RESUMEN
A novel method for synthesizing cationic styryl dyes through a nucleic acid-templated reaction has been developed. This approach overcomes issues associated with traditional synthesis methods, such as harsh conditions, low throughput, and wasteful chemicals. The presence of a nucleic acid template accelerated the styryl dye formation from quaternized heteroaromatic and cationic aldehyde substrates. These styryl dyes show remarkable optical properties change when bound to nucleic acids, hence the success of the synthesis could be readily monitored inâ situ by UV-Vis and fluorescence spectroscopy and the optical properties data were also observable at the same time. This method provides the desired products from a broad range of coupling partners. By employing different substrates and templates, it is possible to identify new dyes that can bind to a specific type of nucleic acid such as a G-quadruplex. The templated dye synthesis is also successfully demonstrated in live HeLa cells. This approach is a powerful tool for the rapid synthesis and screening of dyes specific for diverse types of nucleic acids or cellular organelles, facilitating new biological discoveries.
Asunto(s)
Cationes , Colorantes Fluorescentes , Ácidos Nucleicos , Humanos , Células HeLa , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Ácidos Nucleicos/química , Ácidos Nucleicos/síntesis química , Cationes/química , Espectrometría de Fluorescencia , G-Cuádruplex , ADN/química , Estirenos/química , Estirenos/síntesis química , Colorantes/química , Colorantes/síntesis químicaRESUMEN
A novel class of styryl sulfones were designed and synthesized as CAPE derivatives by our work team, which showed a multi-target neuroprotective effect, including antioxidative and anti-neuroinflammatory properties. However, the underlying mechanisms remain unclear. In the present study, the anti-Parkinson's disease (PD) activity of 10 novel styryl sulfone compounds was screened by the cell viability test and the NO inhibition test in vitro. It was found that 4d exhibited the highest activity against PD among them. In a MPTP-induced mouse model of PD, the biological activity of 4d was validated through suppressing dopamine neurotoxicity, microglial activation, and astrocytes activation. With compound 4d, we conducted the mechanistic studies about anti-inflammatory responses through inhibition of p38 phosphorylation to protect dopaminergic neurons, and antioxidant effects through promoting nuclear factor erythroid 2-related factor 2 (Nrf2). The results revealed that 4d could significantly inhibit 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP+)-induced p38 mitogen-activated protein kinase (MAPK) activation in both in vitro and in vivo PD models, thus inhibiting the NF-κB-mediated neuroinflammation-related apoptosis pathway. Simultaneously, it could promote Nrf2 nuclear transfer, and upregulate the expression of antioxidant phase II detoxification enzymes HO-1 and GCLC, and then reduce oxidative damage.
Asunto(s)
Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Estirenos/farmacología , Sulfonas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Células Cultivadas , Inflamación/metabolismo , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Estirenos/síntesis química , Estirenos/química , Sulfonas/síntesis química , Sulfonas/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Alzheimer's disease (AD) is associated with the presence of amyloid plaques in the brain mainly comprised of aggregated forms of amyloid-ß (Aß). Molecules radiolabeled with technetium-99m that cross the blood-brain barrier (BBB) and selectively bind to Aß plaques have the potential to assist in the diagnosis of AD using single-photon emission computed tomography imaging. In this work, three new tetradentate ligands of pyridyl, amide, amine and thiol donors, featuring a styrylpyridyl group that is known to interact with amyloid plaques, were prepared. The new ligands formed charge-neutral and lipophilic complexes with the [TcâO]3+ and [ReâO]3+ motifs, and two rhenium complexes were characterized by X-ray crystallography. The rhenium(V) complexes interact with synthetic Aß1-40 and amyloid plaques on human brain tissue. Two of the new ligands were radiolabeled with 99mTc using a kit-based approach, and their biodistribution in wild-type mice was evaluated. The presence of amide donors in the tetradentate ligand increased the stability of the respective [TcâO]3+ complexes but reduced brain uptake. While the complexes were able to cross the BBB, the degree of uptake in the brain was not sufficient to justify further investigation of these complexes.