RESUMO
BACKGROUND: Organocatalytic asymmetric Michael addition is a strong approach for C-C bond formation. The objective of the study is to design molecules by exploiting the efficiency of Michael Adducts. We proceeded with the synthesis of Michael adducts by tailoring the substitution pattern on maleimide and trans-ß-nitro styrene as Michael acceptors. The synthesized compounds were evaluated for dual cyclooxygenases (COX) and lipoxygenase (LOX) inhibition. METHODS: The compounds (4, 9-11) were synthesized through Michael additions. The cyclooxygenases (COX-1 and 2) and lipoxygenase (5-LOX) assays were used for in vitro evaluations of compounds. After the acute toxicity studies, the in vivo analgesic potential was determined with acetic acid induced writhing, tail immersion, and formalin tests. Furthermore, the possible roles of adrenergic and dopaminergic receptors were also studied. Extensive computational studies were performed to get a better understanding regarding the binding of this compound with protein target. RESULTS: Four Michael adducts (4, 9-11) were synthesized. Compound 4 was obtained in enantio- and diastereopure form. The stereopure compound 4 showed encouraging COX-1 and-2 inhibitions with IC50 values of 128 and 65 µM with SI of 1.94. Benzyl derivative 11 showed excellent COX-2 inhibition with the IC50 value of 5.79 µM and SI value 7.96. Compounds 4 and 11 showed good results in in vivo models of analgesia like acetic acid test, tail immersion, and formalin tests. Our compounds were not active in dopaminergic and adrenergic pathways and so were acting centrally. Through extensive computational studies, we computed binding energies, and pharmacokinetic predictions. CONCLUSION: Our findings conclude that our synthesized Michael products (pyrrolidinedione 4 and nitroalkane 11) can be potent centrally acting analgesics. Our in silico predictions suggested that the compounds have excellent pharmacokinetic properties. It is concluded here that dual inhibition of COX/LOX pathways provides a convincing step towards the discovery of safe lead analgesic molecules.
Assuntos
Analgésicos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Edema/tratamento farmacológico , Inibidores de Lipoxigenase/farmacologia , Maleimidas/farmacologia , Estireno/farmacologia , Ácido Acético , Analgésicos/síntese química , Analgésicos/química , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Edema/induzido quimicamente , Edema/metabolismo , Feminino , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/química , Masculino , Maleimidas/síntese química , Maleimidas/química , Camundongos , Camundongos Endogâmicos BALB C , Prostaglandina-Endoperóxido Sintases/metabolismo , Estireno/síntese química , Estireno/químicaRESUMO
Styrene is an important petroleum-derived molecule that is polymerized to make versatile plastics, including disposable silverware and foamed packaging materials. Finding more sustainable methods, such as biosynthesis, for producing styrene is essential due to the increasing severity of climate change as well as the limited supply of fossil fuels. Recent metabolic engineering efforts have enabled the biological production of styrene in Escherichia coli, but styrene toxicity and volatility limit biosynthesis in cells. To address these limitations, we have developed a cell-free styrene biosynthesis platform. The cell-free system provides an open reaction environment without cell viability constraints, which allows exquisite control over reaction conditions and greater carbon flux toward product formation rather than cell growth. The two biosynthetic enzymes required for styrene production were generated via cell-free protein synthesis and mixed in defined ratios with supplemented L-phenylalanine and buffer. By altering the time, temperature, pH, and enzyme concentrations in the reaction, this approach increased the cell-free titer of styrene from 5.36 ± 0.63 mM to 40.33 ± 1.03 mM, the highest amount achieved using biosynthesis without process modifications and product removal strategies. Cell-free systems offer a complimentary approach to cellular synthesis of small molecules, which can provide particular benefits for producing toxic molecules.
Assuntos
Escherichia coli/química , Estireno/síntese química , Sistema Livre de Células/química , Escherichia coli/metabolismo , Estireno/química , Estireno/metabolismoRESUMO
In this study, an N-heterocyclic carbene (NHC)-based metallosurfactant (MS), NHC-PdMS, was synthesized, where Pd(II) was bound to the NHC framework via a robust Pd-carbene bond with NEt3 as a co-ligand. Surface tension measurements revealed that the critical micelle concentration (CMC) of NHC-PdMS (1.8×10-4 M) was one order of magnitude lower than that of its MS precursor (imidazolium bromide). Coordination of the MS precursor and NEt3 to Pd(II) also influenced micelle size; the hydrodynamic diameters of NHC-PdMS and the MS precursor were observed to be 25.8±5.6 nm and 2.5±0.3 nm, respectively. Furthermore, small angle X-ray scattering measurements indicated that NHC-PdMS exhibited liquid crystalline behavior above 26 wt%, with a spacing ratio of 1:2:3 for the first, second, and third Bragg peaks. To understand the role of the reactive interface, NHC-PdMS was also applied to aqueous catalytic reactions. Owing to its low CMC value, a catalytic amount of NHC-PdMS (3 mol%) provided the reactive interface, which facilitated the aqueous Mizoroki-Heck reaction of various aryl iodides and styrene in good yields (72-95%). These results suggest that MS formation results in a drastic change in selfassembling properties, which are important for the development of highly reactive chemical interfaces in water.
