RESUMEN
A benign electrochemical method to access 6-methylphenanthridines from 2-isocyanobiaryls using N,N-dimethylformamide (DMF) as a methyl source is reported. The protocol operates at ambient temperature without the need for harmful methylating reagents. Mechanistic studies suggested that DMF delivered a methylene synthon, followed by reduction at the cathode and tautomerization. The method offers environmental benefits by avoiding metal-based reagents and harsh conditions.
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The structures of potent cytotoxic cycloheptapeptides, mallotumides A-C (1-3, respectively) isolated from the roots of Mallotus spodocarpus Airy Shaw, were elucidated by extensive spectroscopic analysis. The absolute configuration of 1 was determined by single-crystal X-ray crystallographic data. All three cycloheptapeptides exhibited potent cytotoxicity against various cancer cell lines with IC50 values ranging from 0.60 to 4.02 nM.
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Antineoplásicos , Mallotus (Planta) , Péptidos Cíclicos , Línea Celular Tumoral , Cristalografía por Rayos X , Mallotus (Planta)/química , Estructura Molecular , Raíces de Plantas/química , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacologíaRESUMEN
Base-catalyzed diastereodivergent thia-Michael addition of thiols to chiral ß-trifluoromethyl-α,ß-unsaturated N-acylated oxazolidin-2-ones is reported. By tuning the base-catalyst (i-Pr2NEt, DABCO, or P2-t-Bu), a range of chiral thia-Michael adducts was synthesized in good yields with high diastereoselectivities. A plausible mechanism was proposed on the basis of the experimental results. This work is complementary to the existing methods offering advantages, e.g., switchable diastereoselectivity using a readily synthesized chiral starting material, a cheap and readily available base catalyst, and a simple and practical operation, enabling synthetic application in organic synthesis.
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The epidermal growth factor receptor (EGFR) has been considered a potential target for lung cancer therapy due to its essential role in regulating the survival and proliferation of cancer cells. Although erlotinib, a potent EGFR tyrosine kinase (EGFR-TK) inhibitor, has been used as the first-line drug for lung cancer treatment, acquired drug resistance caused by the T790M secondary mutation of EGFR-TK inevitably develops after a median response duration of 9-13 months. Thus, the search for promising compounds to effectively target EGFR-TK has become an imperative necessity. In this study, the kinase inhibitory activities of a series of sulfonylated indeno[1,2-c]quinolines (SIQs) against EGFR-TK were experimentally and theoretically investigated. Among the 23 SIQ derivatives studied, eight compounds showed enhanced EGFR-TK inhibitory activity (IC50 values of ca. 0.6-10.2 nM) compared to the known drug erlotinib (IC50 of â¼20 nM). In a cell-based assay in human cancer cell lines with EGFR overexpression (A549 and A431 cells), the eight selected SIQs all showed more significant cytotoxicity against A431 than A549 cells, consistent with the higher EGFR expression in A431 cells. Molecular docking and FMO-RIMP2/PCM calculations revealed that SIQ17 occupies the ATP-binding site of EGFR-TK, where its sulfonyl group is mainly stabilized by C797, L718, and E762 residues. Triplicate 500 ns molecular dynamics (MD) simulations also confirmed the binding strength of SIQ17 in complex with EGFR. Overall, the potent SIQ compounds obtained in this work could be further optimized for developing novel anticancer drug candidates targeting EGFR-TK.
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For the first time, a series of vinyl sulfone-NH2-based push-pull fluorophores (4a-4d) were introduced for their potential use in biological applications. The fluorophores 4a-4d were readily synthesized upon reduction of the corresponding vinyl sulfones-NO2 (3a-3d), which were prepared by sulfonylation of nitrostyrene. Both types of probes can be prepared in high yields through a few steps with minimal cost. In diverse solvents, probes 4a-4d exhibited fluorescence with strong emission peaking around 403-490 nm. Additionally, the fluorescence intensity of probe 4d rose approximately 85-fold with increasing viscosity. The probes 4a-4d demonstrated good stability and photostability in a broad pH range. Moreover, probes 4a-4d showed significantly improved biocompatibility compared to those derived from 3a-3d. For cell imaging applications, the developed probes 4a-4d exhibited much stronger blue fluorescence in cancer cells (HepG2) compared to 3a-3d. In addition, probes 4a-4d exhibited low cytotoxicity within 24 h toward both cancer and normal cells (HEK-293). Interestingly, probe 4d showed great sensitivity to viscosity in cancer cells. As a result, readily prepared vinyl sulfone-NH2-based push-pull fluorophores (4a-4d) offer a promising strategy for further development as cancer cell staining agents.