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Complejos de Coordinación/química , Compuestos de Organotecnecio/química , Radiofármacos/química , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/diagnóstico por imagen , Complejos de Coordinación/síntesis química , Complejos de Coordinación/metabolismo , Complejos de Coordinación/farmacocinética , Humanos , Ligandos , Ratones , Compuestos de Organotecnecio/síntesis química , Compuestos de Organotecnecio/metabolismo , Compuestos de Organotecnecio/farmacocinética , Fragmentos de Péptidos/metabolismo , Piridinas/síntesis química , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacocinética , Radiofármacos/síntesis química , Radiofármacos/metabolismo , Radiofármacos/farmacocinética , Renio/química , Estirenos/síntesis química , Estirenos/química , Estirenos/metabolismo , Estirenos/farmacocinéticaRESUMEN
A series of fluorescent ligands, which were systematically constructed from thiazole orange scaffold, was investigated for their interactions with G-quadruplex structures and antitumor activity. Among the ligands, compound 3 was identified to exhibit excellent specificity toward telomere G4-DNA over other nucleic acids. The affinity of 3-Htg24 was almost 5 times higher than that of double-stranded DNA and promoter G4-DNA. Interaction studies showed that 3 may bind to both G-tetrad and the lateral loop near the 5'-end. The intracellular colocalization with BG4 and competition studies with BRACO19 reveal that 3 may interact with G4-structures. Moreover, 3 reduces the telomere length and downregulates hTERC and hTERT mRNA expression in HeLa cells. The cytotoxicity of 3 against cancer cells (IC50 = 12.7-16.2 µM) was found to be generally higher than noncancer cells (IC50 = 52.3 µM). The findings may support that the ligand is telomere G4-DNA specific and may provide meaningful insights for anticancer drug design.
Asunto(s)
Benzotiazoles/farmacología , ADN/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Colorantes Fluorescentes/farmacología , G-Cuádruplex , Quinolinas/farmacología , Estirenos/farmacología , Benzotiazoles/síntesis química , Benzotiazoles/metabolismo , Línea Celular Tumoral , ADN/genética , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/metabolismo , Humanos , Ligandos , Microscopía Confocal , Microscopía Fluorescente , Quinolinas/síntesis química , Quinolinas/metabolismo , ARN/metabolismo , Estirenos/síntesis química , Estirenos/metabolismo , Telomerasa/metabolismoRESUMEN
We report a strategy for effecting catalytic, enantioselective carbocationic rearrangements through the intermediacy of alkyl iodanes as stereodefined carbocation equivalents. Asymmetric Wagner-Meerwein rearrangements of ß-substituted styrenes are catalyzed by the C2-symmetric aryl iodide 1 to provide access to enantioenriched 1,3-difluorinated molecules possessing interesting and well-defined conformational properties. Hammett and kinetic isotope effect studies, in combination with computational investigations, reveal that two different mechanisms are operative in these rearrangement reactions, with the pathway depending on the identity of the migrating group. In reactions involving alkyl-group migration, intermolecular fluoride attack is product- and enantio-determining. In contrast, reactions in which aryl rearrangement occurs proceed through an enantiodetermining intramolecular 1,2-migration prior to fluorination. The fact that both pathways are promoted by the same chiral aryl iodide catalyst with high enantioselectivity provides a compelling illustration of generality across reaction mechanisms in asymmetric catalysis.
Asunto(s)
Hidrocarburos Yodados/química , Estirenos/síntesis química , Catálisis , Estructura Molecular , Estereoisomerismo , Estirenos/químicaRESUMEN
The dealkenylative alkenylation of alkene C(sp3 )-C(sp2 ) bonds has been an unexplored area for C-C bond formation. Herein 64 examples of ß-alkylated styrene derivatives, synthesized through the reactions of readily accessible feedstock olefins with ß-nitrostyrenes by ozone/FeII -mediated radical substitutions, are reported. These reactions proceed with good efficiencies and high stereoselectivities under mild reaction conditions and tolerate an array of functional groups. Also demonstrated is the applicability of the strategy through several synthetic transformations of the products, as well as the syntheses of the natural product iso-moracin and the drug (E)-metanicotine.
