Acid Derivatives Research Articles

Discovery and optimization of tetrahydroacridine derivatives as a novel class of antibiotics against multidrug-resistant Gram-positive pathogens by targeting type I signal peptidase and disrupting bacterial membrane

Increasing antimicrobial resistance underscores the urgent need for new antibiotics with unique mechanisms. Type I signal peptidase (SPase I) is crucial for bacterial survival and a promising target for antibiotics. Herein we designed and synthesized innovative tetrahydroacridine-9-carboxylic acid derivatives by optimizing the initial hit compound SP11 based on virtual screening. Structure-activity relationship (SAR) studies and bioactivity assessments identified compound C09 as a standout, showing excellent in vitro antimicrobial activity against MRSA and other multidrug-resistant Gram-positive pathogens. C09 targets SPase I with a favorable affinity, disrupts bacterial cell membranes, and eradicates biofilms, reducing resistance risk. In vivo tests in a murine MRSA skin infection model demonstrated significant efficacy. Additionally, C09 has good liver microsome metabolic stability, safe hemolytic activity and mammalian cytotoxicity, as well as a good in vivo safety profile. Overall, our findings highlight the potential of tetrahydroacridine-9-carboxylic acid derivatives as a novel class of antibiotics against multidrug-resistant Gram-positive bacteria.

Synthesis and Thiol-Ene Photopolymerization of Bio-Based Hybrid Aromatic–Aliphatic Monomers Derived from Limonene, Cysteamine and Hydroxycinnamic Acid Derivatives

Three novel bio-based monomers were synthesized through an amidation reaction involving allylated derivatives of coumaric, ferulic and phloretic acid and a diamine obtained from a thiol-ene coupling reaction between limonene and cysteamine. The monomers containing the enone bond of the cinnamic moiety underwent photoisomerization and photocycloaddition reactions upon UV light irradiation. All three monomers were photocured via thiol-ene photopolymerization using a glycerol-derived trifunctional thiol, resulting in fully bio-based poly(amide–thioether)s. The polymers derived from monomers that contain the enone bond exhibited glass transition (Tg) temperatures of 85 °C when a stoichiometric ratio of the thiol was used, whereas polymers in which an excess of thiol was used exhibited Tg temperatures of 61 and 74 °C. The higher Tg of the synthesized polymers, compared with other reported polymers produced from thiol-ene photopolymerizations, was attributed to the combination of the aromatic rings of the cinnamic moiety and the cycloaliphatic ring of limonene, as well as the presence of the amide groups in the polymer, which can induce hydrogen bonding. The development of high Tg polymers from bio-based monomers through thiol-ene photopolymerization represents a significant advancement in the polymer synthesis sector, offering an improved performance and sustainability.

In Silico Evaluation of Some Computer-Designed Fluoroquinolone–Glutamic Acid Hybrids as Potential Topoisomerase II Inhibitors with Anti-Cancer Effect

Background/Objectives: Fluoroquinolones (FQs) are topoisomerase II inhibitors with antibacterial activity, repositioned recently as anti-cancer agents. Glutamic acid (GLA) is an amino acid that affects human metabolism. Since an anti-cancer mechanism of FQs is human topoisomerase II inhibition, it is expected that FQ-GLA hybrids can act similarly. Methods: We designed 27 hypothetical hybrids of 6 FQs and GLA through amide bonds at the 3- and 7-position groups of FQs or via ethylenediamine/ethanolamine linkers at the carboxyl group of the FQ. Hydroxamic acid derivatives were also theoretically formulated. Computational methods were used to predict their physicochemical, pharmacokinetic, or toxicological properties and their anti-cancer activity. For comparison, etoposide was used as an anti-cancer agent inhibiting topoisomerase II. Molecular docking assessed whether the hybrids could interact with the human topoisomerase II beta in the same binding site and interaction sites as etoposide. Results: All the hybrids acted as potential topoisomerase II inhibitors, demonstrating possible anti-cancer activity on several cancer cell lines. Among all the proposed hybrids, MF-7-GLA would be the ideal candidate as a lead compound. The hybrid OF-3-EDA-GLA and the hydroxamic acid derivatives also stood out. Conclusions: Both FQs and GLA have advantageous structures for obtaining hybrids with favourable properties. Improvements in the hybrids’ structure could lead to promising results.