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Persulfate-promoted radical cascade trifluoromethylthiolation and cyclization of 3-alkyl-1-(2-(alkynyl)phenyl)indoles with AgSCF3 were investigated. This protocol provides a novel route to CF3S-substituted indolo[1,2-a]quinoline-7-carbaldehydes and CF3S-substituted indolo[1,2-a]quinoline-7-methanone derivatives via the formation of the C-SCF3 bond and C-C bond and benzylic carbon oxidation in a single step. This reaction can accommodate a broad range of functional groups. The single-crystal X-ray diffraction data confirm the chemical structure of the product. A scale-up experiment and radical inhibition experiments were operated in the reaction system. Photophysical properties of some selected 5-((trifluoromethyl)thio)indolo[1,2-a]quinoline-7-carbaldehydes were studied by UV-visible and fluorescence spectroscopy.
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An efficient trifluoromethylation of 2-isocyanobiaryls was developed through the constant current electrolysis, employing sodium trifluoromethanesulfinate (CF3SO2Na) as the trifluoromethyl source. The method enabled the syntheses of a series of 6-(trifluoromethyl)phenanthridine derivatives in moderate to high yields under metal- and oxidant-free conditions. A gram-scale synthesis highlights the synthetic versatility of the reported protocol.
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Seven previously undescribed compounds, including five pyranonaphthoquinones (ventilanones L-P) and two naphthoquinones (ventilanones Q and R), along with 15 known compounds were isolated from the stem bark of Ventilago harmandiana (Rhamnaceae). The structures were established by extensive analysis of their spectroscopic data. The absolute configuration of ventilanone L was established from single crystal X-ray crystallographic analysis using Cu Kα radiation and from its electronic circular dichroism data. Anti-HIV-1 activity using a syncytium inhibition assay and the cytotoxic activities of some isolated compounds were evaluated. Compounds 12, 13, 15, and 16 showed activity against syncytium formation with half maximal effective concentration (EC50) values ranging from 9.9 to 47 µM (selectivity index (SI) 2.4-4.5).
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Naftoquinonas , Rhamnaceae , Estructura Molecular , Naftoquinonas/farmacología , Naftoquinonas/química , Corteza de la Planta/química , Dicroismo Circular , Rhamnaceae/químicaRESUMEN
BACKGROUND: Massive parallel sequencing technologies have enabled the elucidation of plant phylogenetic relationships from chloroplast genomes at a high pace. These include members of the family Rhamnaceae. The current Rhamnaceae phylogenetic tree is from 13 out of 24 Rhamnaceae chloroplast genomes, and only one chloroplast genome of the genus Ventilago is available. Hence, the phylogenetic relationships in Rhamnaceae remain incomplete, and more representative species are needed. RESULTS: The complete chloroplast genome of Ventilago harmandiana Pierre was outlined using a hybrid assembly of long- and short-read technologies. The accuracy and validity of the final genome were confirmed with PCR amplifications and investigation of coverage depth. Sanger sequencing was used to correct for differences in lengths and nucleotide bases between inverted repeats because of the homopolymers. The phylogenetic trees reconstructed using prevalent methods for phylogenetic inference were topologically similar. The clustering based on codon usage was congruent with the molecular phylogenetic tree. The groups of genera in each tribe were in accordance with tribal classification based on molecular markers. We resolved the phylogenetic relationships among six Hovenia species, three Rhamnus species, and two Ventilago species. Our reconstructed tree provides the most complete and reliable low-level taxonomy to date for the family Rhamnaceae. Similar to other higher plants, the RNA editing mostly resulted in converting serine to leucine. Besides, most genes were subjected to purifying selection. Annotation anomalies, including indel calling errors, unaligned open reading frames of the same gene, inconsistent prediction of intergenic regions, and misannotated genes, were identified in the published chloroplast genomes used in this study. These could be a result of the usual imperfections in computational tools, and/or existing errors in reference genomes. Importantly, these are points of concern with regards to utilizing published chloroplast genomes for comparative genomic analysis. CONCLUSIONS: In summary, we successfully demonstrated the use of comprehensive genomic data, including DNA and amino acid sequences, to build a reliable and high-resolution phylogenetic tree for the family Rhamnaceae. Additionally, our study indicates that the revision of genome annotation before comparative genomic analyses is necessary to prevent the propagation of errors and complications in downstream analysis and interpretation.
