Ketone Moiety Research Articles

Microwave assisted synthesis of novel spiro diarylidenes and their antimicrobial assay

A rapid and high yield microwave assisted synthesis of a series of novel 7,9-bis-(arylidene)-4-methyl-2,6,10-triphenyl-2,3-diazaspiro[4,5]dec-3- -ene-1,8-dione has been explored. The spiro diarylidene derivatives having nitrogen atom and ?,?-unsaturated ketone moiety were synthesized by aldol condensation between 4-methyl-2,6,10-triphenyl-2,3-diazaspiro[4,5]dec-3-ene-1,8- -dione and corresponding aryl aldehydes followed by dehydration. The synthesized series of novel spirodiarylidene derivatives were characterized using IR, 1H- and 13C-NMR and mass spectra. Density functional theory (DFT) study was performed by Gaussian 09 software. The antimicrobial activities of the synthesized derivatives were evaluated against two pathogenic Gram-positive and Gram-negative bacterial strain and three pathogenic fungal species by disk diffusion method. The minimum inhibitory concentration was determined by the microbroth dilution technique. The results of the present study demonstrated that the examined compounds marked 5a and 5c, possessing 4-NO2 and 5-Br-2-OH substituents, are found to be more active against Gram-positive bacterium Staphylococcus aureus, 8 and 16 ?g mL-1, respectively, and moderately active against Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli, compared to other synthetic derivatives. However, none of the synthesized derivatives showed any activity against Streptococcus pyrogenes. Compound 5e, possessing 2,4,6-(OCH3)3C6H3 moiety, exhibited broad spectrum activity against all fungal strains under study, but showed no antibacterial activity.

Photoinduced rearrangement of α-(2-nitrophenyl)ketones.

Photoirradiation of α-(2-nitrophenyl)ketones produced cyclic hydroxamates. The reaction proceeded via photoinduced oxygen transfer from the nitro group to the benzylic position, forming an α-hydroxyketone having a nitroso group. Subsequent addition of the nitroso group to the ketone moiety and the concomitant cleavage of the C-C σ bond between the carbonyl group and the benzyl position produced hydroxamic acid, which underwent formation of a hemiacetal to give cyclic hydroxamate.

Identification of limonoids from Walsura yunnanensis and evaluation of their cytotoxicity against cancer cell lines

Three new limonoids, walsurauias A-C (1–3), along with four known ones, were isolated from the leaves and twigs of Walsura yunnanensis C. Y. Wu. Their structures were determined on the basis of comprehensive spectroscopic data analysis. The new limonoids were screened for their cytotoxic activity (IC50 0.81–5.73 μM) against four human cancer cell lines, including A549, HepG2, HCT116 p21KO and CNE-2. And α,β-unsaturated ketone moieties in rings A and B are essential for their cytotoxic activity. Selected compounds were further investigated. Compounds 1–3 effectively induced G2/M cell cycle arrest and apoptosis in a dose-dependent manner in cancer cells. In addition, compounds 1–3 inhibited the colony formation and compounds 2 and 3 suppressed the migration of cancer cells.

Discovery of a Series of Pyrimidine Carboxamides as Inhibitors of Vanin-1.

A diaryl ketone series was identified as vanin-1 inhibitors from a high-throughput screening campaign. While this novel scaffold provided valuable probe 2 that was used to build target confidence, concerns over the ketone moiety led to the replacement of this group. The successful replacement of this moiety was achieved with pyrimidine carboxamides derived from cyclic secondary amines that were extensively characterized using biophysical and crystallographic methods as competitive inhibitors of vanin-1. Through optimization of potency and physicochemical and ADME properties, and guided by co-crystal structures with vanin-1, 3 was identified with a suitable profile for advancement into preclinical development.

Nickel-Catalyzed Allylic Defluorinative Cross-Electrophile Coupling with Cycloalkyl Silyl Peroxides as the Alkyl Source.

Herein we demonstrate the first successful application of cycloalkyl silyl peroxides (CSP) as an electrophilic coupling partner in the cross-electrophile coupling reaction. Diverse CSP are efficiently cross-coupled with an array of α-trifluoromethyl alkenes under the catalysis of nickel with the assistance of zinc as the reducing agent. This method allows the use of unstrained CSP as the carbonyl-containing alkyl source in the allylic defluorinative reaction, to access a variety of gem-difluoroalkenes bearing a pendent ketone moiety with high functionality tolerance.