Assuntos
Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Metano/análogos & derivados , Paládio/química , Tensoativos/química , Tensoativos/síntese química , Água/química , Brometos/química , Catálise , Cristalografia por Raios X , Imidazóis/química , Iodetos/síntese química , Ligantes , Cristais Líquidos/química , Metano/síntese química , Metano/química , Micelas , Conformação Molecular , Fenômenos de Química Orgânica , Espalhamento de Radiação , Estireno/síntese química , Tensão SuperficialRESUMO
Biologics, such as antibody-drug conjugates, are becoming mainstream therapeutics. Consequently, methods to functionalize biologics without disrupting their native properties are essential for identifying, characterizing, and translating candidate biologics from the bench to clinical practice. Here, we present a method for site-specific, carboxy-terminal modification of single-chain antibody fragments (scFvs). ScFvs displayed on the surface of yeast were isolated and functionalized by combining intein-mediated expressed protein ligation (EPL) with inverse electron-demand Diels-Alder (IEDDA) cycloaddition using a styrene-tetrazine pair. The high thiol concentration required to trigger EPL can hinder the subsequent chemoselective ligation reactions; therefore, the EPL reaction was used to append styrene to the scFv, limiting tetrazine exposure to damaging thiols. Subsequently, the styrene-functionalized scFv was reacted with tetrazine-conjugated compounds in an IEDDA cycloaddition to generate functionalized scFvs that retain their native binding activity. Rapid functionalization of yeast surface-derived scFv in a site-directed manner could find utility in many downstream laboratory and preclinical applications.
Assuntos
Reação de Cicloadição/métodos , Compostos Heterocíclicos com 1 Anel/química , Imunoconjugados/química , Anticorpos de Cadeia Única/química , Estireno/química , Técnicas de Visualização da Superfície Celular , Compostos Heterocíclicos com 1 Anel/síntese química , Estireno/síntese química , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/químicaRESUMO
The beneficial use of computer simulations to track the microstructural evolution of individual species is highlighted in view of macromolecular engineering and design, considering two case studies on catalytic polymerization, and both "low" (<100) and "high" (>100) chain lengths, that is, i) atom transfer radical copolymerization of n-butyl acrylate and styrene aiming at the synthesis of functional macrospecies of "identical' chain length; and ii) chain shuttling polymerization of ethylene and 1-octene toward the production of segmented block copolymers with "soft" and "hard" segments. Model parameters are validated and/or tuned based on literature data. The modeling strategy supports the future identification of chemical structure-polymer property relationships and is based on the combination of principles from polymer reaction engineering, chemistry, and physics.
Assuntos
Catálise , Substâncias Macromoleculares/química , Polímeros/química , Acrilatos/síntese química , Acrilatos/química , Alcenos/síntese química , Alcenos/química , Simulação por Computador , Etilenos/síntese química , Etilenos/química , Cinética , Substâncias Macromoleculares/síntese química , Polimerização , Polímeros/síntese química , Estireno/síntese química , Estireno/químicaRESUMO
Deoxypodophyllotoxin is a secondary metabolite lignan possessing potent anticancer activity with potential as a precursor for known anticancer drugs, but its use is limited by scarcity from natural sources. We here report the total synthesis of racemic deoxypodophyllotoxin in seven steps using an intramolecular styryl Diels-Alder reaction strategy uniquely suited to assemble the deoxypodophyllotoxin core. Density functional theory was used to analyze concerted, polar, and singlet-open-shell diradical reaction pathways, which identified a low-energy concerted [4 + 2] Diels-Alder pathway followed by a faster di-t-butylhydroxytoluene assisted [1,3]-formal hydrogen shift.