Integration of lipidomics with targeted, single cell, and spatial transcriptomics defines an unresolved pro-inflammatory state in colon cancer

BackgroundOver a century ago, Virchow proposed that cancer represents a chronically inflamed, poorly healing wound. Normal wound healing is represented by a transitory phase of inflammation, followed by a pro-resolution...

Phase I pharmacokinetic study of etmaben, a malonic acid derivative

Introduction. Etmaben is a malonic acid derivative that has shown cardiotropic activity and is a promising candidate for treating ischemic heart disease and chronic heart failure. It is currently undergoing Phase I clinical trials, and its pharmacokinetics have not yet been studied in humans.Aim. The aim of the study is to investigate the pharmacokinetics of Etmaben, film-coated tablets, 300 mg (SPCPU, Russia) in healthy volunteers after fasting administration of different doses following both single and multiple dosing over a 7-day period.Materials and methods. The open-label, non-randomized clinical trial involved 48 healthy volunteers divided into 6 cohorts. Volunteers in cohort 1 received a single dose of 600 mg of etmaben, cohort 2 received 900 mg, and cohort 3 received 1200 mg. Cohorts 4, 5, and 6 received daily doses of 600 mg, 900 mg, and 1200 mg, respectively. Plasma concentrations of etmaben were measured using high-performance liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using Microsoft Excel with the Boomer extension (Department of Pharmacokinetics and Drug Metabolism, Allergan, Irvine, CA 92606, USA).Results and discussion. Pharmacokinetic parameters were calculated for 6 cohorts of 8 volunteers after single and multiple dosing of Etmaben at doses of 600, 900, and 1200 mg. The maximum plasma concentration (Cmax) of etmaben was reached on average within 0.5 h. Cmax values ranged from 2.708 ± 1.461 µg/mL to 19.871 ± 4.415 µg/mL. The maximum half-life was 0.874 ± 0.236 h, with an elimination rate constant not exceeding 1.053 ± 0.149 h–1. The mean residence time (MRT) of etmaben in plasma did not exceed 1.527 ± 0.272 h. The average volume of distribution was above 45 L, and clearance exceeded 42 L, indicating significant tissue distribution and rapid drug elimination. Due to low area under the curve values and high elimination rates, the accumulation of etmaben is minimal.Conclusion. Pharmacokinetic parameters were calculated, and averaged pharmacokinetic profiles were constructed in linear and semilogarithmic coordinates after single and multiple dosing of various etmaben doses. This study represents the first investigation of etmaben pharmacokinetics in humans, paving the way for subsequent clinical trials.

Cytochalasins and orsellinic acid derivatives with cytotoxicity from the soil-derived fungus Trichocladium asperum

Four undescribed cytochalasins (1−4), three undescribed orsellinic acid derivatives (5−7) and two known metabolites including methyl lecanorate (8) and methyl orsellinate (9) were isolated from the solid-state cultivation of a soil-derived fungus Trichocladium asperum SQ2-3 collected in Qinghai-Tibet Plateau. Their structures were elucidated by analysis of NMR (1D and 2D) and mass spectrometry data. The absolute configurations of 1−7 were assigned by a combination of the modified Mosher's method, microscale derivatization and Mo2(OAc)4-induced circular dichroism experiment. Compounds 1, 2, 3 and 6 showed significant cytotoxicity against HL-60, A3494, SMMC-7721, MDA-MB-231 and SW480 cell lines with IC50 values ranging from 4.74 to 15.84 μM, respectively. Meanwhile, compound 1 could obviously damage mitochondrial membrane potential and induce G2/M cell cycle arrest in A549 cells.

Lithocholic Acid’s Ionic Compounds as Promising Antitumor Agents: Synthesis and Evaluation of the Production of Reactive Oxygen Species (ROS) in Mitochondria

The development of a methodology for the synthesis of new compounds with antitumor activity represents a significant and priority task within the field of medicinal chemistry. As a continuation of our research group’s earlier studies on the antitumor activity of ionic derivatives of natural compounds, we have synthesized a series of previously undescribed pyrazole ionic compounds through a series of transformations of lithocholic acid methyl ester. To investigate the biological activity of the newly synthesized lithocholic acid derivatives, a series of modern flow cytometry techniques were employed to assess their cytotoxic activity, effects on the cell cycle, and induction of apoptosis. This included the analysis of alterations in the mitochondrial potential, accumulation of ROS ions in mitochondria, and loss of cytochrome c. These compounds demonstrate promising antitumor activity through their effects on mitochondrial oxidation and phosphorylation processes. These compounds, which we have designated as “soft dissociators”, exhibit enhanced biopharmacological properties relative to the original lithocholic acid molecule.