Asunto(s)
Alquenos/química , Carbono/química , Alquenos/síntesis química , Alquilación , Catálisis , Metales/química , Conformación Molecular , Nicotina/análogos & derivados , Nicotina/síntesis química , Nicotina/química , Estereoisomerismo , Estirenos/síntesis química , Estirenos/químicaRESUMEN
Despite various advances in the arena of the current system of medicine, there are numerous side effects associated with the therapeutics which essentially demand research on the development of safer therapeutics. One way is to explore the bioactive plant secondary metabolites and their semisynthetic derivatives. In context to this, we analyzed OA-DHZ, a dehydrozingerone derivative as the later has been reported to show anti-inflammatory and analgesic properties. OA-DHZ was found to be having promising anti-inflammatory and analgesic potential. OA-DHZ was found to inhibit the carrageenan-induced edema and leukocyte migration, acetic acid-induced increase in vascular permeability and lipopolysaccharide-induced pro-inflammatory cytokines like TNF-α, IL-6, and IL-1ß. Meanwhile, it was also found to potentially inhibit thermally as well as chemically induced pain signifying its analgesic/nociceptive potential. Further, safety pharmacology studies using in vivo animal models for the central nervous system, gastrointestinal tract, the cardio-respiratory system suggest that optimum functioning of vital organ systems does not get altered after single oral administration. Also, the acute toxicity study revealed its nontoxic nature up to 2000 mg/kg. This study paves the way for future exploration and development of OA-DHZ based on its potent activity and nontoxic nature.
Asunto(s)
Antiinflamatorios/uso terapéutico , Edema/tratamiento farmacológico , Estirenos/uso terapéutico , Triazoles/uso terapéutico , Administración Oral , Animales , Carragenina , Citocinas/metabolismo , Edema/inducido químicamente , Femenino , Zingiber officinale , Humanos , Mediadores de Inflamación/metabolismo , Extractos Vegetales , Ratas , Ratas Wistar , Estirenos/síntesis química , Triazoles/síntesis químicaRESUMEN
A new N2O-type BODIPY probe (LF-Bop) has been proposed for the selective and sensitive detection of biologically relevant small molecular thiols. This detection is based on the Michael addition reaction between the thiol and nitrostyrene groups in the probe, which decreases the quenching effect from the nitro group, thus resulting in the recovery of the deep-red fluorescence from the BODIPY structure. The results show that LF-Bop is able to detect all tested free thiols through a fluorescence turn-on assay. The lowest limit of detection (LOD) for glutathione was found to be down to nanomolar levels (220 nM). Based on this probe, we have developed a new fluorescence assay for the screening of acetylcholinesterase inhibitors. In total, 11 natural and synthetic alkaloids have been evaluated. Both experimental measurements and theoretical molecular docking results reveal that both natural berberine and its synthetic derivative dihydroberberine are potential inhibitors of acetylcholinesterase.
Asunto(s)
Compuestos de Boro/química , Inhibidores de la Colinesterasa/química , Colorantes Fluorescentes/química , Glutatión/análisis , Estirenos/química , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Animales , Berberina/análogos & derivados , Berberina/química , Berberina/metabolismo , Compuestos de Boro/síntesis química , Inhibidores de la Colinesterasa/metabolismo , Evaluación Preclínica de Medicamentos , Elasmobranquios , Pez Eléctrico , Colorantes Fluorescentes/síntesis química , Glutatión/química , Límite de Detección , Simulación del Acoplamiento Molecular , Unión Proteica , Estirenos/síntesis química , Tacrina/química , Tacrina/metabolismoRESUMEN
The resurgence of interest in monoamine oxidases (MAOs) has been fueled by recent correlations of this enzymatic activity with cardiovascular, neurological, and oncological disorders. This has promoted increased research into selective MAO-A and MAO-B inhibitors. Here, we shed light on how selective inhibition of MAO-A and MAO-B can be achieved by geometric isomers of cis- and trans-1-propargyl-4-styrylpiperidines. While the cis isomers are potent human MAO-A inhibitors, the trans analogues selectively target only the MAO-B isoform. The inhibition was studied by kinetic analysis, UV-vis spectrum measurements, and X-ray crystallography. The selective inhibition of the MAO-A and MAO-B isoforms was confirmed ex vivo in mouse brain homogenates, and additional in vivo studies in mice show the therapeutic potential of 1-propargyl-4-styrylpiperidines for central nervous system disorders. This study represents a unique case of stereoselective activity of cis/trans isomers that can discriminate between structurally related enzyme isoforms.