Assuntos
Antineoplásicos/síntese química , Hidroxitolueno Butilado/química , Podofilotoxina/análogos & derivados , Teoria Quântica , Estireno/síntese química , Antineoplásicos/química , Reação de Cicloadição , Medicamentos de Ervas Chinesas , Estrutura Molecular , Podofilotoxina/síntese química , Podofilotoxina/química , Estereoisomerismo , Estireno/químicaRESUMO
The 1,3-dipolar cycloaddition reaction between an alkene and a tetrazole represents one elegant and rare example of fluorophore-forming bioorthogonal chemistry. This is an attractive reaction for imaging applications in live cells that requires less intensive washing steps and/or needs spatiotemporal resolutions. In the present work, as an effort to improve the fluorogenic property of the alkene-tetrazole reaction, an aromatic alkene (styrene) was investigated as the dipolarophile. Over 30-fold improvement in quantum yield of the reaction product was achieved in aqueous solution. According to our mechanistic studies, the observed improvement is likely due to an insufficient protonation of the styrene-tetrazole reaction product. This finding provides useful guidance to the future design of alkene-tetrazole reactions for biological studies. Fluorogenic protein labeling using the styrene-tetrazole reaction was demonstrated both in vitro and in vivo. This was realized by the genetic incorporation of an unnatural amino acid containing the styrene moiety. It is anticipated that the combination of styrene with different tetrazole derivatives can generally improve and broaden the application of alkene-tetrazole chemistry in real-time imaging in live cells.
Assuntos
Alcenos/química , Proteínas de Escherichia coli/análise , Escherichia coli/química , Corantes Fluorescentes/química , Tetrazóis/química , Alcenos/síntese química , Reação de Cicloadição , Escherichia coli/citologia , Corantes Fluorescentes/síntese química , Microscopia de Fluorescência/métodos , Modelos Moleculares , Processos Fotoquímicos , Estireno/síntese química , Estireno/química , Tetrazóis/síntese químicaRESUMO
BACKGROUND: Fragment-based approaches have now become an important component of the drug discovery process. At the same time, pharmaceutical chemists are more often turning to the natural world and its extremely large and diverse collection of natural compounds to discover new leads that can potentially be turned into drugs. In this study we introduce and discuss a computational pipeline to automatically extract statistically overrepresented chemical fragments in therapeutic classes, and search for similar fragments in a large database of natural products. By systematically identifying enriched fragments in therapeutic groups, we are able to extract and focus on few fragments that are likely to be active or structurally important. RESULTS: We show that several therapeutic classes (including antibacterial, antineoplastic, and drugs active on the cardiovascular system, among others) have enriched fragments that are also found in many natural compounds. Further, our method is able to detect fragments shared by a drug and a natural product even when the global similarity between the two molecules is generally low. CONCLUSIONS: A further development of this computational pipeline is to help predict putative therapeutic activities of natural compounds, and to help identify novel leads for drug discovery.
Assuntos
Produtos Biológicos/química , Descoberta de Drogas/métodos , Engenharia Metabólica , Preparações Farmacêuticas/química , Antineoplásicos Fitogênicos/química , Cafeína/síntese química , Bases de Dados de Produtos Farmacêuticos , Paclitaxel/química , Estireno/síntese químicaRESUMO
Metal-free hydrogenation of 2,7-disubstituted 1,8-naphthyridines was successfully realized for the first time using in situ generated borane catalysts under mild conditions to furnish 1,2,3,4-tetrahydro-1,8-naphthyridine derivatives in 83-98% yields. Significantly, up to 74% ee was achieved for the corresponding asymmetric hydrogenation reactions.
Assuntos
Boranos/química , Naftiridinas/síntese química , Boranos/síntese química , Catálise , Hidrogenação , Naftiridinas/química , Estereoisomerismo , Estireno/síntese química , Estireno/químicaRESUMO
All elementary steps in the mechanism of Pd-catalyzed decarbonylation of hydrocinnamic acid through formation of a mixed anhydride species have been characterized through electronic structure calculations. Oxidative addition of the mixed anhydride to a singly or doubly ligated Pd is followed by decarbonylation, alkene formation, and catalyst regeneration. Metal-assisted deprotonation of the alkyl-Pd species by a coordinated carboxylate is predicted to be the rate-determining step; theory suggests that bulkier phosphine ligands (e.g., P(o-Tol)3) reduce the free energy of activation substantially, while variation of the auxiliary anhydride has little influence on efficiency.
