RESUMO
Fluoroalkyl groups profoundly affect the physical properties of pharmaceuticals and influence almost all metrics associated with their pharmacokinetic and pharmacodynamic profile1-4. Drug candidates increasingly contain trifluoromethyl (CF3) and difluoromethyl (CF2H) groups, and the same trend in agrochemical development shows that the effect of fluoroalkylation translates across human, insect and plant life5,6. New fluoroalkylation reactions have undoubtedly stimulated this shift; however, methods that directly convert C-H bonds into C-CF2X groups (where X is F or H) in complex drug-like molecules are rare7-13. Pyridines are the most common aromatic heterocycles in pharmaceuticals14, but only one approach-via fluoroalkyl radicals-is viable for achieving pyridyl C-H fluoroalkylation in the elaborate structures encountered during drug development15-17. Here we develop a set of bench-stable fluoroalkylphosphines that directly convert the C-H bonds in pyridine building blocks, drug-like fragments and pharmaceuticals into fluoroalkyl derivatives. No preinstalled functional groups or directing groups are required. The reaction tolerates a variety of sterically and electronically distinct pyridines, and is exclusively selective for the 4-position in most cases. The reaction proceeds through initial formation of phosphonium salts followed by sp2-sp3 coupling of phosphorus ligands-an underdeveloped manifold for forming C-C bonds.
Assuntos
Carbono/química , Flúor/química , Hidrogênio/química , Fósforo/química , Piridinas/química , Alquilação , Animais , Humanos , Ligantes , Preparações Farmacêuticas/química , Farmacocinética , Fosfinas/químicaRESUMO
The substitution of an alkyl electrophile by a nucleophile is a foundational reaction in organic chemistry that enables the efficient and convergent synthesis of organic molecules. Although there has been substantial recent progress in exploiting transition-metal catalysis to expand the scope of nucleophilic substitution reactions to include carbon nucleophiles1-4, there has been limited progress in corresponding reactions with nitrogen nucleophiles5-8. For many substitution reactions, the bond construction itself is not the only challenge, as there is a need to control stereochemistry at the same time. Here we describe a method for the enantioconvergent substitution of unactivated racemic alkyl electrophiles by a ubiquitous nitrogen-containing functional group, an amide. Our method uses a photoinduced catalyst system based on copper, an Earth-abundant metal. This process for asymmetric N-alkylation relies on three distinct ligands-a bisphosphine, a phenoxide and a chiral diamine. The ligands assemble in situ to form two distinct catalysts that act cooperatively: a copper/bisphosphine/phenoxide complex that serves as a photocatalyst, and a chiral copper/diamine complex that catalyses enantioselective C-N bond formation. Our study thus expands enantioselective N-substitution by alkyl electrophiles beyond activated electrophiles (those bearing at least one sp- or sp2-hybridized substituent on the carbon undergoing substitution)8-13 to include unactivated electrophiles.
Assuntos
Amidas/química , Cobre/química , Fotoquímica , Brometos/química , Carbono/química , Catálise , Ciclização , Diaminas/química , Ligantes , Nitrogênio/química , Fosfinas/químicaRESUMO
Hydroamination of alkenes, the addition of the N-H bond of an amine across an alkene, is a fundamental, yet challenging, organic transformation that creates an alkylamine from two abundant chemical feedstocks, alkenes and amines, with full atom economy1-3. The reaction is particularly important because amines, especially chiral amines, are prevalent substructures in a wide range of natural products and drugs. Although extensive efforts have been dedicated to developing catalysts for hydroamination, the vast majority of alkenes that undergo intermolecular hydroamination have been limited to conjugated, strained, or terminal alkenes2-4; only a few examples occur by the direct addition of the N-H bond of amines across unactivated internal alkenes5-7, including photocatalytic hydroamination8,9, and no asymmetric intermolecular additions to such alkenes are known. In fact, current examples of direct, enantioselective intermolecular hydroamination of any type of unactivated alkene lacking a directing group occur with only moderate enantioselectivity10-13. Here we report a cationic iridium system that catalyses intermolecular hydroamination of a range of unactivated, internal alkenes, including those in both acyclic and cyclic alkenes, to afford chiral amines with high enantioselectivity. The catalyst contains a phosphine ligand bearing trimethylsilyl-substituted aryl groups and a triflimide counteranion, and the reaction design includes 2-amino-6-methylpyridine as the amine to enhance the rates of multiple steps within the catalytic cycle while serving as an ammonia surrogate. These design principles point the way to the addition of N-H bonds of other reagents, as well as O-H and C-H bonds, across unactivated internal alkenes to streamline the synthesis of functional molecules from basic feedstocks.