Asunto(s)
Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Inhibidores de la Monoaminooxidasa/uso terapéutico , Piperidinas/uso terapéutico , Estirenos/uso terapéutico , Animales , Antidepresivos/síntesis química , Antidepresivos/metabolismo , Encéfalo , Dominio Catalítico , Humanos , Isoenzimas/antagonistas & inhibidores , Cinética , Masculino , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Monoaminooxidasa/química , Monoaminooxidasa/clasificación , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/metabolismo , Piperidinas/síntesis química , Piperidinas/metabolismo , Unión Proteica , Estereoisomerismo , Relación Estructura-Actividad , Estirenos/síntesis química , Estirenos/metabolismoRESUMEN
G-Quadruplex DNAs, formed by G-rich DNA sequences in human genes, are promising targets for design of cancer drugs. In this study, two naphthalimide substituted styryl dyes with different sizes of aromatic groups were synthesized. The spectral analysis showed that the dye X-2 with a large aromatic group formed aggregates in buffer solution displaying very weak fluorescence intensity, and disaggregated in the presence of G-Quadruplex DNAs with large intensity enhancements (up to ~1800 fold). Moreover, X-2 displayed good selectivity to G-Quadruplex DNAs. In contrast, dye X-3 with the smaller aromatic group had much lower fluorescence enhancements and poor selectivity to G-Quadruplex DNAs, suggesting that the suitably sized aromatic ring was essential for the interaction with G-Quadruplex. Further binding studies suggested that X-2 mainly bound on G-quartet surface through end-stacking mode. Cytotoxicity assay showed that both of the two dyes showed good anti-proliferative activities against the cancer cell lines and less cytotoxicity in non-malignant cell lines, which were better than a standard drug 5-fluorouracil. In addition, living cell imaging was also studied and demonstrated the potential applications of the new dye X-2 in bioassays and cell imaging.
Asunto(s)
Antineoplásicos/farmacología , ADN/química , Colorantes Fluorescentes/farmacología , Naftalimidas/farmacología , Estirenos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Sitios de Unión/efectos de los fármacos , Bovinos , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/química , G-Cuádruplex/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Naftalimidas/síntesis química , Naftalimidas/química , Relación Estructura-Actividad , Estirenos/síntesis química , Estirenos/químicaRESUMEN
A series of dehydrozingerone derivatives were synthesized, and their fungicidal activities and action mechanism against Colletotrichum musae were evaluated. The bioassay result showed that most compounds exhibited excellent fungicidal activity in vitro at 50 µg mL-1. Compounds 13, 16, 18, 19, and 27 exhibited broad-spectrum fungicidal activity; especially, compounds 19 and 27 were found to have more potent fungicidal activity than azoxystrobin. The EC50 values of compounds 19 and 27 against Rhizoctonia solani were 0.943 and 0.161 µg mL-1 respectively. Moreover, compound 27 exhibited significant in vitro bactericidal activity against Xanthomonas oryzae pv. oryzae, with an EC50 value of 11.386 µg mL-1, and its curative effect (49.64%) and protection effect (51.74%) on rice bacterial blight disease was equivalent to that of zhongshengmycin (42.90%, 40.80% respectively). Compound 27 could also effectively control gray mold (87.10%, 200 µg mL-1) and rice sheath blight (100%, 200 µg mL-1; 82.89%, 100 µg mL-1) in vivo. Preliminary action mechanism study showed that compound 27 mainly acted on the cell membrane and significantly inhibited ergosterol biosynthesis in Colletotrichum musae.