Assuntos
Anidridos/química , Paládio/química , Fenilpropionatos/química , Estireno/síntese química , Catálise , Transferência de Energia , Cinética , Ligantes , Modelos Químicos , Oxirredução , Fosfinas/química , Teoria QuânticaRESUMO
A copper-catalyzed highly efficient protocol for the synthesis of bis-deuterated ß-borylated α,ß-styrene derivatives, which can be further transformed to practical isotopically labeled compounds, has been developed. Alkynyl carboxylic acids are employed as alkyne synthons yet demonstrate a sharp discrepancy in reactivity and selectivity compared to terminal alkynes. Meanwhile, this reaction offers a novel and efficient strategy for highly selective trifunctionalization of the carbon-carbon triple bond at ambient temperature.
Assuntos
Alcinos/química , Ácidos Carboxílicos/química , Cobre/química , Compostos Organometálicos/química , Estireno/síntese química , Catálise , Estrutura Molecular , Estireno/química , TemperaturaRESUMO
A mild and practical protocol for manganese-catalyzed aerobic oxytrifluoromethylation of olefinic bonds of styrene derivatives using CF3SO2Na (Langlois' reagent) as the CF3 source is described. A distinguishing feature of this method is the generation of trifluoromethyl radicals from CF3SO2Na using the simple manganese salt/O2 system. The reaction proceeds under ambient conditions, free of added peroxide initiators, and provides moderate to good selectivities for alcohol versus ketone product.
Assuntos
Alcenos/química , Estireno/síntese química , Sulfonas/química , Catálise , Manganês/química , Metilação , Estrutura MolecularRESUMO
A novel nanodiamond/CNT-SiC monolith catalyst has been prepared by a facile two-step approach. The as-synthesized monolith afforded high activity and stability for ethylbenzene direct dehydrogenation to styrene, showing its potential application as a metal free catalyst in gaseous catalytic reactions.
Assuntos
Derivados de Benzeno/química , Compostos Inorgânicos de Carbono/química , Nanodiamantes/química , Nanotubos de Carbono/química , Compostos de Silício/química , Estireno/síntese química , CatáliseRESUMO
A specific series of dumbbell-shaped bis-carbazoles or bis-phenothiazines dyes (1, 2, 3 and 4) constructed with styrene or biphenylethyne as the π-bridge have been synthesized and characterized. Detailed spectral properties including linear absorption, one and two-photon fluorescence properties were investigated. The results show that extending conjugated chain and introducing donors have substantial effect on their photophysical properties. Among them, two-photon absorption cross sections (σ) of the four dyes in DMF determined by the Z-scan technique are successively increased from 1 to 4 with enhancing electron-donating ability and extending conjugated chain, but electron-donating ability has larger contribution to the σ values than extending conjugated chain based on the comparison of small molecules (D-π-D). Two-photon initiation polymerization (TPIP) microfabrication experiments have been carried out using compound 4 as an initiator under irradiation of 200 fs, 76 MHz femtosecond laser at 760 nm. The results confirm that the four dyes can be effectively used as organic two-photon photopolymerization initiators.
Assuntos
Carbazóis/síntese química , Corantes Fluorescentes/síntese química , Fenotiazinas/síntese química , Acetileno/análogos & derivados , Acetileno/síntese química , Fótons , Polimerização , Espectrometria de Fluorescência , Estireno/síntese químicaRESUMO
Three derivatives of styrene monomer, 4-chlorophenyl-4-vinylbenzyl ether (I), 4-methoxyphenyl-4-vinylbenzyl ether (II) and 4-ethylphenyl-4-vinylbenzyl ether (III) were synthesized. The synthesized two novel compounds (I and III) and one with undefined structural features were identified by experimental spectroscopic techniques and density functional approach. The optimized geometrical structure, vibrational and electronic transitions along with chemical shifts of those compounds were presented in this study. The vibrational spectra of investigated compounds were recorded in solid state with FT-IR spectrometry in the range of 4000-400 cm(-1). The computational vibrational wavenumbers and also ground state equilibrium conformations were carried out by using density functional method with 6-311++G(d,p) basis set. Assignments of the fundamental vibrational modes were examined on the basis of the measured data and total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanical (SQM) method. Isotropic chemical shift of hydrogen and carbon nuclei were investigated via observed (1)H and (13)C NMR spectra in deuterated DMSO solution and predicted data applied with gauge-invariant atomic orbitals (GIAOs) method. The UV absorption spectra of monomers were observed in the range of 200-800 nm in ethanol, and time dependent DFT method was used to obtain the electronic properties. A detailed description of spectroscopic behaviors of compound was given based on the comparison of experimental measurements and theoretical computations.
