Β-unsaturated Ketones Research Articles

Discovery of ent-kaurane diterpenoid glucosides as potent analgesics from the leaves of Pieris formosa

To search for structurally novel analgesics from Ericaceae plants, the leaves of Pieris formosa collected at Yichang, Hubei, China, were phytochemically investigated for the first time. A total of fifteen ent-kaurane diterpene glucosides (1–15) including twelve new ones, named forminosides A–L (1–12), were isolated. Their structures were elucidated by comprehensive spectroscopic data analyses, quantum chemical calculations (13C NMR and ECD calculations and DP4+ analysis), and chemical methods. The absolute configures of 1–3, 5–8, 11, and 13 were further determined by single-crystal X-ray diffraction analysis. Forminoside A (1) represents the first 3α-(β-d-glucopyranosyloxy)-11,16-epoxy-ent-kaurane diterpenoid bearing a unique 12-oxa-pentacyclo[9.3.3.01,10.04,9.013,16]heptadecane core. Forminoside J (10) is the first 17-nor-ent-kaurane type diterpenoid from Ericaceae family, while forminoside L (12) represents the first example of 4,5-seco-ent-kaurane diterpenoid glycoside bearing an unusual α-hydroxyl-α,β-unsaturated ketone block. Notably, the structure of mollisside A was revised to 3β-(β-d-glucopyranosyloxy)-16β,17-dihydroxy-ent-kaurane based on the NMR and single-crystal X-ray diffraction data analysis of forminoside C (3). All the isolates 1–15 showed potent analgesic activity in the HOAc-induced writhing test in mice. Among them, compounds 1–3, 5–12, and 15 exhibited significant analgesic effects at a dose of 5.0 mg/kg with the inhibition rates over 50%. Compounds 1, 5, 7, and 9–12 still displayed significant analgesic effects with the inhibition rates exceeding 50% at a lower dose of 1.0 mg/kg. Forminosides J (10) and L (12) still showed significant analgesic potency even at a lower dose of 0.2 mg/kg, comparable to that of the positive control, morphine. This is first report of the analgesic activity of 11,16-epoxy-ent-kaurane diterpenoid. A preliminary structure–activity relationship was explored, providing new clues to design novel analgesics based on the ent-kaurane and related diterpenoids.

Site-Selective Access to Functionalized Pyrroloquinoxalinones via H-Atom Transfer from N═Csp2-H Bonds of Quinoxalinones.

Site-selective hydrogen atom transfer (HAT) from the N═Csp2-H bonds of quinoxaline-2(1H)-ones is a highly attractive but underdeveloped domain. Reported herein is a highly selective, practical, and economically efficient approach for facile assembly of pyrroloquinoxalinones by synergistic photocatalysis and HAT catalysis. The reaction proceeds through bromine radical-mediated HAT of quinoxalinones and imine radical addition to α-cyano-α,β-unsaturated ketones that establishes a cross-coupling/annulation cascade process, resulting in the synthesis of a series of functionalized pyrroloquinoxalinones. This protocol does not require transition metals or excess oxidants and uses easy-to-synthesize starting materials with excellent scalability and broad substrate scope. The establishment of N═Csp2 radical chemistry illustrates great potential for the synthesis of imine-containing molecules that are not possible with some traditional methods.

Michael Acceptor Pyrrolidone Derivatives and Their Activity against Diffuse Large B-cell Lymphoma.

This study aimed to design and evaluate the efficacy of pyrrolidone derivatives as potential therapeutic agents against diffuse large B-cell lymphoma (DLBCL), a common and heterogeneous malignancy of the adult lymphohematopoietic system. Given the limitations of current therapies, there is a pressing need to develop new and effective drugs for DLBCL treatment. A series of pyrrolidone derivatives were synthesized, and their antitumor activities were assessed, particularly against DLBCL cell lines. Structure-activity relationship (SAR) analysis was conducted to identify key structural components essential for activity. The most promising compound, referred to as compound 7, was selected for further mechanistic studies. The expression levels of relevant mRNA and protein were detected by RT-qPCR and Western blotting, and the expression of mitochondrial membrane potential and ROS was detected using flow cytometry for further assessment of cell cycle arrest and apoptosis. The compound 7 exhibited good antitumor activity among the synthesized derivatives, specifically in DLBCL cell lines. SAR analysis highlighted the critical role of α, β-unsaturated ketones in the antitumor efficacy of these compounds. Mechanistically, compound 7 was found to induce significant DNA damage, trigger an inflammatory response, cause mitochondrial dysfunction, and disrupt cell cycle progression, ultimately leading to apoptosis of DLBCL cells. The compound 7 has good antitumor activity and can induce multiple cellular mechanisms leading to cancer cell death. These findings warrant further investigation of the compound 7 as a potential therapeutic agent for DLBCL.