Screening of Promising Chemotherapeutic Candidates from Plants against Human Adult T-Cell Leukemia/Lymphoma (VII): Active Principles from Thuja occidentalis L.

During the screening of novel chemotherapeutic candidates from plants against adult T-cell leukemia/lymphoma, we identified that the extracts of Thuja occidentalis (Cupressaceae) showed potent anti-proliferative activity in MT-1 and MT-2 cells. Therefore, we attempted to isolate the active components from this plant. We isolated and identified 32 compounds (1–32; eight lignans, 18 terpenoids, and six flavonoids) from the extracts of the leaves and cones. Their structures were determined by spectroscopic analysis. Several of the isolated compounds inhibited the growth of both cell lines. Lignans showed more potent activity than other classes of compounds. A comparison of the activities of compounds 1–8 revealed that the presence of a trans-lactone (linkage of C-6 to C-7) correlated with increased activity. Diterpenes showed moderate activity, and the presence of a ketone moiety at the C-7 position correlated with increased activity in compounds 12–21. In addition, biflavones showed moderate activity, and the presence of methoxy functions appeared to influence the activity of these compounds. Several lignans were lead compound of anti-cancer reagent (etoposide). In conclusion, not only lignans, but also diterpenes and/or biflavones, may be promising candidates for the treatment of adult T-cell leukemia/lymphoma.

Cover Feature: Weinreb Amide, Ketone and Amine as Potential and Competitive Secondary Molecular Stations for Dibenzo‐[24]Crown‐8 in [2]Rotaxane Molecular Shuttles (Chem. Eur. J. 70/2021)

A chemical way to bistable molecular shuttles that hold a combination of amine, Weinreb amide and/or ketone as secondary stations for dibenzo-[24]crown-8 (DB24C8) is reported. Ketone and amine moieties have similar affinity for DB24C8 that is better than the Weinreb amide has. Hydrogen bonds between DB24C8 and an unhindered axle usually favor a co-conformation; unless steric restrictions, hence the constrained co-conformation, impose a predominance of alternative and unexpected even weaker H-bonds. More information can be found in the Research Article by M. Gauthier and F. Coutrot (DOI: 10.1002/chem.202103805).

A base-controlled switch of SO2 reincorporation in photocatalyzed radical difunctionalization of alkenes

A base-controlled switch of SO2 reincorporation in photocatalyzed radical difunctionalization of alkenes

Expeditious Asymmetric Synthesis of Polypropionates Relying on Sulfur Dioxide-Induced C–C Bond Forming Reactions

For a long time, the organic chemistry of sulfur dioxide (SO2) consisted of sulfinates that react with carbon electrophiles to generate sulfones. With alkenes and other unsaturated compounds, SO2 generates polymeric materials such as polysulfones. More recently, H-ene, sila-ene and hetero-Diels–Alder reactions of SO2 have been realized under conditions that avoid polymer formation. Sultines resulting from the hetero-Diels–Alder reactions of conjugated dienes and SO2 are formed more rapidly than the corresponding more stable sulfolenes resulting from the cheletropic additions. In the presence of a protic or Lewis acid catalyst, the sultines derived from 1-alkoxydienes are ionized into zwitterionic intermediates bearing 1-alkoxyallylic cation moieties which react with electro-rich alkenes such as enol silyl ethers and allylsilanes with high stereoselectivity. (C–C-bond formation through Umpolung induced by SO2). This produces silyl sulfinates that react with carbon electrophiles to give sulfones (one-pot four component asymmetric synthesis of sulfones), or with Cl2, generating the corresponding sulfonamides that can be reacted in situ with primary and secondary amines (one-pot four component asymmetric synthesis of sulfonamides). Alternatively, Pd-catalyzed desulfinylation generates enantiomerically pure polypropionate stereotriads in one-pot operations. The chirons so obtained are flanked by an ethyl ketone moiety on one side and by a prop-1-en-1-yl carboxylate group on the other. They are ready for two-directional chain elongations, realizing expeditious synthesis of long-chain polypropionates and polyketides. The stereotriads have also been converted into simpler polypropionates such as the cyclohexanone moiety of baconipyrone A and B, Kishi’s stereoheptad unit of rifamycin S, Nicolaou’s C1–C11-fragment and Koert’s C16–CI fragment of apoptolidin A. This has also permitted the first total synthesis of (-)-dolabriferol.