Assuntos
Benzeno/química , Éteres/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estireno/química , Estireno/síntese química , Dimetil Sulfóxido/química , Elétrons , Etanol/química , Soluções , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , VibraçãoRESUMO
A novel, highly selective palladium-catalyzed vinylation reaction for the direct synthesis of allylic amines from styrenes and aminals has been established. The utility of this method was also demonstrated by the rapid synthesis of cinnarizine from aldehydes, amines, and simple alkenes in one-pot manner. Mechanistic studies suggested that the reaction proceeds through a valuable cyclometalated Pd(II) complex generated by the oxidative addition of aminal to a Pd(0) species.
Assuntos
Alcenos/química , Alilamina/síntese química , Paládio/química , Estireno/química , Alcenos/síntese química , Catálise , Cinarizina/síntese química , Modelos Moleculares , Oxirredução , Estireno/síntese químicaRESUMO
The iron-catalyzed hydrocarboxylation of aryl alkenes has been developed using a highly active bench-stable iron(II) precatalyst to give α-aryl carboxylic acids in excellent yields and with near-perfect regioselectivity. Using just 1 mol % FeCl(2), bis(imino)pyridine 6 (1 mol %), CO(2) (atmospheric pressure), and a hydride source (EtMgBr, 1.2 equiv), a range of sterically and electronically differentiated aryl alkenes were transformed to the corresponding α-aryl carboxylic acids (up to 96% isolated yield). The catalyst was found to be equally active with a loading of 0.1 mol %. Preliminary mechanistic investigations show that an iron-catalyzed hydrometalation is followed by transmetalation and reaction with the electrophile (CO(2)).
Assuntos
Alcenos/química , Dióxido de Carbono/química , Ácidos Carboxílicos/síntese química , Hidrocarbonetos Aromáticos/síntese química , Ferro/química , Estireno/química , Alcenos/síntese química , Dióxido de Carbono/síntese química , Ácidos Carboxílicos/química , Catálise , Hidrocarbonetos Aromáticos/química , Estereoisomerismo , Estireno/síntese químicaRESUMO
The synthesis and photophysical properties of a series of naphthalene-containing solvatochromic fluorophores are described within. These novel fluorophores are prepared using a microwave-assisted dehydrogenative Diels-Alder reaction of styrene, followed by a palladium-catalyzed cross coupling reaction to install an electron donating amine group. The new fluorophores are structurally related to Prodan. Photophysical properties of the new fluorophores were studied and intriguing solvatochromic behavior was observed. For most of these fluorophores, high quantum yields (60-99%) were observed in methylene chloride in addition to large Stokes shifts (95-226 nm) in this same solvent. As the solvent polarity increased, so did the observed Stokes shift with one derivative displaying a Stokes shift of ~300 nm in ethanol. All fluorophore emission maxima, and nearly all absorption maxima were significantly red-shifted when compared to Prodan. Shifting the absorption and emission maxima of a fluorophore into the visible region increases its utility in biological applications. Moreover, the cyclopentane portion of the fluorophore structure provides an attachment point for biomolecules that will minimize disruptions of the photophysical properties.
Assuntos
Corantes Fluorescentes/química , Naftalenos/química , Aminas/química , Reação de Cicloadição , Elétrons , Corantes Fluorescentes/síntese química , Naftalenos/síntese química , Paládio/química , Espectrometria de Fluorescência , Estireno/síntese química , Estireno/químicaRESUMO
Hydrogel particles composed of poly(N-isopropylacrylamide) were used as a particulate steric stabilizer for the dispersion polymerization of styrene for the first time. The effects of the size and concentration of the hydrogel particles on the resultant polystyrene particles were investigated. As expected, the hydrogel particles indeed play the role of steric stabilizer for dispersion polymerization. Moreover, some of the resultant polystyrene particles were covered with hydrogel particles, which was confirmed by electron microscopy and X-ray photoelectron spectroscopy.
Assuntos
Hidrogel de Polietilenoglicol-Dimetacrilato/química , Material Particulado/química , Polimerização , Estireno/síntese química , Acrilamidas/química , Resinas Acrílicas , Tamanho da Partícula , Polímeros/química , Estireno/química , Propriedades de SuperfícieRESUMO
An efficient one-pot multi-component synthesis of flavans using perchloric acid supported on silica as a recyclable heterogeneous catalyst has been described. This is the first report of direct one-step construction of a flavan skeleton from a phenolic precursor. The method involves a Knoevenagel-type condensation leading to in situ formation of transient O-quinone methide which further undergoes [4 + 2]-Diels-Alder cycloaddition with styrene to yield a flavan skeleton. The method provides easy access to a wide range of bio-active natural products viz. flavonoids, anthocyanins and catechins.