Assuntos
Alcenos/química , Aminas/química , Técnicas de Química Sintética , Hidrogênio/química , Nitrogênio/química , Aminação , Aminopiridinas/química , Amônia/química , Catálise , Indicadores e Reagentes/química , Irídio/química , Ligantes , Fosfinas/químicaRESUMO
Carbon-hydrogen (C-H) and carbon-carbon (C-C) bonds are the main constituents of organic matter. Recent advances in C-H functionalization technology have vastly expanded our toolbox for organic synthesis1. By contrast, C-C activation methods that enable editing of the molecular skeleton remain limited2-7. Several methods have been proposed for catalytic C-C activation, particularly with ketone substrates, that are typically promoted by using either ring-strain release as a thermodynamic driving force4,6 or directing groups5,7 to control the reaction outcome. Although effective, these strategies require substrates that contain highly strained ketones or a preinstalled directing group, or are limited to more specialist substrate classes5. Here we report a general C-C activation mode driven by aromatization of a pre-aromatic intermediate formed in situ. This reaction is suitable for various ketone substrates, is catalysed by an iridium/phosphine combination and is promoted by a hydrazine reagent and 1,3-dienes. Specifically, the acyl group is removed from the ketone and transformed to a pyrazole, and the resulting alkyl fragment undergoes various transformations. These include the deacetylation of methyl ketones, carbenoid-free formal homologation of aliphatic linear ketones and deconstructive pyrazole synthesis from cyclic ketones. Given that ketones are prevalent in feedstock chemicals, natural products and pharmaceuticals, these transformations could offer strategic bond disconnections in the synthesis of complex bioactive molecules.
Assuntos
Carbono/química , Cetonas/química , Acilação , Hidrazinas/química , Irídio/química , Fosfinas/química , Pirazóis/síntese química , Pirazóis/químicaRESUMO
2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on ß-2'-deoxynucleosides with the natural ß-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and ß-2'-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2'-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O-glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial N-glycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P-heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2'-deoxynucleoside with IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its ß-anomer exhibited no inhibition at 100 µM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.
Assuntos
Neuroblastoma , Fosfinas , Humanos , GlicosilaçãoRESUMO
Increasing evidence of sperm RNA's role in fertilization and embryonic development has provided impetus for its isolation and thorough characterization. Sperm are considered tough-to-lyse cells due to the compact condensed DNA in sperm heads. Lack of consensus among bovine sperm RNA isolation protocols introduces experimental variability in transcriptome studies. Here, we describe an optimized method for total RNA isolation from bovine sperm using the TRIzol reagent. This study critically investigated the effects of various lysis conditions on sperm RNA isolation. Sperm suspended in TRIzol were subjected to a combination of mechanical treatments (sonication and passage through a 30G needle and syringe) and chemical treatments (supplementation with reducing agents 1,4-dithiothreitol and tris(2-carboxyethyl) phosphine hydrochloride (TCEP)). Microscopic evaluation of sperm lysis confirmed preferential sperm tail versus sperm head lysis. Interestingly, only TCEP-supplemented TRIzol (both mechanical treatments) had progressive sperm head lysis and consistently yielded total sperm RNA. Furthermore, RNA integrity was confirmed based on the electrophoresis profile and an absence of genomic DNA and somatic cells (e.g., epithelial cells, spermatids, etc.) with RT-qPCR. Our findings highlighted the importance of sperm lysis, specifically of the sperm head using TCEP with mechanical treatment, in total RNA isolation and presented a bovine-specific sperm RNA isolation method to reduce experimental variabilities.