Development of ketalized unsaturated saccharides as multifunctional cysteine-targeting covalent warheads

Multi-functional cysteine-targeting covalent warheads possess significant therapeutic potential in medicinal chemistry and chemical biology. Herein, we present novel unsaturated and asymmetric ketone (oxazolinosene) scaffolds that selectively conjugate cysteine residues of peptides and bovine serum albumin under normal physiological conditions. This unsaturated saccharide depletes GSH in NCI-H1299 cells, leading to anti-tumor effects in vitro. The acetyl group of the ketal moiety on the saccharide ring can be converted to other carboxylic acids in a one-pot synthesis. In this way, the loaded acid can be click-released during cysteine conjugation, making the oxazolinosene a potential multifunctional therapeutic agent. The reaction kinetic model for oxazolinosene conjugation to GSH is well established and was used to evaluate oxazolinosene reactivity. The aforementioned oxazolinosenes were stereoselectively synthesized via a one-step reaction of nitriles with saccharides and conveniently converted into a series of α, β-unsaturated ketone N-glycosides as prevalent synthetic building blocks. The reaction mechanisms of oxazolinosene synthesis were investigated through calculations and validated with control experiments. Overall, these oxazolinosenes can be easily synthesized and developed as cysteine-targeted covalent warheads carrying useful click-releasing groups.

TBAB-catalyzed assisted C-C/C-N bond formations: An efficient approach to dihydrobenzo[b][1,8]naphthyridin derivatives via metal free Cascade annulation

An eco-friendly, metal-free approach for synthesizing dihydrobenzo[b][1,8]naphthyridine derivatives has been established. This method employs ortho-chloroquinolin-α,β-unsaturated ketones as dipolarophiles and acyclic enaminones as amphiphilic nucleophiles, enabling a formal [3 + 3] annulation reaction under phase-transfer catalysis to offed the targeted products. It boasts transition-metal-free conditions, broad functional group compatibility, and straightforward operational procedures.

Discovery of Loureirin analogues with colorectal cancer suppressive activity via regulating cell cycle and Fas death receptor

Chalcones and dihydrochalcones (DHCs) are important bioactive natural products (BNPs) isolated from traditional Chinese medicine. In this study, 13 chalcones were designed with the inspiration of Loureirin, a DHC extracted from Resina Draconis, and synthesized by classical Claisen-Schmidt reactions. Afterwards the reduction reactions were carried out to obtain the corresponding DHCs. Cytotoxicity assay indicated chalcones and DHCs possessed selective cytotoxicity against colorectal cancer (CRC) cells. The preliminary structure-activity relationships (SAR) of these compounds suggested the α, β-unsaturated ketone of the chalcones were crucial for the anticancer activity. Interestingly, compounds 3d and 4c exhibited selective anticancer activity against CRC cell line HCT116 with IC50s of 8.4 and 17.9 μM but not normal cell. Moreover, 4c could also inhibit the migration and invasion of CRC cells. Mechanism investigations showed 4c could induce cell cycle G2/M arrest by regulating cell cycle-associated proteins and could also up-regulate Fas cell surface death receptor. The virtual docking further pointed out that compounds 3d and 4c could nicely bind to the Fas/FADD death domain complex (ID: 3EZQ). Furthermore, silencing of Fas significantly enhanced the proliferation of CRC cells and attenuated the cytotoxicity induced by 4c. These results suggested 4c exerted its anticancer activity possibly regulating cell cycle and Fas death receptor. In summary, this study investigated the anticancer activity and mechanism of Loureirin analogues in CRC, suggesting these compounds may warrant further investigation as promising anticancer drug candidates for the treatment of CRC.