Asunto(s)
Ergosterol/antagonistas & inhibidores , Fungicidas Industriales/síntesis química , Fungicidas Industriales/farmacología , Estirenos/síntesis química , Estirenos/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Colletotrichum/efectos de los fármacos , Colletotrichum/metabolismo , Ergosterol/biosíntesis , Fungicidas Industriales/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oryza/microbiología , Enfermedades de las Plantas/microbiología , Rhizoctonia/efectos de los fármacos , Rhizoctonia/metabolismo , Relación Estructura-Actividad , Estirenos/química , Xanthomonas/efectos de los fármacos , Xanthomonas/metabolismoRESUMEN
Fluorescent hybridization probes are important tools for rapid, specific and sensitive analysis of genetic mutations. In this work, we synthesized novel alkyne-modified styryl dyes for conjugation with pyrrolidinyl peptide nucleic acid (acpcPNA) by click chemistry for the development of hybridization responsive fluorescent PNA probes. The free styryl dyes generally exhibited weak fluorescence in aqueous media, and the fluorescence was significantly enhanced (up to 125-fold) upon binding with DNA duplexes. Selected styryl dyes that showed good responses with DNA were conjugated with PNA via sequential reductive alkylation-click chemistry. Although these probes showed little fluorescence change when hybridized to complementary DNA, significant fluorescence enhancements were observed in the presence of structural defects including mismatched, abasic and base-inserted DNA targets. The largest increase in fluorescence quantum yield (up to 14.5-fold) was achieved with DNA carrying base insertion. Although a number of probes were designed to give fluorescence response to complementary DNA targets, probes that are responsive to mutations such as single nucleotide polymorphism (SNP), base insertion/deletion and abasic site are less common. Therefore, styryl-dye-labeled acpcPNA is a unique probe that is responsive to structural defects in the duplexes that may be further applied for diagnostic purposes.
Asunto(s)
Sondas de ADN/química , ADN/análisis , Fluorescencia , Colorantes Fluorescentes/química , Ácidos Nucleicos de Péptidos/química , Pirrolidinas/química , Estirenos/química , Química Clic , ADN/genética , Colorantes Fluorescentes/síntesis química , Estructura Molecular , Mutación , Estirenos/síntesis químicaRESUMEN
A red-emitting and ratiometric fluorescence probe 1 for detecting H2O2, based on a styrylnaphthalimide-boronate ester was developed. Upon a H2O2-mediated hydrolysis of boronate ester, probe 1 was transformed to 2 with a ratiometric fluorescence change, decrease at 535 and increase at 640â¯nm. It was also found that the fluorescent reaction of 1 with H2O2 in solution could be completed within 10â¯min and the detection limit was estimated to be 0.30⯵M. Moreover, this ratiometric change was highly selective for H2O2 over other redox species, metal ions, and anions. Also, this system was found to be capable of detecting H2O2 in the pH range of 6-9. Furthermore, probe 1 was preferentially accumulated into the endoplasmic reticulum (ER) in the live HeLa cells, and an increased H2O2 level in the presence of an ER stress inducer, thapsigargin was revealed.
Asunto(s)
Ácidos Borónicos/química , Colorantes Fluorescentes/química , Peróxido de Hidrógeno/análisis , Naftalimidas/química , Estirenos/química , Ácidos Borónicos/síntesis química , Estrés del Retículo Endoplásmico/efectos de los fármacos , Colorantes Fluorescentes/síntesis química , Células HeLa , Humanos , Límite de Detección , Microscopía Confocal/métodos , Microscopía Fluorescente/métodos , Naftalimidas/síntesis química , Estirenos/síntesis química , Tapsigargina/farmacologíaRESUMEN
In this work, one kind of biocompatible and all-in-one dual-modal nanoprobe, based on Au nanoparticles and NIR emissive semiconducting fluorescence polymers, was developed by the one-step solvent-mediated self-assembly method for in vivo X-ray computed tomography (CT) and fluorescence bioimaging for the first time. After preparation, a series of comprehensive evaluations were performed, and the nanoprobe exhibited smart size and modification, good compatibility, inducement of autophagy, long blood circulation, unconspicuous in vivo toxicity, and excellent fluorescence/CT imaging effects. Overall, the studies in this work assuredly indicate that the synthesized Au@FP nanoparticles as a noninvasive contrast agent is suitable for in vivo fluorescence/X-ray CT bimodality biomedical imaging and diagnosis.