Assuntos
Guanidinas , Fenóis , Fosfinas , Sêmen , Espermatozoides , Masculino , Animais , Bovinos , Espermatozoides/química , Cabeça do Espermatozoide , RNA/análise , DNARESUMO
Tris-(2-carboxyethyl)phosphine (TCEP) linked to agarose beads is widely used for reducing disulfide bridges in proteins and peptides. The immobilization of TCEP on beads allows efficient removal after reduction to prevent its reaction with alkylating reagents and thus interference with conjugation reactions. However, a limitation of agarose TCEP is its relatively low reduction capacity per milliliter of wet beads (about 15â µmol/ml), making it unsuitable for the reduction of disulfides from molecules at millimolar concentrations. In this work, we tested the immobilization of TCEP to a range of different solid supports and found that conjugation to silica gel offers TCEP beads with about 8-fold higher reduction capacity (129±16â µmol/ml wet beads). We show that it allows reducing disulfide-cyclized peptides at millimolar concentrations for subsequent cyclization by bis-electrophile linker reagents. Given the substantially higher reduction capacity, the robust performance in different solvents, the low cost of the silica gel, and the ease of functionalization with TCEP, the silica gel-TCEP is suited for reducing disulfide bridges in essentially any peptide and is particularly useful for reducing peptides at higher concentrations.
Assuntos
Fosfinas , Dióxido de Silício , Compostos de Sulfidrila , Sefarose , Sílica Gel , Peptídeos/química , Indicadores e Reagentes , Alquilação , Dissulfetos/química , OxirreduçãoRESUMO
Some studies suggested that gastrointestinal (GIT) decontamination with oil may improve the prognosis of patients who ingested aluminum phosphide (AlP). The aim of this study is to compare the efficacy and safety of gastric lavage with oil-based solutions to any method of gastric decontamination not using oils in patients presenting with acute AlP poisoning. The literature was searched for English-published randomized controlled trials (RCTs) from inception to 16 September 2023. The searched electronic databases included MEDLINE/PubMed, Cochrane Library, Web of Science, Egyptian Knowledge Bank, Scopus, and Google Scholar. Data were extracted and pooled by calculating the risk ratio (RR) for categorical outcomes and standardized mean difference (SMD) for numerical outcomes, with 95% confidence intervals (CI). Seven RCTs were included. Paraffin oil was significantly associated with a lower risk of mortality (RR = 0.59 [95% CI: 0.45, 0.76], p < .001), intubation (RR = 0.59 [95% CI: 0.46, 0.76], p < .001) and vasopressor need (RR = 0.71 [95% CI: 0.56, 0.91], p = .006). Survival time was significantly prolonged with paraffin oil (SMD = 0.72 [95% CI: 0.32, 1.13], p < .001). Coconut oil was significantly associated with prolonged survival time (SMD = 0.83 [95% CI: 0.06, 1.59], p = .03) as well as decreased risk of requiring intubation (RR = 0.78 [95% CI: 0.62, 0.99], p = .04). Oil-based GIT decontamination using paraffin oil showed benefits over conventional lavage regarding the incidence of in-hospital mortality and endotracheal intubation, and survival time. Coconut oil showed some benefits in terms of the intubation incidence and survival time. Decontamination using paraffin oil is recommended. Future clinical trials are warranted with larger sample sizes and focusing on cost-benefit and safety.