Chromene meroterpenoids from Rhododendron dauricum L. and their anti-inflammatory effects

Rhododendron dauricum L. is a perennial herb belonging to the genus Rhododendron, commonly utilized in formulations for treating coughs and bronchitis, as well as in herbal teas for enhancing immunity and preventing tracheitis. In this study, fifteen previously undescribed chromene meroterpenoids (1a/1b-4a/4b, 5–8, 9b, 10a, 11b), along with twenty-one known compounds were isolated from the dried twigs and leaves of Rhododendron dauricum L. Of these, (−)-rhodonoid E (9b), (+)-confluentin (10a), and (−)-rubiginosin D (11b) were separated for the first time by chiral HPLC separation. The elucidation of their structures, including absolute configurations, was achieved through a combination of techniques such as NMR, HRESIMS, modified Mosher's method and quantum-chemical calculation of electronic circular dichroism (ECD) spectra. Seven pairs of enantiomers, compounds 1a/1b-4a/4b and 9a/9b-11a/11b, were initially obtained in a racemic manner and were further separated by chiral HPLC preparation. The biological assessment of these compounds against NO production was conducted in the LPS-induced RAW264.7 macrophage cells model. Compounds 9a, 9b, and 11a displayed inhibitory rates exceeding 80%, with IC50 values ranging from 8.69 ± 0.94 to 13.01 ± 1.11 μM. A preliminary examination of the structure-activity relationship (SAR) for these isolates indicated that chromene meroterpenoids with α, β-unsaturated ketone carbonyl and Δ12(13) double bond functionalities exhibited enhanced anti-inflammatory properties.

Flash vacuum pyrolysis of steroid propargyl ethers

Owing to its unique rearrangement and cyclization processes via flash vacuum pyrolysis (FVP), the acetylenic moiety has attracted considerable attention by organic chemists as a key building block in the construction of innovative organic architects. Herein, a series of seven steroid propargyl ether precursors have been successfully synthesized and pyrolyzed. Analysis and characterization of the FVP products revealed that the propargyl ethers of phenolic steroids undergo Claisen-rearrangement to give 2-indanone and benzo cyclobutene derivatives, while propargyl ethers of non-aromatic steroids resulted in the corresponding α, β-unsaturated ketones.

Testing of Anti-EMT, Anti-Inflammatory and Antibacterial Activities of 2',4'-Dimethoxychalcone.

Chalcone (1,3-diaryl-2-propen-1-one) is an α, β-unsaturated ketone that serves as an active constituent or precursor of numerous natural substances, exhibiting a broad spectrum of pharmacological effects. In this study, the classical Claisen-Schmidt condensation method was used to synthesize the chalcone derivative 2',4'-dimethoxychalcone (DTC) and evaluate its pharmacological activity. By upregulating the expression of the epithelial cell marker E-cadherin and downregulating the expression of the mesenchymal cell marker vimentin, DTC was found to inhibit transforming growth factor-β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) process in A549 cells, maintaining the cells' epithelial-like morphology and reducing the ability of the cells to migrate. Additionally, DTC demonstrated the ability to decrease the expression levels of nitric oxide (NO), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in RAW264.7 cells, suggesting a possible anti-inflammatory effect. Furthermore, DTC was found to exhibit bacteriostatic activity against Staphylococcus aureus (S. aureus), Proteus vulgaris (P. vulgaris), methicillin-resistant Staphylococcus aureus (MRSA), and Candida albicans (C. albicans), indicating that this chemical may possess broad-spectrum antibacterial activity.

In-silico design and synthesis of curcumin derivatives with enhanced antibacterial and anti-inflammatory activities

Since curcumin and curcuminoids include potential functional groups (such as α, β-unsaturated β-diketone, α, β-unsaturated ketone, and β 0-hydroxy-α, β-unsaturated ketone linked with aromatic rings on both sides), they have been the subject of much discussion. These groups have anti-inflammatory, anti-cancer, and antioxidant qualities, among other bioactivities. Using spectroscopic techniques, novel compounds of curcumin were created and described. This study assessed the antibacterial and anti-inflammatory properties of PDB ID:1IU 4 and PDB ID: 4LHF molecular docking, utilizing in silico models. In terms of binding affinity, compounds C-04 and C-05 they had a greater affinity for the 1IU4 and 4LHF, respectively. Using the Agar disc diffusion plate method (500μg/mL), the derivatized compounds were evaluated for their in-vitro antibacterial properties against two strains: S. Aureus and E. coli. When compared to conventional ciprofloxacin, compound C-04 demonstrated good to exceptional antibacterial efficacy against two distinct strains. they were further tested utilizing the carrageenan-induced paw edema method for anti-inflammatory efficacy. By using the HRBC membrane stabilizing test method, Compound C-05 showed strong anti-inflammatory action, while Compounds C-05 &and C-06 demonstrated noteworthy anti-inflammatory activity.