Injectable Acylhydrazone-Linked RAFT Polymer Hydrogels for Sustained Protein Release and Cell Encapsulation.

A new class of temperature responsive polymer, termed PADO, is synthesized by reversible addition-fragmentation chain-transfer polymerization. Synthesized from copolymerization of diacetone acrylamide (DAAM), di(ethylene glycol) ethyl ether acrylate, and oligo(ethylene glycol) methyl ether acrylate, PADO polymer phase separates at temperature above its lower critical solution temperature (36-42°C) due to enhanced hydrophobic interactions between the short ethylene glycol side chains. Solution of PADO polymers exhibit injectable shear-thinning properties and reach sol-gel transition rapidly (<5min) at 37°C.Whenthe ketone moieties on DAAM are linked by adipic acid dihydrazdie, PADO polymers form crosslinked and injectable acylhydrazone hydrogels, which are hydrolytically degradable at a mild acidic environment owing to the pH sensitive acylhydrazone bonds. The pH-responsive degradation kinetics can be controlled by tuning polymer contents and ketone/hydrazide ratio. Importantly, the injectable PADO hydrogels are highly cytocompatible and can be easily formulated for pH-responsive sustained protein delivery.

Characterization of an aromatic trifluoromethyl ketone as a new warhead for covalently reversible kinase inhibitor design

An aromatic trifluoromethyl ketone moiety was characterized as a new warhead for covalently reversible kinase inhibitor design to target the non-catalytic cysteine residue. Potent and selective covalently reversible inhibitors of FGFR4 kinase were successfully designed and synthesized by utilizing this new warhead. The binding mode of a representative inhibitor was fully characterized by using multiple technologies including MALDI-TOF mass spectrometry, dialysis assay and X-ray crystallographic studies etc. This functional group was also successfully applied to discovery of a new JAK3 inhibitor, suggesting its potential application in designing other kinase inhibitors.

Structure modification and biological evaluation of indole-chalcone derivatives as anti-tumor agents through dual targeting tubulin and TrxR

Microtubule target agents (MTAs) are widely-used clinical anti-cancer drugs for decades, but the acquired drug resistance severely restricted their application. Thioredoxin reductases (TrxR) was reported to be overexpressed in most tumors and closely related to high risk of cancer recurrence and drug resistance, making it a potential target for anticancer drug discovery. Multi-target-directed ligands (MTDLs) by a single molecule provide a logical and alternative approach to drug combinations. In this work, based on the structure-activity relationships obtained in our previous study, some structure modifications were performed. On one hand, the retained skeleton structure of MTAs endowed its tubulin polymerization inhibition activity, on the other hand, the selenium-containing structure and α,β-unsaturated ketone moiety endowed the TrxR inhibition activity. As results, the newly obtained compounds exhibited superior anti-proliferative activities towards various human cancer cells and drug-resistance cells, and displayed high selectivity towards various human normal cells. The mechanism study revealed that the dual effect of cell cycle arrest triggered by targeting tubulin and the abnormal accumulation of ROS caused by TrxR inhibition eventually lead to cell apoptosis. Notably, compared with the MTA agents CA-4P, and the TrxR inhibitor Ethaselen, the optimized compound 14c, which served as dual-targeting inhibitor of tubulin and TrxR, exerted greatly improved in vivo anti-tumor activity. In summary, 14c deserved further consideration for cancer therapy.