Asunto(s)
Materiales Biocompatibles , Medios de Contraste , Colorantes Fluorescentes , Oro , Nanopartículas del Metal , Imagen Multimodal/métodos , Imagen Óptica/métodos , Puntos Cuánticos , Tensoactivos , Tomografía Computarizada por Rayos X/métodos , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Autofagia , Benzotiazoles/síntesis química , Benzotiazoles/farmacocinética , Benzotiazoles/toxicidad , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/farmacocinética , Materiales Biocompatibles/toxicidad , Células Cultivadas , Medios de Contraste/toxicidad , Fluorenos/farmacocinética , Fluorenos/toxicidad , Transferencia Resonante de Energía de Fluorescencia , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/farmacocinética , Colorantes Fluorescentes/toxicidad , Oro/farmacocinética , Oro/toxicidad , Células Endoteliales de la Vena Umbilical Humana , Humanos , Rayos Infrarrojos , Masculino , Nanopartículas del Metal/toxicidad , Polietilenglicoles/farmacocinética , Polietilenglicoles/toxicidad , Polímeros/farmacocinética , Polímeros/toxicidad , Puntos Cuánticos/química , Puntos Cuánticos/toxicidad , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno , Solubilidad , Estirenos/síntesis química , Estirenos/farmacocinética , Estirenos/toxicidad , Tensoactivos/síntesis química , Tensoactivos/farmacocinética , Tensoactivos/toxicidad , Distribución TisularRESUMEN
A series of styrylquinolines was designed and synthesized based on the four main quinoline scaffolds including oxine, chloroxine and quinolines substituted with a hydroxyl group or chlorine atom at the C4 position. All of the compounds were tested for their anticancer activity on wild-type colon cancer cells (HCT 116) and those with a p53 deletion. Analysis of SAR revealed the importance of electron-withdrawing substituents in the styryl part and chelating properties in the quinoline ring. The compounds that were more active were also tested on a panel of four cancer cell lines with mutations in TP53 tumor suppressor gene. The results suggest that styrylquinolines induce cell cycle arrest and activate a p53-independent apoptosis. The apparent mechanism of action was studied for the most promising compounds, which produced reactive oxygen species and changed the cellular redox balance.
Asunto(s)
Antineoplásicos/farmacología , Quinolinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Estirenos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Hemo-Oxigenasa 1/metabolismo , Humanos , Estructura Molecular , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Quinolinas/síntesis química , Quinolinas/química , Quinolinas/toxicidad , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Relación Estructura-Actividad , Estirenos/síntesis química , Estirenos/química , Estirenos/toxicidad , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The mechanism of the enantioselective Michael addition of diethyl malonate to trans-ß-nitrostyrene catalyzed by a tertiary amine thiourea organocatalyst is explored using experimental 13C kinetic isotope effects and density functional theory calculations. Large primary 13C KIEs on the bond-forming carbon atoms of both reactants suggest that carbon-carbon bond formation is the rate-determining step in the catalytic cycle. This work resolves conflicting mechanistic pictures that have emerged from prior experimental and computational studies.
Asunto(s)
Tiourea/química , Catálisis , Teoría Funcional de la Densidad , Malonatos/química , Estructura Molecular , Estereoisomerismo , Estirenos/síntesis química , Estirenos/químicaRESUMEN
A fluorescent bis-styryl-benzothiadiazole (BTD) with carboxylic acid functional groups (X-34/Congo red analogue) showed lower binding affinity toward Aß1-42 and Aß1-40 fibrils than its neutral analogue. Hence, variable patterns of neutral OH-substituted bis-styryl-BTDs were generated. All bis-styryl-BTDs showed higher binding affinity to Aß1-42 fibrils than to Aß1-40 fibrils. The para-OH on the phenyl rings was beneficial for binding affinity while a meta-OH decreased the affinity. Differential staining of transgenic mouse Aß amyloid plaque cores compared to peripheral coronas using neutral compared to anionic bis-styryl ligands indicate differential recognition of amyloid polymorphs. Hyperspectral imaging of transgenic mouse Aß plaque stained with uncharged para-hydroxyl substituted bis-styryl-BTD implicated differences in binding site polarity of polymorphic amyloid plaque. Most properties of the corresponding bis-styryl-BTD were retained with a rigid alkyne linker rendering a probe insensitive to cis-trans isomerization. These new BTD-based ligands are promising probes for spectral imaging of different Aß fibril polymorphs.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Colorantes Fluorescentes/farmacología , Fragmentos de Péptidos/metabolismo , Placa Amiloide/metabolismo , Estirenos/farmacología , Tiadiazoles/farmacología , Animales , Femenino , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/metabolismo , Ligandos , Ratones Transgénicos , Microscopía Confocal , Microscopía Fluorescente , Unión Proteica , Estirenos/síntesis química , Estirenos/metabolismo , Tiadiazoles/síntesis química , Tiadiazoles/metabolismoRESUMEN
