA-MB-231, PPC-1 and U-87 cell lines. Compounds 14 and 22 were most selective against PPC-1 and U-87 cell lines, and their EC50 values against these cell lines ranged from 3.1 to 47.2 µM. Most tested compounds showed lower activity against the triple-negative breast cancer MDA-MB-231 cell line. None of the imidazole derivatives possessed an inhibiting effect on the migration of PPC-1 and U-87 cells by ‘wound’ healing assay. In spheroid assay, the most promising were compounds 14 and 22, especially in PPC-1 3D cultures. They efficiently reduced both the size and the viability of PPC-1 spheroid cells.

Lysergic acid diethylamide (LSD), a semisynthetic ergoline alkaloid analogue and hallucinogen, is a potent psychoplastogen with promising therapeutic potential. While a variety of synthetic strategies for accessing ergoline alkaloids have emerged, the complexity of the tetracyclic ring system results in distinct challenges in preparing analogues with novel substitution patterns. Methods of modulating the hallucinogenic activity of LSD by functionalization at previously inaccessible positions are of continued interest, and efficient syntheses of the ergoline scaffold are integral toward this purpose. Here, we report novel C-C bond forming strategies for preparing the ergoline tetracyclic core, focusing on the relatively unexplored strategy of bridging the B- and D-ring systems last. Following cross-coupling to first join the A- and D-rings, we explored a variety of methods for establishing the C-ring, including intramolecular α-arylation, borrowing hydrogen alkylation, and rhodium-catalyzed C-H insertion. Our results led to a seven-step formal synthesis of LSD and the first methods for readily introducing substitution on the C-ring. These strategies are efficient for forming ergoline-like tetracyclic compounds and analogues, though they each face unique challenges associated with elaboration to ergoline natural products. Taken together, these studies provide important insights that will guide future synthetic strategies toward ergolines.

The cellular response to oxidants or xenobiotics comprises two key pathways, resulting in modulation of NRF2 and FOXO transcription factors, respectively. Both mount a cytoprotective response, and their activation relies on crucial protein thiol moieties. Using fumaric acid esters (FAEs), known thiol‐reactive compounds, we tested for activation of NRF2 and FOXO pathways in cultured human hepatoma cells by dimethyl/diethyl as well as monomethyl/monoethyl fumarate. Whereas only the diesters caused acute glutathione depletion and activation of the stress kinase p38MAPK, all four FAEs stimulated NRF2 stabilization and upregulation of NRF2 target genes. However, no significant FAE‐induced activation of FOXO‐dependent target gene expression was observed. Therefore, while both NRF2 and FOXO pathways are responsive to oxidants and xenobiotics, FAEs selectively activate NRF2 signaling.

In this study, a novel approach for the tertiary α‐alkylation of ketones using alkanes with electron‐deficient C─H bonds is presented, employing a synergistic catalytic system combining inexpensive copper salts with aminocatalysis. This methodology addresses the limitations of traditional alkylation methods, such as the need for strong metallic bases, regioselectivity issues, and the risk of over alkylation, by providing a high reactivity and chemoselectivity without the necessity for pre‐functionalized substrates. The dual catalytic strategy enables the direct functionalization of C(sp3)─H bonds, demonstrating remarkable selectivity in the presence of conventional C(sp3)─H bonds that are adjacent to heteroatoms or π systems, which are typically susceptible to single‐electron transfer processes. The findings contribute to the advancement of alkylation techniques, offering a practical and efficient route for the construction of C(sp3)─C(sp3) bonds, and paving the way for further developments in the synthesis of complex organic molecules. [ABSTRACT FROM AUTHOR]