Three-Component Regioselective Aryl- and Alkenyl-Aminoalkylation of Alkenes via Cooperative Photoredox/Nickel Catalysis.

Recently, metallaphotoredox-catalyzed alkene dicarbofunctionalization reactions have been extensively investigated. Most cases are related to alkyl-arylation processes by conjugate coupling of alkyl radical precursors and aryl electrophiles across alkenes. By contrast, reported examples of alkylvinylation by coupling of vinyl electrophiles are largely limited. Herein, we represent a three-component aminoalkyl-vinylation of alkenes enabled by photoredox/nickel catalysis. This redox-neutral protocol exhibits broad substrate scope and good chemo-, regio- and E/Z-stereoselectivity. A series of valuable α-vinyl γ-amino acid derivatives are conveniently synthesized by the assembly of readily available starting materials.

Three New Depsipeptides, Homiamides A–C, Isolated from Streptomyces sp., ROA-065

Three new depsipeptides, homiamides A–C (1–3), were isolated from a marine sediment-derived strain of Streptomyces sp., ROA-065. The planar structures of homiamides A–C (1–3) were elucidated using mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopic data. The absolute configurations of 1–3 were deduced from the application of the Marfey’s method and GC-MS analysis after formation of the O-trifluoroacetylated (S)-(+)-methyl-2-butyl ester derivatives of amino acids. Compounds 1–3 exhibited weak anti-bacterial activities against both Gram-positive bacteria and Gram-negative bacteria, with compound 1 showing MIC values of 32–64 μg/mL. In antifouling assays, compounds 1 and 2 displayed moderate activity against Micrococcus luteus KCTC 3063, while compound 3 exhibited weak activity against all tested bacteria.

Synthesis, (bio)degradation, and utilization of starch-derived biopolymers in defined hard waters

Climate change is causing a change in local rainfall, which generally brings with it a reduction in rainfall and, consequently, an increase in water hardness. This study explores the suitability and stability of various dextrin-derived polymers for cation removal in simulated hard water conditions. Thermal analysis and Fourier-transform infrared spectroscopy confirm the polymers' thermal stability and proper formation. Biodegradability assessments reveal KLEPTOSE®LINECAPS (LC) and GLUCIDEX2® (Glu2) dextrin with pyromellitic dianhydride (PMDA) derivatives have higher durability as they were able to endure enzymatic activity. Adsorption experiments at 300 and 600 ppm indicate significant variations influenced by monomer and crosslinker types, with linear monomers demonstrating superior performance. Notably, different crosslinkers exhibit varying affinities for calcium and magnesium ions, with PMDA derivatives excelling for magnesium and citric acid (CA) derivatives for calcium. Kinetic and isotherm studies reveal a favorable trend towards quasi-second-order kinetics and Freundlich isotherm models, attributed to cavity heterogeneity and diverse attachment points as evidenced in existing literature. These findings suggest promising applications for these polymers, traditionally employed for organic contaminant removal, as additional filters to mitigate water hardness.

Design, synthesis and bioactivity evaluation of cinnamic acid derivatives as potential anti-inflammatory agents against LPS-induced acute lung injury

Acute lung injury (ALI), a common critical disease in clinical practice, has a mortality rate as high as 30–40 %, yet currently, no effective treatment methods are available. Research on ALI indicated that inhibition of overexpressed inflammatory factors might be a potential treatment for ALI. In this study, a series of cinnamic acid derivatives were obtained by introducing diverse aminothiazole fragments into the natural product cinnamic acid. Among these derivatives, compound 22 displayed excellent activity of inhibiting the release of IL-6 in J774A.1 cells. Moreover, it also ameliorated the LPS-induced ALI in mouse model by suppressing cytokine expression, reducing lung edema and macrophage infiltration. These findings indicated that compound 22 might provide a new lead structure for the development of drugs for ALI.