Selective and sensitive detection of G-quadruplex DNA structures is an important issue and attracts extensive interest. To this end, numerous small molecular fluorescent probes have been designed. Here, we present a series of N-alkylated styrylquinolinium dyes named Ls-1, Ls-2 and Ls-3 with varying side groups at the chain end. We found that these dyes exhibited different binding behaviors to DNAs, and Ls-2 with a sulfonato group at the chain end displayed sensitivity and selectivity to G-quadruplex DNA structures in vitro. The characteristics of this dye and its interaction with G-quadruplex DNA were comprehensively investigated by means of UV-vis spectrophotometry, fluorescence, circular dichroism and molecular docking. Furthermore, confocal fluorescence images and MTT assays indicated dye Ls-2 could pass through membrane and enter the living HepG2 cells with low cytotoxicity.
Asunto(s)
ADN/análisis , Colorantes Fluorescentes/química , Compuestos de Quinolinio/química , Estirenos/química , Alquilación , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/farmacología , G-Cuádruplex , Células Hep G2 , Humanos , Estructura Molecular , Imagen Óptica , Compuestos de Quinolinio/síntesis química , Compuestos de Quinolinio/farmacología , Relación Estructura-Actividad , Estirenos/síntesis química , Estirenos/farmacologíaRESUMEN
A moderate elevation in reactive oxygen species (ROS) levels can generally be controlled in normal cells, but may lead to death of cancer cells as the ROS level in cancer cells is already elevated. Therefore, a ROS-generating compound can act as a selective chemotherapeutic agent for cancer cells that does not affect normal cells. In our previous study, a compound containing a Michael acceptor was selectively cytotoxic to cancer cells without affecting normal cells; therefore, we designed and synthesized 26 compounds containing a Michael acceptor. Their cytotoxicities against HCT116 human colon cancer cell lines were measured by using a clonogenic long-term survival assay. To derive the structural conditions required to obtain stronger cytotoxicity against cancer cells, the relationships between the half-maximal cell growth inhibitory concentration values of the synthesized compounds and their physicochemical properties were evaluated by Comparative Molecular Field Analysis and Comparative Molecular Similarity Indices Analysis. It was confirmed that the compound with the best half-maximal cell growth inhibitory concentration triggered apoptosis through ROS generation, which then led to stimulation of the caspase pathway.
Asunto(s)
Antineoplásicos/farmacología , Chalconas/farmacología , Estirenos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Supervivencia Celular/efectos de los fármacos , Chalconas/síntesis química , Chalconas/química , Células HCT116 , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad Cuantitativa , Especies Reactivas de Oxígeno/metabolismo , Estirenos/síntesis química , Estirenos/químicaRESUMEN
Identification of a novel catalyst-allenoate pair allows enantioselective [2+2] cycloaddition of α-methylstyrene. To understand the origin of selectivity, a detailed mechanistic investigation was conducted. Herein, two competing reaction pathways are proposed, which operate simultaneously and funnel the alkenes to the same axially chiral cyclobutanes. In agreement with the Woodward-Hoffmann rules, this mechanistic curiosity can be rationalized through a unique symmetry operation that was elucidated by deuteration experiments. In the case of 1,1-diarylalkenes, distal communication between the catalyst and alkene is achieved through subtle alteration of electronic properties and conformation. In this context, a Hammett study lends further credibility to a concerted mechanism. Thus, extended scope exploration, including ß-substitution on the alkene to generate two adjacent stereocenters within the cyclobutane ring, is achieved in a highly stereospecific and enantioselective fashion (33 examples, up to >99:1 er).