The human alkylation B (AlkB) homologs, ALKBH2 and ALKBH3, respond to methylation damage to maintain genomic integrity and cellular viability. Both ALKBH2 and ALKBH3 are direct reversal repair enzymes that remove 1-methyladenine (1meA) and 3-methylcytosine (3meC) lesions commonly generated by alkylating chemotherapeutic agents. Thus, the existence of deficiencies in ALKBH proteins can be exploited in synergy with chemotherapy. In this study, we investigated possible interactions between ALKBH2 and ALKBH3 with other proteins that could alter damage response and discovered an interaction with the mismatch repair (MMR) system. To test whether the lack of active MMR impacts ALKBH2 and/or ALKBH3 response to methylating agents, we generated cells deficient in ALKBH2, ALKBH3, or both in addition to Mlh homolog 1 (MLH1), another MMR protein. We found that MLH1koALKBH3ko cells showed enhanced resistance toward SN1- and SN2-type methylating agents, whereas MLH1koALKBH2ko cells were only resistant to SN1-type methylating agents. Concomitant loss of ALKBH2 and ALKBH3 (ALKBH2ko3ko) rendered cells sensitive to SN1- and SN2-agents, but the additional loss of MLH1 enhanced resistance to both types of damage. We also showed that ALKBH2ko3ko cells have an ATR-dependent arrest at the G2/M checkpoint, increased apoptotic signaling, and replication fork stress in response to methylation. However, these responses were not observed with the loss of functional MLH1 in MLH1koALKBH2ko3ko cells. Finally, in MLH1koALKBH2ko3ko cells, we observed elevated mutant frequency in untreated and temozolomide treated cells. These results suggest that obtaining a more accurate prognosis of chemotherapeutic outcome requires information on the functionality of ALKBH2, ALKBH3, and MLH1. [ABSTRACT FROM AUTHOR]

In the Neurospora circadian system, the White Collar Complex (WCC) formed by WC-1 and WC-2 drives expression of the frequency (frq) gene whose product FRQ feedbacks to inhibit transcriptional activity of WCC. Phosphorylation of WCC has been extensively studied, but the extent and significance of other post-translational modifications (PTM) have been poorly studied. To this end, we used mass-spectrometry to study alkylation sites on WCC, resulting in discovery of nine acetylation sites. Mutagenesis analysis showed most of the acetylation events individually do not play important roles in period determination. Moreover, mutating all the lysines falling in either half of WC-1 or all the lysine residues in WC-2 to arginines did not abolish circadian rhythms. In addition, we also found nine mono-methylation sites on WC-1, but like acetylation, individual ablation of most of the monomethylation events did not result in a significant period change. Taken together, the data here suggest that acetylation or mono-methylation on WCC is not a determinant of the pace of the circadian feedback loop. The finding is consistent with a model in which repression of WCC’s circadian activity is mainly controlled by phosphorylation. Interestingly, light induced expression of some light-responsive genes has been modulated in certain wc-1 acetylation mutants, suggesting that WC-1 acetylation events differentially regulate light responses. [ABSTRACT FROM AUTHOR]

A novel synthesis strategy to access 2-alkoxyquinoline derivatives via a palladium-driven cascade reaction is disclosed. Unlike classic methods based on the alkylation of 2-quinolones with alkyl halides, the present method benefits from the de novo assembly of the quinoline core starting from 1,3-butadiynamides. Palladium-catalyzed reaction cascades with N-(2-iodophenyl)-N-tosyl-1,3-butadiynamides and primary alcohols as external nucleophiles proceed under mild reaction conditions and selectively deliver a variety of differently functionalized 4-alkenyl 2-alkoxyquinolines in a single batch transformation. [ABSTRACT FROM AUTHOR]

As an important class of nitrogen-containing fused heterocyclic compounds, imidazo[1,2-a]pyridines often exhibit significant biological activities, such as analgesic, anticancer, antiosteoporosis, anxiolytic, etc. Using Y(OTf)3 as a Lewis acid catalyst, a simple and efficient method has been developed for the synthesis of C3-alkylated imidazo[1,2-a]pyridines through the three-component aza-Friedel–Crafts reaction of imidazo[1,2-a]pyridines, aldehydes, and amines in the normal air atmosphere without the protection of inert gas and special requirements for anhydrous and anaerobic conditions. A series of imidazo[1,2-a]pyridine derivatives were obtained with moderate to good yields, and their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Furthermore, this conversion has the advantages of simple operation, excellent functional group tolerance, high atomic economy, broad substrate scope, and can achieve gram-level reactions. Notably, this methodology may be conveniently applied to the further design and rapid synthesis of potential biologically active imidazo[1,2-a]pyridines with multifunctional groups. [ABSTRACT FROM AUTHOR]

The cellular response to oxidants or xenobiotics comprises two key pathways, resulting in modulation of NRF2 and FOXO transcription factors, respectively. Both mount a cytoprotective response, and their activation relies on crucial protein thiol moieties. Using fumaric acid esters (FAEs), known thiol‐reactive compounds, we tested for activation of NRF2 and FOXO pathways in cultured human hepatoma cells by dimethyl/diethyl as well as monomethyl/monoethyl fumarate. Whereas only the diesters caused acute glutathione depletion and activation of the stress kinase p38MAPK, all four FAEs stimulated NRF2 stabilization and upregulation of NRF2 target genes. However, no significant FAE‐induced activation of FOXO‐dependent target gene expression was observed. Therefore, while both NRF2 and FOXO pathways are responsive to oxidants and xenobiotics, FAEs selectively activate NRF2 signaling. [ABSTRACT FROM AUTHOR]