In vitro and in vivo evaluation of novel ursolic acid derivatives as potential antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA)

The misuse and abuse of antibiotics have led to the increase of drug resistance and the emergence of multi-drug resistant bacteria. Therefore, it is an urgent need to develop novel antimicrobial agents to address this problem. Natural products (NPs) could provide an effective strategy for the discovery of drug due to their wide range of source and biological activities. Ursolic acid (UA) is a naturally occurring compound known for its wide range of biological properties. In this study, a series of UA derivatives were rationally designed and synthesized by incorporating antibacterial potential fragments of benzenesulfonamide and indole, with the aim of obtaining novel UA derivatives for the treatment of bacterial infections. Based on the preliminary screening, UA derivatives 27 (yield of 26 %), containing 4-chlorobenzenesulfonamide and 6-carboxyindole pharmacophores, as well as 34 (yield of 42 %), containing 4-carboxybenzenesulfonamide and unsubstituted indole pharmacophores, were identified as promising antibacterial agents against Staphylococcus aureus, especially for methicillin-resistant Staphylococcus aureus (MRSA), possessing MICs of 1 μM. Furthermore, both of them also displayed low hemolytic activity, non-resistance, and low-toxicity to mammalian cells. In addition, further mechanistic studies revealed that 27 and 34 were able to inhibit and eliminate MRSA biofilm formation, affecting the permeability of bacterial cell membrane, leading to increase intracellular reactive oxygen species (ROS) and ultimately inducing bacterial death. Notably, 27 and 34 also showed promising in vivo efficacy against MRSA in a mouse wound model. These results suggested that 27 and 34 should have promising applications against MRSA infection.

In Vitro and In Vivo Antitumor Activities of Isothiourea and Cinnamic Acid Derivative with NOS/MCT Inhibitory Effect.

This work presents the method of synthesis and physicochemical characterization of isothiourea and cinnamic acid original derivative α-cyano-4-hydroxycinnamate 1-cyclohexanoy-l-2-ethylisothiourea (T1114). In studies of the cytotoxic and antitumor activity of T1114, it has been found that the combination in one molecular structure of NOS-inhibitory fragment (1-cyclohexanoyl-2-ethylisothiourea) and a fragment inhibiting monocarboxylate lactate transporters (MCT) (α-cyano-4-hydroxycinnamic acid) does not modify the cytotoxic activity of bifunctional NOS/MCT-inhibitor T1114 in vitro. But in vivo inhibition of NOS and MCT is able to realize effects on the tumor microenvironment and hypoxic tumor cells. Such structural and functional modification has significantly extended the antitumor activity of the new NOS/MCT inhibitor. The bifunctional compound not only realized a more pronounced antitumor effect, but also prevented the development of hypoxic adaptation in solid Ehrlich carcinoma and acquired the ability to overcome the resistance of mouse cervical cancer (RShM-5). Therefore, the combination of NOS-inhibitory, anti-vasculogenic and hypoxia-oriented toxic effects can create new opportunities in antiangiogenic therapy of malignant neoplasms.

DFT Analysis on Adipic Acid to Propel Creative Advancements in Supercapacitor Technology

The increasing dependence on non-renewable resources for energy storage has accelerated the development of supercapacitor technology, which is now essential to portable devices and electric cars because of its high-power density and quick charge/discharge speed. Optimized geometry, weak C-H‧‧‧O hydrogen bonding interactions inside methylene groups affect bond lengths, and the carboxylic group in adipic acid (ADPI) shortens bond lengths (C14–C15 and C4–C5). DFT simulations demonstrate a fair agreement to experimental data. According to vibrational studies, the O-H and C=O groups' vibrational frequencies are greatly influenced by the reactive hydrogen bonding displayed by the -COOH group in carboxylic acid derivatives. With theoretical values demonstrating significant PED contributions, these interactions reduce the O-H stretching frequency, which is seen as an O-H stretching band at 3405 cm⁻¹ in the FT-IR spectra. In ADPI, atoms interact with neighboring atoms' σ* orbitals (O2-C4), (O12-C14), (C4-C5), (C14-C15), (O1-C4), and (O11-C14) through lone pairs of electrons localized on O1 (LP2), O11 (LP2), O2 (LP1), and O12 (LP1); these interactions have fairly high stabilization values of 33.78, 33.78, 17.91, 17.91, 6.75, and 6.75 kcal/mol, accordingly. Redox peaks and increased specific capacitance with scan rate are revealed by cyclic voltammetry study of ADPI, suggesting efficient electron transport, improved charge storage, and encouraging prospects for electrochemical energy storage applications. ADPI's appropriateness for high-performance electrochemical applications such as supercapacitors is supported by its impedance analysis, which is displayed by a Nyquist plot with a decreased semicircle and a sharp low-frequency slope. This plot demonstrates effective electron transfer, ion diffusion, and capacitive behavior.