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Genoma del Cloroplasto , Rhamnaceae , Genoma del Cloroplasto/genética , Rhamnaceae/genética , Filogenia , Genómica/métodos , Cloroplastos/genéticaRESUMEN
A convenient and efficient synthetic strategy to prepare enantioenriched gem-difluoromethylenated spiro-pyrrolidinyl and spiro-piperidinyl oxindoles is described. Fluoride-mediated diastereoselective nucleophilic addition of PhSCF2SiMe3 to chiral N-tert-butanesulfinyl ketimines derived from isatins was a key step and provided diastereomeric adducts, which were readily separable. Removal of the chiral sulfinyl group followed by structural manipulation afforded chiral gem-difluoromethylenated spiro-pyrrolidinyl and spiro-piperidinyl oxindoles.
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Isatina , Oxindoles , Isatina/química , Estereoisomerismo , Iminas/químicaRESUMEN
Breast cancer accounts for up to 10% of the newly diagnosed cancer cases worldwide, making it the most common cancer found in women. The use of superparamagnetic iron oxide nanoparticles (SPIONs) has been beneficial in the advancement of contrast agents and magnetic hyperthermia (MH) for the diagnosis and treatment of cancers. To achieve delivery of SPIONs to cancer cells, surface functionalization with specific ligands are required. Riboflavin carrier protein (RCP) has been identified as an alternative target for breast cancer cells. Here, we report a novel riboflavin (Rf)-based ligand that provides SPIONs with enhanced colloidal stability and high uptake potential in breast cancer cells. This is achieved by synthesizing an Rf-citrate ligand. The ligand was tested in a multicore SPION system, and affinity to RCP was assessed by isothermal titration calorimetry which showed a specific, entropy-driven binding. MRI and MH responses of the coated Rf-SPIONs were tested to evaluate the suitability of this system as a theranostic platform. Finally, interaction of the Rf-SPIONs with breast cancer cells was evaluated by in vitro cellular uptake in MCF-7 breast cancer cells. The overall characterization of the Rf-SPIONs highlighted the excellent performance of this platform for theranostic applications in breast cancer.
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The combination of ion mobility mass spectrometry (IM-MS) and chromatography is a valuable tool for identifying compounds in natural products. In this study, using an ultra-performance liquid chromatography system coupled to a high-resolution quadrupole/traveling wave ion mobility spectrometry/time-of-flight MS (UPLC-TWIMS-QTOF), we have established and validated a comprehensive TWCCSN2 and MS database for 112 plant specialized metabolites. The database included 15 compounds that were isolated and purified in-house and are not commercially available. We obtained accurate m/z, retention times, fragment ions, and TWIMS-derived CCS (TWCCSN2) values for 207 adducts (ESI+ and ESI-). The database included novel 158 TWCCSN2 values from 79 specialized metabolites. In the presence of plant matrix, the CCS measurement was reproducible and robust. Finally, we demonstrated the application of the database to extend the metabolite coverage of Ventilago harmandiana Pierre. In addition to pyranonaphthoquinones, a group of known specialized metabolites in V. harmandiana, we identified flavonoids, xanthone, naphthofuran, and protocatechuic acid for the first time through targeted analysis. Interestingly, further investigation using IM-MS of unknown features suggested the presence of organonitrogen compounds and lipid and lipid-like molecules, which is also reported for the first time. Data are available on the MassIVE (https://massive.ucsd.edu, data set identifier MSV000090213).