Identification of peroxiredoxin 6 as a direct target of withangulatin A by quantitative chemical proteomics in non-small cell lung cancer

Peroxiredoxin 6 (PRDX6), as a bifunctional enzyme with glutathione peroxidase activity (GPx) and Ca2+-independent phospholipase A2 (iPLA2) activity, has a higher expression in various cancer cells, which leads to the increase of antioxidant properties and promotes tumorigenesis. However, only a few inhibitors of PRDX6 have been discovered to date, especially the covalent inhibitors of PRDX6. Here, we firstly identified Withangulatin A (WA), a natural small molecule, as a novel covalent inhibitor of PRDX6. SILAC-ABPP identified that WA could directly bind to PRDX6 and inactivate the enzyme activity of PRDX6 by the α, β-unsaturated ketone moiety. Moreover, WA also facilitated the generation of ROS, and inhibited the GPx and iPLA2 activities. However, WA-1, with a reduced α, β-unsaturated ketone moiety, had no significant inhibition of the GPx and iPLA2 activities. Biolayer interferometry and LC-MS/MS analysis further demonstrated the selectively covalent binding of WA to the cysteine 47 residue (Cys47) of PRDX6, while mutation of Cys47 blocked the binding of WA to PRDX6. Notably, WA-mediated cytotoxicity and inhibition of the GPx and iPLA2 activities were almost abolished by the deficiency of PRDX6. Therefore, this study indicates that WA is a novel PRDX6 covalent inhibitor, which could covalently bind to the Cys47 of PRDX6 and holds great potential in developing anti-tumor agents for targeting PRDX6.

Design, synthesis and molecular modeling study of substituted indoline-2-ones and spiro[indole-heterocycles] with potential activity against Gram-positive bacteria.

Longstanding and firsthand infectious diseases are challenging community health threats. A new series of isatin derivatives bearing β-hydroxy ketone, chalcone, or spiro-heterocycle moiety, was synthesized in a good yield. Chemical structures of the synthesized compounds were elucidated using spectroscopic techniques and elemental analysis. Antibacterial activities of the compounds were then evaluated in vitro and by in silico modeling. The compounds were more active against Gram-positive bacteria, Staphylococcus aureus (MIC = 0.026-0.226 mmol L-1) and Bacillus subtilis (MIC = 0.348-1.723 mmol L-1) than against Gram-negative bacteria (MIC = 0.817-7.393 mmol L-1). Only 3-hydroxy-3-(2-(2,5-dimethylthiophen-3-yl)-2-oxoethyl)indolin-2-one (1b) was found as active as imipenem against S. aureus (MIC = 0.026 mmol L-1). In silico docking of the compounds in the binding sites of a homology modeled structure of S. aureus histidine kinase-Walk allowed us to shed light on the binding mode of these novel inhibitors. The highest antibacterial activity of 1b is consistent with its highest docking score values against S. aureus histidine kinase.

Discovery of 8,9-seco-ent-Kaurane Diterpenoids as Potential Leads for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a lethal malignancy without safe and effective therapeutic drugs. In this study, the anti-TNBC bioassay-guided isolation of the medicinal plant Croton kongensis followed by the structural modification led to the construction of a small ent-kaurane diterpenoid library (1-25). With subsequent biological screening, 20 highly potent compounds (IC50s < 3 μM) were identified. Among them, 8,9-seco-ent-kaurane 6 displayed comparable activity (IC50s ∼ 80 nM) to doxorubicin but with better selectivity. The analysis of structure-activity relationships suggested that the cleavage of the C8-C9 bond and the presence of α,β-unsaturated ketone moiety were essential for the activity. The mechanistic study revealed that 6 induced apoptosis, autophagy, and metastasis suppression in TNBC cells via inhibition of Akt. In vivo, 6 significantly suppressed the TNBC tumor growth without causing side effects. All these results suggested that 6 may serve as a promising lead for the development of novel anti-TNBC agents in the future.

Synthesis of Enantiopure ω-(4-Fluorophenyl)-6,11-Methylene Lipoxin B4 Methyl Ester

AbstractThe synthesis of Lipoxin B4 analogues (LXB4) to gain access to stabilized inflammation-resolving compounds is an active field of research. Focusing on variation and stabilization of the conjugated E,Z,E,E C6–C13 tetraene moiety of natural LXB4, a methylene bridge introduced between C6 and C11 suppresses any Z/E isomerization of the C8–C9 olefin. Furthermore, rapid ω-oxidation (C20) should be avoided by replacing the C18–C20 segment by an aromatic moiety. Optically active C1–C12 building blocks were accessed from methyl cycloheptatriene-1-carboxylate (C6–C11, C21) and glutaryl chloride (C1–C5) as described earlier. The ω-segment was generated via a five-step sequence starting from 4-arylbutanoic acid. Horner key olefination enabled assembly of the carbon backbone. A final five-step sequence including a chelate Cram reduction of the unsaturated ketone moiety afforded the target ω-aryl 6,11-methylene-LXB4 methyl ester.