Facile synthesis, Spectral investigation, in vitro and in silico studies of Thiophenecarboxamide-α,β-unsaturated ketone hybrids

Thiophenecarboxamide-α,β-unsaturated ketone (TCKs) hybrids were synthesized and scrupulously characterized by nuclear magnetic resonance spectroscopy (NMR) by the theoretical and experimental methods, Electrospray ionization mass (ESI-MS), Fourier transform infrared (FT-IR) and ultraviolet-visible spectroscopic techniques by experimental and theoretical methods. The anti-inflammatory and antidiabetic activities were tested for TCKs using protein anti-denaturation and the α-amylase inhibitory methods respectively. The molecular docking studies for TCKs were inspected and data were supported by their molecular parameters that were determined using density functional theory calculations (DFT). The obtained results of TCKs showed a lower band gap and higher electrophilicity index values. Molecular docking studies were investigated against the α-amylase and cyclooxygenase enzymes to compare the tentative results. The TCKs showed very good hydrogen bonding interactions with amino acid residues of the enzymes. In addition, ADMET study, Protox-II toxicity predictions were performed to check the pharmacological properties of TCKs.

Rhodium(III)-Catalyzed Oxidative 1,3-Aryl Migration of α-Aryl Allylic Alcohols.

A Rh(III)-catalyzed oxidative 1,3-aryl migration of α-arylallylic alcohols via Csp2-Csp3 σ bond activation has been developed. This method provides an efficient strategy to allow for allylic alcohol-based skeleton rearrangement, in which various secondary and tertiary α-arylallylic alcohols are rapidly converted to β-aryl-α, β-unsaturated ketones and aldehydes.

SCpRh(III)-Catalyzed Asymmetric C-H Trifluoromethylalkylation of N-Methoxybenzamides with β-Trifluoromethyl-α,β-Unsaturated Ketones.

Asymmetric C-H trifluoromethylalkylation represents a novel and straightforward synthetic method for the construction of chiral CF3-containing compounds. However, the reported examples remain limited, given the challenges of reactivity and enantioselective control. Herein, we report a SCpRh(III)-catalyzed asymmetric aryl and alkenyl C-H trifluoromethylalkylation reaction with β-trifluoromethyl-α,β-unsaturated ketones. The chiral CF3-bearing adducts were obtained in moderate to good yields with high enantioselectivity (up to 81% yield and 96% ee). The reaction features mild conditions and broad substrate scope. The chiral CF3-bearing products could undergo diverse functional group transformations.

Discovery of Pyroptosis-inducing Drugs and Antineoplastic Activity based on the ROS/ER Stress/Pyroptosis Axis.

Pyroptosis, a cell death process triggered by chemotherapy drugs, has emerged as a highly promising mechanism for combating tumors in recent years. As the lead of new drugs, natural products play an important role in the discovery of anticancer drugs. Compared to other natural products, the medicine food homologous natural products (MFHNP) exhibit a superior safety profile. Among a series of MFHNP molecular skeletons, this study found that only benzylideneacetophenone (1) could induce cancer cell pyroptosis. However, the anti-cancer activity of 1 remains to be improved. This study aimed to find a pyroptosis inducer with highly effective antitumor activity by modifying the chalcone structure. To examine the effect of the Michael receptor in compound 1 on the induction of pyroptosis, several analogs were synthesized by modifying the Michael acceptor. Subsequently, the anticancer activity was tested by MTT assay, and morphological indications of pyroptosis were observed in human lung carcinoma NCI-H460 and human ovarian cancer CP-70 cell lines. Furthermore, to improve the activity of the chalcone skeleton, the anticancer group 3,4,5- trimethoxyphenyl was incorporated into the phenyl ring. Subsequently, compounds 2-22 were designed, synthesized, and screened in human lung cancer cells (NCI-H460, H1975, and A549). Additionally, a quantitative structure-activity relationship (QSAR) model was established using the eXtreme Gradient Boosting (XGBoost) machine learning library to identify the pharmacophore. Furthermore, both in vitro and in vivo experiments were conducted to investigate the molecular mechanisms of pyroptosis induced by the active compound. α, β-unsaturated ketone was the functional group of the chalcone skeleton and played a pivotal role in inducing cancer cell pyroptosis. QSAR models showed that the regression coefficients (R2) were 0.992 (A549 cells), 0.990 (NCI-H460 cells), and 0.998 (H1975 cells). Among these compounds, compound 7 was selected to be the active compound. Moreover, compound 7 was found to induce pyroptosis in lung cancer cells by upregulating the expression of CHOP by increasing the ROS level. Furthermore, it effectively suppressed the growth of lung cancer xenograft tumors. Compound 7 exhibits antineoplastic activity by regulating the ROS/ER stress/pyroptosis axis and is a kind of promising pyroptosis inducer.