Carboxylates are ideal directing groups because they are widely available, readily cleavable and excellent linchpins for diverse follow-up reactions. However, their use in meta-selective C−H functionalizations remains a substantial unmet catalytic challenge. Herein, we report the ruthenium-catalyzed meta-C–H alkylation of aromatic carboxylic acids with various functionalized alkyl halides. A bidentate N-ligand increases the electron density at the metal center of ortho-benzoate ruthenacycles to the extent that single-electron reductions of alkyl halides can take place. The subsequent addition of alkyl radicals is exclusively directed to the position para to the CAr–Ru bond, i.e., meta to the carboxylate group. The resulting catalytic meta-C−H alkylation extends to a wide range of (hetero)aromatic carboxylic acids including benzofused five-membered ring heteroarenes but no pyridine derivatives in combination with secondary/tertiary alkyl halides, including fluorinated derivatives. It also allows site-selective C5−H alkylation of 1-naphthoic acids. The products are shown to be synthetic hubs en route to meta-alkylated aryl ketones, nitriles, amides, esters and other functionalized products. Carboxylates are ideal directing groups for aryl C–H functionalizations, given their wide availability and relative ease of functional group interconversion; however, their potential in meta-selective functionalizations has not been fully realized. Here, the authors use carboxylates for meta-selective alkylations via ruthenium catalysis. [ABSTRACT FROM AUTHOR]

With the continuous advancement of industrial technology, higher demands have been placed on the properties of gear oils, such as oxidation stability and shear resistance. Herein, the oxidation stability of high-viscosity metallocene poly- α -olefins (mPAOs) was improved by chemical modification via aromatic amine alkylation. The modified mPAO base oils were synthesized separately with diphenylamine (mPAO-DPA) and N-phenyl- α -naphthylamine (mPAO-NPA), and their applicability in industrial gear oil formulations was evaluated. The composition and physicochemical properties of the obtained samples were assessed using 1H NMR spectroscopy, Fourier transform infrared spectroscopy, gel permeation chromatography, and the American Society for Testing and Materials standards (ASTM D445, ASTM D2270, ASTM D92, etc.) confirming the successful completion of the alkylation reaction. The oxidation stability of the samples was also evaluated using pressurized differential scanning calorimetry. The initial oxidation temperature of mPAO-NPA (230 °C) was 53 °C higher than that of mPAO, and the oxidation induction period of mPAO-DPA was nearly twice that of mPAO-NPA. Thermogravimetric analysis in air revealed the increased thermal decomposition temperature and improved thermal stability of modified mPAO. ISO VG 320 industrial gear oils were formulated using mPAO alkylated with N-phenyl- α -naphthylamine(Lub-2) and commercially purchased PAO100 (Lub-1) as base oil components. The antioxidant performance of two industrial gear oils was evaluated through oven oxidation and rotating oxygen bomb tests. The oxidation induction period of Lub-2 was 30% higher than that of Lub-1, with the latter having a lower acid number and a smaller increase in viscosity at 40 °C. Finally, the friction performance of the samples was assessed on a four-ball friction tester, revealing the synergistic effect of the mPAO-NPA base oil with the HiTEC 3339 additive, forming a more stable oil film with a smaller wear scar diameter. [ABSTRACT FROM AUTHOR]

The generation of alkyl radical from C(sp3)−H substrates via hydrogen atom abstraction represents a desirable yet underexplored strategy in alkylation reaction since involving common concerns remain adequately unaddressed, such as the harsh reaction conditions, limited substrate scope, and the employment of noble metal- or photo-catalysts and stoichiometric oxidants. Here, we utilize the synergistic strategy of photoredox and hydrogen atom transfer (HAT) catalysis to accomplish a general and practical functionalization of unactived C(sp3)−H centers with broad reaction scope, high functional group compatibility, and operational simplicity. A combination of validation experiments and density functional theory reveals that the N-centered radicals, generated from free N − H bond in a stepwise electron/proton transfer event, are the key intermediates that enable an intramolecular 1,5-HAT or intermolecular HAT process for nucleophilic carbon-centered radicals formation to achieve heteroarylation, alkylation, amination, cyanation, azidation, trifluoromethylthiolation, halogenation and deuteration. The practical value of this protocol is further demonstrated by the gram-scale synthesis and the late-stage functionalization of natural products and drug derivatives. Hydrogen atom abstraction from C(sp3)−H substrates for the generation of alkyl radical represents an underexplored strategy in alkylation reactions. Here the authors describe the synergistic utilization of photoredox and hydrogen atom transfer catalysis to accomplish a general and practical functionalization of unactived C(sp3)−H centers. [ABSTRACT FROM AUTHOR]