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Productos Biológicos , Rhamnaceae , Xantonas , Flavonoides , Iones/química , Lípidos , Espectrometría de Masas/métodosRESUMEN
Heptagon-embedded polycyclic aromatic dicarboximides were developed as new push-pull fluorescent dyes through palladium-catalysed [4+3] annulation followed by nucleophilic substitution. The introduction of a seven-membered ring in these push-pull systems can efficiently modulate the optical properties leading to an enhancement of the fluorescence quantum yields up to 0.93 with color tunable emission covering the visible-NIR spectrum.
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Colorantes Fluorescentes , Paladio , Catálisis , Espectrometría de FluorescenciaRESUMEN
The electrophilic potential of vinyl sulfone permits the rapid capture of cysteine-containing proteins under physiological conditions. These cysteine proteinases play vital roles in bacterial survival and pathogenesis of Staphylococcus aureus (S. aureus) and the global health threat methicillin resistant S. aureus (MRSA). Here in, total of 28 vinyl sulfones were synthesized and subjected to susceptibility testing of pathogenic bacteria, including global epidemic MRSA PFGE strain type USA300 (SF8300). Number of antibacterial vinyl sulfone derivatives were discovered. Among these, nitrile-substituted vinyl phenyl sulfones showed potent antibacterial activity. (E)-3-((4-methoxyphenyl)sulfonyl)acrylonitrile exhibited the strongest potency with MIC of 1.875 µg/mL against methicillin susceptible S. aureus and 3.75 µg/mL against MRSA USA300. Based on the structure-activity relationship analysis, the antibacterial activity of these compounds may involve sulfhydryl conjugation. In addition, the nitrile-substituted vinyl phenyl sulfone could also impair host cell adhesion. With their promising antibacterial activities, these vinyl sulfones have potential for S. aureus and MRSA therapeutics.
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Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Antibacterianos/farmacología , Bacterias , Humanos , Pruebas de Sensibilidad Microbiana , Nitrilos , Staphylococcus aureus , Sulfonas/farmacologíaRESUMEN
Human topoisomerase II alpha (TopoIIα) is a crucial enzyme involved in maintaining genomic integrity during the process of DNA replication and mitotic division. It is a vital therapeutic target for designing novel anticancer agents in targeted cancer therapy. Sulfones, members of organosulfur compounds, have been reported to possess various biological activities such as antimicrobial, anti-inflammatory, anti-HIV, anticancer, and antimalarial properties. In the present study, a series of sulfones was selected to evaluate their inhibitory activity against TopoIIα using computational approaches. Molecular docking results revealed that several sulfone analogs bind efficiently to the ATPase domain of TopoIIα. Among them, sulfones 18a, 60a, *4 b, *8 b, *3c, and 8c exhibit higher binding affinity than the known TopoII inhibitor, salvicine. Molecular dynamics simulations and free energy calculations based on MM/PB(GB)SA method demonstrated that sulfone *8 b strongly interacts with amino acid residues in the ATP-binding pocket (E87, N91, D94, I125, I141, F142, S149, G161, and A167), driven mainly by an electrostatic attraction and a strong H-bond formation at G161 residue. Altogether, the obtained results predicted that sulfones could have a high potential to be a lead molecule for targeting TopoIIα.Communicated by Ramaswamy H. Sarma.
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Antineoplásicos , Simulación de Dinámica Molecular , Adenosina Trifosfatasas/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , ADN-Topoisomerasas de Tipo II/química , ADN-Topoisomerasas de Tipo II/genética , ADN-Topoisomerasas de Tipo II/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Sulfonas/farmacologíaRESUMEN
The current gold standard for classifying lupus nephritis (LN) progression is a renal biopsy, which is an invasive procedure. Undergoing a series of biopsies for monitoring disease progression and treatments is unlikely suitable for patients with LN. Thus, there is an urgent need for non-invasive alternative biomarkers that can facilitate LN class diagnosis. Such biomarkers will be very useful in guiding intervention strategies to mitigate or treat patients with LN. Urine samples were collected from two independent cohorts. Patients with LN were classified into proliferative (class III/IV) and membranous (class V) by kidney histopathology. Metabolomics was performed to identify potential metabolites, which could be specific for the classification of membranous LN. The ratio of picolinic acid (Pic) to tryptophan (Trp) ([Pic/Trp] ratio) was found to be a promising candidate for LN diagnostic and membranous classification. It has high potential as an alternative biomarker for the non-invasive diagnosis of LN.