Itaconic acid/cellulose-based hydrogels with fire-resistant and anti-freezing properties via vat photopolymerization 3D printing

Hydrogel-born materials have garnered significant interest due to their inherent flame retardant properties and eco-friendly characteristics. In light of the diminishing petroleum reserves and the escalating environmental challenges, there is an urgent impetus to exploit high-value applications of naturally occurring resources and to advance research in sustainable manufacturing technologies. In this vein, we describe an innovative and sustainable methodology for the development and production of flame-retardant hydrogels. This approach perfectly integrates renewable itaconic acid and cellulose derivatives with rapid vat photopolymerization (VP) 3D printing technology, which affords a green and efficient route for materials processing. Specifically, the biomass-based ink formulated for 3D printing demonstrates excellent visible-light curing properties, achieving a maximum double-bond conversion of 45.3 % within 10 min of exposure to visible-light LED under ambient conditions. Moreover, the resultant 3D-printed biomass-based hydrogels exhibit commendable flame-retardant performance, as evidenced by a V-0 flammability rating and a Limiting Oxygen Index (LOI) value of 60.2 %. They also possess desirable mechanical attributes (95.2 kPa) and exceptional thermal stability, enduring high temperatures for up to 12 min. Notably, these hydrogels exhibit remarkable freeze tolerance, maintaining their functionality even at profoundly low temperatures. This study demonstrates a novel strategy for the design and production of flame-retardant materials, contributing to the pursuit of green sustainability.

Green Synthesis and Characterization of Silver Nanoparticles from Minthostachys acris Schmidt Lebuhn (Muña) and Its Evaluation as a Bactericidal Agent Against Escherichia coli and Staphylococus aureus

The search for new synthesis methodologies based on the principles of green chemistry has led to various studies for the production of silver nanoparticles (AgNPs) using extracts from different parts of plants. Based on this, the present study aims to carry out green synthesis (biosynthesis), characterization, and antibacterial evaluation of reduced and stabilized silver nanoparticles (AgNPs) with aqueous extracts of Minthostachys acris in a simple, ecological, and environmentally safe manner. The extraction process of the organic components is performed using two methods: immersion and the agitation of the leaves of Minthostachys acris Schmidt Lebuhn (Muña) at 0.1% for different times (0.5, 1, 3, 6, and 10 min). Compounds such as hydroxycinnamic acid derivatives, quinic, caffeic, rosmarinic acids, and flavonols present in the Muña extract facilitate the formation of AgNPs; this compounds act as a coating and stabilizing agent. The bioactive components from natural resources facilitate the formation of AgNPs, partially or completely replacing the contaminating and toxic elements present in chemical reagents. The biosynthesis is carried out at room temperature for pH 7 and 8. The synthesized AgNPs are characterized by UV-visible spectroscopy to identify the surface plasmon resonance (SPR) band, which shows an absorption peak around 419 nm and 423 nm for pH 7 and p.H 8, respectively, and Fourier-transform infrared spectroscopy (FTIR) to identify the possible biomolecules responsible for bioreduction and stabilization, with a peak at 1634 cm−1. Dynamic light scattering (DLS) shows the hydrodynamic size of the colloidal nanoparticles between 11 and 200 nm, and scanning electron microscopy (SEM) reveals monodisperse AgNPs of different morphologies, mostly nanospheres, while Laser-Induced Breakdown Spectroscopy (LIBS) demonstrates the presence of Ag in the colloidal solution. The evaluation of the bactericidal activity of the AgNPs using the disk diffusion method against Escherichia coli (E. coli) and Staphylococus aureus (S.aureus) shows that the synthesized AgNPs have effective antibacterial activity against E. coli for the extracts obtained at 6 min for both the immersion and agitation methods, respectively. The significance of this work lies in the use of bioactive components from plants to obtain AgNPs in a simple, rapid, and economical way, with potential applications in biomedical fields.

Homologation of Carboxylic Acids Using a Radical-Polar Conjunctive Reagent.

Homologations of organic molecules that add a carbon atom to the substrate are useful in drug discovery to access compounds with improved properties that otherwise present a synthetic challenge. Carboxylic acids are present in many bioactive molecules and are widely available building blocks for chemical synthesis, yet their direct homologation is unknown. This valuable transformation currently necessitates implementation of multistep processes that require the use of carboxylic acid derivatives rather than the native substrates, and commonly involves highly reactive and toxic reagents. Herein, we report the first one-step homologation directly from native carboxylic acids using a novel, bench-stable (1-phosphoryl)vinyl sulfonate reagent under mild conditions. This strategy was applied to a wide range of aliphatic carboxylic acid building blocks and biologically relevant complex molecules to access an array of ester, amide, and carboxylic acid homologues in a single step. The (1-phosphoryl)vinyl sulfonate reagent participates in complementary homologation protocols featuring either radical-chain transfer or organic photoredox catalysis and introduces a new synthon, the distonic acylium radical, for molecular diversification. We anticipate this strategy, which addresses a long-standing challenge in organic synthesis, will expedite drug discovery by enabling the rapid synthesis of diversified homologues.