Carboxylic acids are widely available and generally inexpensive from abundant biomass feedstocks, and they are suitable and generic coupling partners in synthetic chemistry. Reported herein is an electroreductive coupling of stable and versatile carboxylic acids with (hetero)arenes using protons as the hydrogen source. The application of an earth-abundant titanium catalyst has significantly improved the deoxygenative reduction process. Preliminary mechanistic studies provide insights into the deoxygenative reduction of in-situ generated ketone pathway, and the intermediacy generation of ketyl radical and alkylidene titanocene. Without the necessity of pressurized hydrogen or stoichiometric hydride as reductants, this protocol enables highly selective and straightforward synthesis of various functionalized and structurally diverse alkylbenzenes under mild conditions. The utility of this reaction is further demonstrated through practical and valuable isotope incorporation from readily available deuterium source. Carboxylic acids are excellent theoretical candidates for alkylation reactions given their low cost and high availability as products from traditional and also modern feedstock derivatization reactions. Here the authors use simple carboxylic acids to functionalize the C–H bonds of electron-rich arenes under electroreductive conditions with a titanium catalyst. [ABSTRACT FROM AUTHOR]

In previous works, we demonstrated that tertiary 3‐chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions. Herein, we report the synthesis of novel secondary 3‐chloropiperidine analogues. The synthesis incorporates a new procedure to monochlorinate unsaturated primary amines utilizing N‐chlorosuccinimide, while carefully monitoring the temperature to prevent dichlorination. Furthermore, we successfully isolated highly strained bicyclic aziridines by treating the secondary 3‐chloropiperidines with a sufficient amount of base. We conclude this work with a DNA cleavage assay as a proof of principle, comparing our previously known substrates to the novel compounds. In this, the secondary 3‐chloropiperidine as well as the isolated bicyclic aziridine, proved to be more effective than their tertiary counterpart. [ABSTRACT FROM AUTHOR]

Recent work on the diazonium ion metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKDI) suggests that 5-(pyridin-3-yl)-3,4-dihydro-2H-furan-1-ium (NNKFI) may form from NNKDI via an intramolecular reaction. NNKDI is an important carcinogen whose role as an alkylating agent has received significant attention. While there is some experimental evidence supporting NNKFI’s production in vitro, it has not yet been directly observed. Little is known about NNKFI’s structure and reactivity. We report the first in silico examination of this ion. Our study utilized Kohn–Sham density functional theory (B3LYP/6-311G**) and coupled cluster theory (CCSD/6-31G*) to produce energy-optimized structures, vibrational normal modes and molecular orbitals for NNKFI. To gain insight into the chemical properties of this species, we calculated electrostatic potential surfaces, natural population analysis charges and local Fukui indices. We report data and results for NNKFI’s cis and trans conformers. Our work confirms C5 as the preferred site for nucleophilic attack in NNKFI. Stretching motions and predicted bond lengths near O1 are consistent with a somewhat weakened carbonyl structure in this ion. Partial charges, electrostatic potential surfaces and local Fukui indices reveal delocalization of cationic charge on the furanium moiety and notable carbocation character at C5.

Transition-metal-mediated “borrowing hydrogen" also known as hydrogen auto-transfer reactions allow the sustainable construction of C–C and C–N bonds using alcohols as hydrogen donors. In recent years, manganese complexes have been explored as efficient catalysts in these reactions. This review highlights the significant progress made in manganese-catalyzed C–C and C–N bond-formation reactions via hydrogen auto-transfer, emphasizing the importance of this methodology and manganese catalysts in sustainable synthesis strategies.

In the title compound, C17H12N2O, the quinoxaline moiety shows deviations of 0.0288 (7) to −0.0370 (7) Å from the mean plane (r.m.s. deviation of fitted atoms = 0.0223 Å). In the crystal, corrugated layers two molecules thick are formed by C—H...N hydrogen bonds and π-stacking interactions.

Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by Kelch-like ECH-associated protein 1 (Keap1) alkylation plays a central role in anti-inflammatory therapy. However, activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified. Deoxynyboquinone (DNQ) is a natural small molecule discovered from marine actinomycetes. The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1. DNQ exhibited significant anti-inflammatory properties both in vitro and in vivo. The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α, β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine. DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway. Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation. The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry. DNQ triggered the ubiquitination and subsequent degradation of Keap1 by alkylation of the cysteine residue 489 (Cys489) on Keap1-Kelch domain, ultimately enabling the activation of Nrf2. Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α, β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain, suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.

In the title compound, C31H24N4O2, the quinoxaline units are distinctly non-planar and twisted end-to-end. In the crystal, C—H...O and C—H...N hydrogen bonds link the molecules into chains extending along the a-axis direction. The chains are linked through π-stacking interactions between inversion-related quinoxaline moieties.

Catalytic asymmetric α-alkylation of carbonyl compounds represents a long-standing challenge in synthetic organic chemistry. Herein, we advance a dual biocatalytic platform for the efficient asymmetric alkylation of α-keto acids. First, guided by our recently obtained crystal structures, we develop SgvMVAV as a general biocatalyst for the enantioselective methylation, ethylation, allylation and propargylation of a range of α-keto acids with total turnover numbers (TTNs) up to 4,600. Second, we mine a family of bacterial HMTs from Pseudomonas species sharing less than 50% sequence identities with known HMTs and evaluated their activities in SAM regeneration. Our best performing HMT from P. aeruginosa, PaHMT, displays the highest SAM regeneration efficiencies (TTN up to 7,700) among HMTs characterized to date. Together, the synergistic use of SgvMVAV and PaHMT affords a fully biocatalytic protocol for asymmetric methylation featuring a record turnover efficiency, providing a solution to the notorious problem of asymmetric alkylation.

A new, eco-friendly process utilising the green solvent propylene carbonate (PC) has been developed to perform N-alkylation of N-, O- and/or S-containing heterocyclic compounds. PC in these reactions served as both the reagent and solvent. Importantly, no genotoxic alkyl halides were required. No auxiliary was necessary when using anhydrous PC. Product formation includes nucleophilic substitution with the concomitant loss of water and carbon dioxide. Substrates prepared, including the newly invented PROTAC drugs, are widely used. [ABSTRACT FROM AUTHOR]

Functionalization of C-H bonds has emerged as a powerful strategy for converting inert, nonfunctional C-H bonds into their reactive counterparts. A wide range of C-H bond functionalization reactions has become possible by the catalysis of metals, typically from the second row of transition metals. First-row transition metals can also catalyze C-H functionalization, and they have the merits of greater earth-abundance, lower cost and better environmental friendliness in comparison to their second-row counterparts. C-H bond alkylation is a particularly important C-H functionalization reaction due to its chemical significance and its applications in natural product synthesis. This review covers Ni-catalyzed C-H bond alkylation reactions using alkyl halides and olefins as alkyl sources. [ABSTRACT FROM AUTHOR]

A polyethylene (PE) film surface modification method is proposed via benzoic acid (BA) alkylation grafting to improve the surface affinity to polar substances. The procedure involves sequentially spraying AlCl3 and BA onto the heat-softened PE surface. The occurrence of the alkylation reaction was evaluated through comparative chemical, morphological, and thermal analyses. It was demonstrated that the grafting reaction of BA onto the PE film surface took place, limited to the surface layer, while preserving the bulk properties of PE. The reaction resulted in the formation of aluminum benzoate complexes, which improved the surface affinity to polar compounds. The impact of grafting on the surface properties of PE was further assessed by comparing the behavior of PE films treated with BA and untreated PE films when painted with watercolors. The PE film grafted with BA exhibited increased affinity towards watercolors, providing strong evidence of a change in surface polarity from hydrophobic to hydrophilic. These findings indicate that the proposed methodology effectively renders the PE surface paintable, even with non-toxic water-based inks, making it suitable for applications such as packaging. [ABSTRACT FROM AUTHOR]