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Combating triple-negative breast cancer (TNBC) is one of the greatest challenges in cancer therapy. This is primarily due to the difficulties in developing drug delivery systems that can effectively target cancer sites. In this study, we demonstrated a proof-of-principle concept using modified surfaces of poly(lactic-co-glycolic acid) nanoparticles linked with a riboflavin analogue (PLGA-CSRf) to obtain a dual-functional material. PLGA-CSRf nanoparticles were able to function as a drug delivery ligand and a photodynamic therapy agent for TNBC cells (MDA-MB-231). Biocompatibility of novel PLGA-CSRf nanoparticles was evaluated with both breast cancer and normal breast (MCF-10A) cells. In vitro studies revealed a six-fold increase in the cellular uptake of PLGA-CSRf nanoparticles in cancer cells compared with normal cells. The results demonstrate the ability of riboflavin (Rf) to enhance the delivery of PLGA nanoparticles to TNBC cells. The viability of TNBC cells was decreased following treatment with doxorubicin-encapsulated PLGA-CSRf nanoparticles in combination with UV irradiation, due to the photosensitizing property of Rf on the surface of the nanoparticles. This work demonstrated the ability of PLGA-CSRf to function both as an effective drug delivery carrier and as a therapeutic entity, with the potential to enhance photodynamic effects in the highly aggressive TNBC model.
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Nanopartículas , Fotoquimioterapia , Neoplasias de la Mama Triple Negativas , Línea Celular Tumoral , Portadores de Fármacos/uso terapéutico , Sistemas de Liberación de Medicamentos , Glicoles/uso terapéutico , Humanos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/uso terapéutico , Riboflavina/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Epidermal growth factor receptor (EGFR), overexpressed in many types of cancer, has been proved as a high potential target for targeted cancer therapy due to its role in regulating proliferation and survival of cancer cells. In the present study, a series of designed vinyl sulfone derivatives was screened against EGFR tyrosine kinase (EGFR-TK) using in silico and in vitro studies. The molecular docking results suggested that, among 78 vinyl sulfones, there were eight compounds that could interact well with the EGFR-TK at the ATP-binding site. Afterwards, these screened compounds were tested for the inhibitory activity towards EGFR-TK using ADP-Glo™ kinase assay, and we found that only VF16 compound exhibited promising inhibitory activity against EGFR-TK with the IC50 value of 7.85 ± 0.88 nM. In addition, VF16 showed a high cytotoxicity with IC50 values of 33.52 ± 2.57, 54.63 ± 0.09, and 30.38 ± 1.37 µM against the A431, A549, and H1975 cancer cell lines, respectively. From 500-ns MD simulation, the structural stability of VF16 in complex with EGFR-TK was quite stable, suggesting that this compound could be a novel small molecule inhibitor targeting EGFR-TK.
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Simulación por Computador , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Sulfonas/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib/química , Clorhidrato de Erlotinib/farmacología , Humanos , Enlace de Hidrógeno , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/química , Sulfonas/química , TermodinámicaRESUMEN
Four previously undescribed tetrahydrofuran lignans, named anorisols A-D (1-4) and fourteen known compounds (5-18) were isolated from the roots, stems, leaves and twigs of Anogeissus rivularis. The chemical structures were elucidated on the basis of their spectroscopic data and by comparison with the literature data. The absolute configurations of 1-4 were established by comparison of the experimental ECD spectra with the calculated ECD spectra. Some isolated compounds were evaluated for their cytotoxic activity as well as anti-HIV-1 activity employing reverse transcriptase (RT) and syncytium reduction assays using the ΔTat/RevMC99 virus in 1A2 cell line systems. Compound 6 displayed the most potent activity in syncytium inhibition assay with effective concentration at 50% (EC50) value of 13.3 µM (SI >3.0). In the reverse transcriptase assay, compound 1 exhibited moderate activity with IC50 value of 213.9 µM.