Wound Healing Potential of Herbal Hydrogel Formulations of Cedrus brevifolia Extracts in Mice.

Wound healing stands as a paramount therapeutic pursuit, imposing significant challenges on healthcare, particularly for vulnerable populations. Cedrus brevifolia, a species endemic to Cyprus, thrives in the Tripylos region, commonly known as Cedar Valley, within the Paphos forest. Despite its endemism, this species exhibits negligible genetic divergence from its Mediterranean related species. This study aims to investigate the potential of C. brevifolia resin and bark extracts in promoting wound healing in a mouse model. Previous in vitro investigations have elucidated the antioxidant and anti-inflammatory potential of extracts and isolates derived from the title plant, warranting further exploration in an in vivo setting. This experimental design employed 40 male SKH-hr2 black and brown mice aged 2-4 months. Wounds measuring 1 cm2 were meticulously induced in the anesthetized mice and the potential healing effect of the herbal hydrogel formulations was evaluated. The healing potential of the C. brevifolia extracts was rigorously assessed through the daily application of gel formulations containing resin concentrations of 5% and 10% w/w, alongside sapwood and heartwood extracts at concentrations of 0.5% and 1% w/w. The evaluation of the treatments encompassed a multifaceted approach, incorporating clinical observations, skin biophysical parameter assessments utilizing an Antera 3D camera, and FT-IR spectroscopy, in addition to histopathological examination. The chemical compositions were also investigated through NMR and bio-guided isolation. The most prominent herbal hydrogel preparation proved to be the 10% resin, followed by the sapwood at 1%. The chemical analysis unveiled abietic acid, manool, and lariciresinol derivatives that potentially contributed to the observed results. Bridging the gap between in vitro observations and in vivo outcomes attempts to shed light on the potential therapeutic benefits of C. brevifolia hydrogels in wound care.

Novel Peptide-Drug Conjugates with Dual Anticancer Activity.

Cationic antimicrobial peptides (AMPs), also called host defence peptides, have established antimicrobial and anticancer activities. Conjugation of an AMP to a bioactive molecule with complementary activity can address some of the clinical limitations of the peptide candidate. This approach has been particularly applied in antimicrobial applications of AMPs, but it remains relatively less explored in the generation of anticancer candidates. In this study, two usnic acid derivatives, based on hydrazinothiazole and benzylidenefuranone pharmacophore moieties, respectively, were conjugated to L-K6, a lysine/leucine-rich AMP, through a new pyrazole ligation intrinsically driven by the cargo molecule. Both components, the usnic acid derivative and the peptide, are selectively active against cancer cells, by targeting the human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) and through DNA damage, respectively. The two conjugates, based on a hydrazone linkage, exhibited pleiotropic effects, ranging from reduction in the activity of the parent drugs to their conservation or even enhancement. Notably, the conjugates retained some anti-TDP1 activity and displayed intermediate, or even higher, cytotoxicities against glioblastoma cells, compared to their individual components.

N-Heterocyclic Carbene Catalyzed Reactions Involving Acetylenic Breslow and/or Acylazolium as Key Intermediates.

N-heterocyclic carbene (NHC) organocatalysis has been developed as a powerful tool in modern synthetic chemistry. NHC catalytic activation of ynals and alkynoic acid derivatives provided versatile reactions that involve acetylenic Breslow and/or acylazolium as key intermediates, and diverse transformations have been established for access to molecules with unique skeletons in efficient fashions. Herein we summarize the recent achievements in NHC-catalyzed reactions involving acetylenic Breslow and/or acylazolium intermediates. Different reactions belonging to three catalytic modes, including (1) conjugate additions to acetylenic Breslow derived α,β-unsaturated acylazolium intermediates, (2) β-umpolung of ynals via acetylenic Breslow intermediates, and (3) conjugate additions to acetylenic acylazolium intermediates, are emphasized with examples and plausible mechanisms cited to guide a better understanding.