Harnessing Additional Capability from in Water Reaction Conditions: Aldol versus Knoevenagel Chemoselectivity

AbstractAldol reaction chemoselectivity, racemic or enantioselective, has not been previously demonstrated in the presence of Knoevenagel active functional groups. Here, we show that unhindered β‐diketones remain unreacted while a ketone moiety undergoes a highly enantioselective aldol desymmetrization resulting in three new stereogenic centers using in water reaction conditions. A mechanistic hypothesis for the chemoselective formation of either aldol or Knoevenagel products is presented. It elucidates how these amino acid catalyzed reactions completely suppress formation of the expected Knoevenagel product under in water (heterogeneous) reaction conditions, but not when water is present as a dissolved cosolvent (homogeneous). Finally, the developed hypothesis reinforces and expands the role of water at an organic‐water interface.magnified image

Synthesis of Sterically Hindered α-Hydroxycarbonyls through Radical-Radical Coupling.

We describe a synthetic approach to sterically hindered α-hydroxy carbonyl compounds through radical-radical coupling. An organic photoredox catalysis reaction converts an aliphatic carboxylic acid and α-ketocarbonyl to a transient alkyl radical and a persistent ketyl radical, respectively, which couple selectively based on the persistent radical effect. This protocol allows the use of primary, secondary, and tertiary aliphatic carboxylic acids to introduce various alkyl substituents onto ketone moieties of α-ketocarbonyls under mild reaction conditions.

Antioxidant studies of 3-(5-(2,4-dichlorophenoxy)-3-methyl-1-phenyl-1Hpyrazole-4-yl)-1-(furan-2-yl)prop-2-en-1-one

Chalcones are flavonoid precursors, abundant in edible plants. The pyrazole moieties in chalcones show various pharmacological activities. Notably, Chalcone-based structures exhibit numerous pharmacological activities like antiinflammatory, antibacterial, antitumor, antioxidant functions because of having α, β-unsaturated ketone moiety. Such broad spectrum biological activities were also observed in several nitrogen containing heterocycles. Among the heterocyclic systems, pyrazole stand unique. All these observations led us to design and synthesize pyrazole fused hybrid thiophenechalcone molecule 3-(5-(2,4-dichlorophenoxy)-3-methyl-1-phenyl-1H-pyrazole-4-yl)-1-(furan-2-yl)prop-2-en-1-one (3a). The synthesis was performed using base catalyzed reaction of pyrazole aldehyde and acetyl furan. Further characterization of the molecule was done by spectroscopy and antioxidant studies. Spectroscopic methods included Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR) and mass spectra (MS). The antioxidant potency of the compound was carried out based on the scavenging activity of 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH). This compound showed moderate free radical scavenging activity of 45.12 %.

Design, synthesis, and anticancer evaluation of novel andrographolide derivatives bearing an α,β-unsaturated ketone moiety

A series of 1,2-didehydro-3-ox-andrographolide derivatives based on two Michael acceptors were designed, synthesized and evaluated for their anticancer activity against two human cancer cell lines (HCT116 and MCF-7). All tested compounds exhibited significant growth inhibitory effect on HCT116 and moderate to good inhibitory effect on MCF-7 cell proliferation. Compound 10b displayed the best inhibitory activities against both HCT116 and MCF-7 cell lines, with IC50 values of 2.49 and 7.80 μM respectively. Preliminary anticancer mechanistic investigation was performed in terms of the cell cycle arrest and cell apoptosis assays of compound 10b against HCT116 using flow cytometry, and the results indicated that 10b blocked the proliferation of HCT116 cells by inducing cell apoptosis in a concentration-dependent manner and arresting cell cycle in G2/M phase.