Mass spectrometry has become the most prominent yet evolving technology in quantitative proteomics. Today, a number of label-free and label-based approaches are available for the relative and absolute quantification of proteins and peptides. However, the label-based methods rely solely on the employment of stable isotopes, which are expensive and often limited in availability. Here we propose a label-based quantification strategy, where the mass difference is identified by the differential alkylation of cysteines using iodoacetamide and acrylamide. The alkylation reactions were performed under identical experimental conditions; therefore, the method can be easily integrated into standard proteomic workflows. Using high-resolution mass spectrometry, the feasibility of this approach was assessed with a set of tryptic peptides of human serum albumin. Several critical questions, such as the efficiency of labeling and the effect of the differential alkylation on the peptide retention and fragmentation, were addressed. The concentration of the quality control samples calculated against the calibration curves were within the ±20% acceptance range. It was also demonstrated that heavy labeled peptides exhibit a similar extraction recovery and matrix effect to light ones. Consequently, the approach presented here may be a viable and cost-effective alternative of stable isotope labeling strategies for the quantification of cysteine-containing proteins. [ABSTRACT FROM AUTHOR]

We demonstrated herein an electrochemical dearomatizative alkylation of Katritzky salts, wherein Katritzky salts were harnessed as both radical acceptors and donors. A wide range of privileged dihydropyridine scaffolds was constructed with good to excellent yields. Cyclic voltammetry (CV) and electron paramagnetic resonance (EPR) results confirmed the key intermediates-dihydropyridine radicals and gram-scale reaction highlighted the practical and sustainable feature of the newly developed protocol. [ABSTRACT FROM AUTHOR]

Catalysed C–H activation has emerged as a transformative platform for molecular synthesis and provides new opportunities in drug discovery by late-stage functionalisation (LSF) of complex molecules. Notably, small aliphatic motifs have gained significant interest in medicinal chemistry for their beneficial properties and applications as sp3-rich functional group bioisosteres. In this context, we disclose a versatile strategy with broad applicability for the ruthenium-catalysed late-stage meta-C(sp2)–H alkylation of pharmaceuticals. This general protocol leverages numerous directing groups inherently part of bioactive scaffolds to selectivity install a variety of medicinally relevant bifunctional alkyl units within drug compounds. Our strategy enables the direct modification of unprotected lead structures to quickly generate an array of pharmaceutically useful analogues without resorting to de novo syntheses. Moreover, productive late-stage modulation of key biological characteristics of drug candidates upon remote C–H alkylation proves viable, highlighting the major benefits of our approach to offer in drug development programmes. Installation of small aliphatic motifs within pharmaceuticals provides a medicinally relevant tool in drug discovery programmes. Here, the authors report a late-stage meta-C–H alkylation method facilitating the biological properties modulation of therapeutic agents. [ABSTRACT FROM AUTHOR]

A four-step synthesis process of bifunctional, noncovalent organocatalysts based on the chiral (1R,2R)-cyclohexane-1,2-diamine scaffold containing a 1,2-benzenediamine H-bond donor was developed. Nucleophilic aromatic substitution of the 2-fluoronitrobenzene derivative with the commercial (1R,2R)-cyclohexane-1,2-diamine was followed by selective alkylation of the primary amino group, reduction of the aromatic nitro group and final derivatization of the primary aromatic amino group, i.e., acylation, sulfonation, reductive alkylation and arylation, leading to the four subtypes of organocatalysts. All new compounds were fully characterized. The prepared organocatalysts (32 examples) were tested in the Michael addition of acetylacetone to trans-β-nitrostyrene, yielding the addition product with incomplete conversions (up to 93%) and enantioselectivities of up to 41% ee. [ABSTRACT FROM AUTHOR]

The side chain alkylation of toluene with methanol was studied on a series of CsX catalysts prepared by varying the Cs species and ion exchange conditions. The effects of various parameters, such as the exchanging temperatures and times on the adsorption/activation properties of different CsX catalysts, were investigated by combining a variety of characterization means for understanding the role of Cs species in the side chain alkylation reaction. On the basis of the various characterization results and their related literature results, it can be proposed that the Cs ions located on the ion-exchanged sites of X zeolites could effectively adsorb and activate toluene molecularly through modifying the basicity of framework oxygen, whereas the cluster of cesium oxide (Cs2O) could ensure the effective conversion of methanol into formaldehyde. Additionally, Cs ions can promote the production of monodentate formate, which enhances the selectivity of styrene. However, too much Cs2O will lead to the excessive decomposition of methanol into CO2, CO, and H2, thus inhibiting the production of styrene. In summary, the presence of suitable amounts of Cs ions and Cs2O clusters plays a significant role in the formation of the side chain products of styrene and ethylbenzene. [ABSTRACT FROM AUTHOR]