Catalytic enantioselective [3+2] and [4+2]-annulation of cyclic N-sulfonyl ketimines with γ- or δ-hydroxy-α,β-unsaturated ketones.

A highly efficient asymmetric [3+2] and [4+2]-annulation of cyclic N-sulfonyl ketimines with γ- or δ-hydroxy-α,β-unsaturated ketones has been developed. This innovative reaction employs an organocatalytic approach, utilizing a hydrogen-bonding bifunctional squaramide-based catalyst. The process enables precise synthesis of chiral polyheterotricyclic oxazolidines and 1,3-oxazinane derivatives, revealing intricate structures with incorporated chiral quaternary centers. Remarkably, this method delivers high yields and exceptional enantioselectivities and diastereoselectivities, achieving up to 99% yield, >20 : 1 dr, and >99% ee.

Merging Photocatalytic Doubly-Decarboxylative Csp 2 -Csp 2 Cross-Coupling for Stereo-Selective (E)-α,β-Unsaturated Ketones Synthesis.

A photocatalytic domain of doubly decarboxylative Csp 2 -Csp 2 cross coupling reaction is disclosed. Merging iridium and palladium photocatalysis manifested carbon-carbon bonds in a tandem dual-radical pathway. Present catalytic platform efficiently cross-coupled α, β-unsaturated acids and α-keto acids to afford a variety of α, β-unsaturated ketones with excellent (E)-selectivity and functional group tolerance. Mechanistically, photocatalyst implicated through reductive quenching cycle whereas cross coupling proceeded over one electron oxidative pallado-cycle.

Synthesis of tetrahydroquinolines by gold-catalyzed cascade ring-opening–intramolecular hydroarylation of 2-alkynylazetidines

Cascade ring-opening–cyclization reaction of 2-alkynylazetidines with gold catalyst is described. A variety of substituted tetrahydroquinolines were obtained from the corresponding 2-alkynylazetidines. The reaction proceeds via alcoholitic ring-opening of 2-alkynylazetidines followed by intramolecular hydroarylation of the resulting δ-amino-α,β-unsaturated ketone derivatives.

Synthesis of thiophene-substituted ketones via Manganese-Catalyzed Dehydrogenative Coupling Reaction.

This study reports an efficient and green one-step method for synthesizing thiophene-substituted ketones from 2-thiophenemethanoland ketonesvia dehydrogenative coupling using manganese complexes as catalysts.The manganese complex demonstrated a broad applicability under mild conditions and extended the range of usable substrates. Utilizing this strategy, we carried out an efficient and diverse reaction of ketones with 2-thiophenemethanol, and successfully synthesized a series of thiophene-substituted saturated ketonesand α,β-unsaturated ketones in good isolated yields.

An α, β-unsaturated ketone alkylation and efficient reduction protocol for the synthesis of 3α-hydroxy-3β-methyl-4,4-dimethyl-5α-21-bromo-19-nor-pregnan-20-one

Alkyl-substituted testosterone derivatives are promising platforms for new drug discovery in medicinal chemistry. This approach provides a simple and efficient method for introducing an alkyl substituent to steroids at the C-4 position. In this study, the novel compound 3α-hydroxy-3β-methyl-4,4-dimethyl-5α-21-bromo-19-nor-pregnan-20-one is synthesized from 19-nor-testosterone. The protocol involves methylation of the dienolate, reduction of the alkene, the Grignard reaction of the carbonyl group, a Wittig reaction, hydroboration with BH3, the oxidation and bromination with a 49% overall yield. For the methylation and reduction steps, the effects of the base, solvent, and reactant ratio on the conversion and yield are investigated. The structures of the synthesized compounds are determined by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) (electrospray ionization (ESI)).

Organocatalytic Asymmetric Domino [3+2]-Cycloaddition-Acyl Transfer Reaction between Azomethine Ylides and α-Nitro-α,β-Unsaturated Ketones.

Here in we have developed an organocatalytic asymmetric domino [3+2]-cycloaddition-acyl transfer reaction between in situ generated azomethine ylides and α-nitro-α,β-unsaturated ketones. The desired penta-substituted pyrrolidine products were obtained in high yields and in moderate to good enantio- and diastereoselectivities. Also, an isomerization reaction in silica gel was performed for the formation of another diastereomer in high yields with retention of enantioselectivities.