The transient electron donor–acceptor (EDA) complex has been an emerging area in the photoinduced organic synthesis field, generating radicals without exogenous transition‐metal or organic dye‐based photoredox catalysts. The catalytic platform to form suitable photoactive EDA complexes for photochemical reduction reactions remains underdeveloped. Herein, a general photoinduced reductive alkylation via the EDA complex strategy is described. A simple yet multifunctional system, triphenylphosphine and iodide salt, promotes the photoinduced decarboxylative hydroalkylation, and reductive defluorinative decarboxylative alkylation of trifluoromethyl alkenes, to access trifluoromethyl alkanes and gem‐difluoroalkenes. Moreover, decarboxylative hydroalkylation can be applied to more kinds of electron‐deficient alkenes as a general Giese addition reaction. [ABSTRACT FROM AUTHOR]

In the title compound, C17H12N2O,the quinoxaline moiety shows deviations of 0.0288 (7) to -0.0370 (7) Å from the mean plane (r.m.s. deviation of fitted atoms = 0.0223 Å). In the crystal, corrugated layers two molecules thick are formed by C--H⋯N hydrogen bonds and π-stacking interactions. [ABSTRACT FROM AUTHOR]

Carbocations, which are positively charged highly electrophilic intermediates, are efficacious for the direct alkylation of low-reactive nucleophiles. The utilization of carbocations in SN1 reactions relies on the activation of their precursors in the presence of a nucleophile. However, undesirable interactions between the nucleophile and the leaving group activator limit the scope of acceptable nucleophiles. Here we report a strategy to conduct SN1 reactions involving unstable carbocations in an alternative stepwise procedure, which was demonstrated by the benzylation of various neutral nucleophiles. In the first step, carbocations were accumulated in a nucleophile-free solution in the form of carbocationoids utilizing the coordinative stabilization of triazinediones. Subsequently, the addition of these solutions in the second step enabled room-temperature alkylation without the need for acidic additives. This methodology overcomes the inherent challenges of carbocations in SN1 reactions. Carbocations are highly electrophilic intermediates involved in SN1 reactions, such as the direct alkylation of low-reactivity nucleophiles, however, in situ activation of leaving groups in such reactions remains challenging due to the unstable nature of the carbocations, leading to cross-reactivity between nucleophiles and leaving group activators. Here, the authors develop a two-step procedure to avoid such cross-reactivity: they generate carbocationoids as coordinatively stabilized carbocations in one nucleophile-free solution, and then complete the alkylation in another reaction vessel under mild conditions. [ABSTRACT FROM AUTHOR]

Transition metal‐catalyzed direct decarboxylative transformations of aromatic carboxylic acids usually require high temperatures, which limit the substrate's scope, especially for late‐stage applications. The development of the selective decarbonylative of carboxylic acid derivatives, especially the most fundamental aroyl chlorides, with stable and cheap electrophiles under mild conditions is highly desirable and meaningful, but remains challenging. Herein, a strategy of nickel‐catalyzed decarbonylative alkylation of aroyl chlorides via phosphine/nitrogen ligand relay is reported. The simple phosphine ligand is found essential for the decarbonylation step, while the nitrogen ligand promotes the cross‐electrophile coupling. Such a ligand relay system can effectively and orderly carry out the catalytic process at room temperature, utilizing easily available aroyl chlorides as an aryl electrophile for reductive alkylation. This discovery provides a new strategy for direct decarbonylative coupling, features operationally simple, mild conditions, and excellent functional group tolerance. The mild approach is applied to the late‐stage methylation of various pharmaceuticals. Extensive experiments are carried out to provide insights into the reaction pathway and support the ligand relay process. [ABSTRACT FROM AUTHOR]

In the title compound, C31H24N4O2, the quinoxaline units are distinctly non-planar and twisted end-to-end. In the crystal, C--H…O and C--H…N hydrogen bonds link the molecules into chains extending along the a-axis direction. The chains are linked through π-stacking interactions between inversion-related quinoxaline moieties. [ABSTRACT FROM AUTHOR]

Intramolecular cycloadditions have the great advantage of forming two rings simultaneously. We report the use of intramolecular [3 + 2] cycloaddition of the nitrile oxide derived from an N-propargylbenzimidazole oxime in the synthesis of a hitherto unreported tetracyclic isoxazole-containing ring system bearing "6-5-5-5"-membered ring fusions. The initial condensation was achieved through reaction of o-phenylenediamine with ethyl diethoxyacetate, followed by alkylation with propargyl bromide, deprotection of the acetal to the aldehyde, formation of an aldoxime, and intramolecular nitrile oxide cycloaddition (INOC). Characterization of the aldoxime and tetracyclic isoxazole is included herein. [ABSTRACT FROM AUTHOR]

Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by Kelch-like ECH-associated protein 1 (Keap1) alkylation plays a central role in anti-inflammatory therapy. However, activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified. Deoxynyboquinone (DNQ) is a natural small molecule discovered from marine actinomycetes. The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1. DNQ exhibited significant anti-inflammatory properties both in vitro and in vivo. The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α, β-unsaturated amides moieties by a chemical reaction between DNQ and N -acetylcysteine. DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway. Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation. The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry. DNQ triggered the ubiquitination and subsequent degradation of Keap1 by alkylation of the cysteine residue 489 (Cys489) on Keap1-Kelch domain, ultimately enabling the activation of Nrf2. Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α, β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain, suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies. [Display omitted] • Small molecule DNQ exhibits potent anti-inflammatory effects via activation of Nrf2. • Target of DNQ was elucidated with a synthesized probe combined with Click Chemistry. • DNQ activates Nrf2 through alkylation and ubiquitination of Keap1-Kelch domain. • DNQ loses the anti-inflammatory capacity when site mutation of Keap1 at Cys489. [ABSTRACT FROM AUTHOR]

Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies. [ABSTRACT FROM AUTHOR]

Abstract In previous works, we demonstrated that tertiary 3‐chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions. Herein, we report the synthesis of novel secondary 3‐chloropiperidine analogues. The synthesis incorporates a new procedure to monochlorinate unsaturated primary amines utilizing N‐chlorosuccinimide, while carefully monitoring the temperature to prevent dichlorination. Furthermore, we successfully isolated highly strained bicyclic aziridines by treating the secondary 3‐chloropiperidines with a sufficient amount of base. We conclude this work with a DNA cleavage assay as a proof of principle, comparing our previously known substrates to the novel compounds. In this, the secondary 3‐chloropiperidine as well as the isolated bicyclic aziridine, proved to be more effective than their tertiary counterpart.

Diaryl difluoromethanes are valuable targets for medicinal chemistry because they are bioisosteres of diaryl ethers and can function as replacements for diaryl methane, ketone, and sulfone groups. However, methods to prepare diaryl difluoromethanes are scarce, especially methods starting from abundant aryl halides. We report the Pd-catalyzed aryldifluoromethylation of aryl halides with aryldifluoromethyl trimethylsilanes (TMSCF2 Ar). The reaction occurs when the catalyst contains a simple, but unusual, dialkylaryl phosphine ligand that promotes transmetallation of the silane. Computational studies show that reductive elimination following transmetallation occurs with a low barrier, despite the fluorine atoms on the α-carbon, due to coordination of the difluorobenzyl π-system to palladium. The co-development of a cobalt-catalyzed synthesis of the silanes broadened the scope of the process including several applications to the synthesis biologically relevant diaryl difluoromethanes.

ABSTRACTUpregulation of Sirtuin Type 1 (SIRT1), a nicotinamide adeninedinucleotide (NAD+)-dependent deacetylase, has been proved to protect against ample ocular diseases, while its effect on retinitis pigmentosa (RP) has not been illustrated. The study was aimed to explore the impacts of resveratrol (RSV), a SIRT1 activator, on the photoreceptor degeneration in a rat model of RP induced by N-methyl-N-nitrosourea (MNU), an alkylation. The rats were induced RP phenotypes via the intraperitoneal injection of MNU. The electroretinogram was conducted and revealed that RSV could not prevent the decline of retinal function in the RP rats. The optical coherence tomography (OCT) and the retinal histological examination were performed and showed that the reduced thickness of the outer nuclear layer (ONL) was not preserved by RSV intervention. The immunostaining technique was applied. Afther the MNU administration, the number of the apoptotic photoreceptors in the ONL throughout the retinasand the number of microglia cells present among the outer part throughout the retinas were not significantly reduced by RSV. Western blotting was also performed. The data showed that the level of SIRT1 protein was decreased after MNU administration, while RSV was not able to obviously alleviate the downregulation. Our data together indicated that RSV was not able to rescue the photoreceptor degeneration in the MNU-induced RP rats, which might be due to the MNU-induced consumption of the NAD+.