Assuntos
Compostos de Alumínio , Lavagem Gástrica , Fosfinas , Humanos , Compostos de Alumínio/intoxicação , Lavagem Gástrica/métodos , Óleos , Parafina , Praguicidas , Fosfinas/intoxicação , Intoxicação , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Methods for computational de novo design of inorganic molecules have paved the way for automated design of homogeneous catalysts. Such studies have so far relied on correlation-based prediction models as fitness functions (figures of merit), but the soundness of these approaches has yet to be tested by experimental verification of de novo-designed catalysts. Here, a previously developed criterion for the optimization of dative ligands L in ruthenium-based olefin metathesis catalysts RuCl2(L)(L')(âCHAr), where Ar is an aryl group and L' is a phosphine ligand dissociating to activate the catalyst, was used in de novo design experiments. These experiments predicted catalysts bearing an N-heterocyclic carbene (L = 9) substituted by two N-bound mesityls and two tert-butyl groups at the imidazolidin-2-ylidene backbone to be promising. Whereas the phosphine-stabilized precursor assumed by the prediction model could not be made, a pyridine-stabilized ruthenium alkylidene complex (17) bearing carbene 9 was less active than a known leading pyridine-stabilized Grubbs-type catalyst (18, L = H2IMes). A density functional theory-based analysis showed that the unsubstituted metallacyclobutane (MCB) intermediate generated in the presence of ethylene is the likely resting state of both 17 and 18. Whereas the design criterion via its correlation between the stability of the MCB and the rate-determining barrier indeed seeks to stabilize the MCB, it relies on RuCl2(L)(L')(âCH2) adducts as resting states. The change in resting state explains the discrepancy between the prediction and the actual performance of catalyst 17. To avoid such discrepancies and better address the multifaceted challenges of predicting catalytic performance, future de novo catalyst design studies should explore and test design criteria incorporating information from more than a single relative energy or intermediate.
Assuntos
Alcenos , Metano/análogos & derivados , Fosfinas , Rutênio , Termodinâmica , PiridinasRESUMO
Breast cancer is one of the most basilisk cancers for women due to its high mortality rate which can be prevented drastically with early-stage detection. In this work, the adsorption mechanism of two volatile organic compounds that are present in the breath of breast cancer patients, 2-Methyloctane and 3, 3-Dimethylpentane, has been investigated on aluminum phosphide nanotubes (AlPNT) and gallium phosphide nanotubes (GaPNT) in order to understand their feasibility as sensor materials to diagnosis breast cancer at early stage. We have used the quantum mechanical approach by employing density functional theory using B3LYP-D3 hybrid potential for noncovalent interaction along with the LanL2DZ basis in the Gaussian 09 software package. The adsorption properties analyses suggest that GaPNT exhibits better sensing behavior as well as proclaims 12.6% greater adsorption energy for 2-Methyloctane and 9.4% greater adsorption energy for 3, 3-Dimethylpentane than AlPNT. Other structural and electric properties analyses satisfy this conclusion and suggest that GaPNT exhibits higher stability than AlPNT and could possibly be a potential candidate for developing biosensors to detect breast cancer at the preliminary stages.
Assuntos
Neoplasias da Mama , Teoria da Densidade Funcional , Nanotubos , Fosfinas , Neoplasias da Mama/diagnóstico , Humanos , Feminino , Nanotubos/química , Fosfinas/química , Adsorção , Gálio/química , Octanos/química , Compostos Orgânicos Voláteis/análise , Técnicas Biossensoriais/métodosRESUMO
Organophosphate flame retardants (OPFRs) are high-production volume chemicals widely present in environmental compartments. The presence of water-soluble OPFRs (tri-n-butyl phosphate (TnBP), tris(2-butoxyethyl) phosphate (TBEP), tris(2-chloroethyl) phosphate (TCEP), tris(2-chloroisopropyl) phosphate (TCPP), and triethyl phosphate (TEP)) in water compartments evidences the struggle of conventional wastewater treatment plants (WWTPs) to effectively eliminate these toxic compounds. This study reports for the first time the use of white-rot fungi as a promising alternative for the removal of these OPFRs. To accomplish this, a simple and cost-efficient quantification method for rapid monitoring of these contaminants' concentrations by GC-MS while accounting for matrix effects was developed. The method proved to be valid and reliable for all the tested parameters. Sample stability was examined under various storage conditions, showing the original samples to be stable after 60 days of freezing, while post-extraction storage techniques were also effective. Finally, a screening of fungal degraders while assessing the influence of the glucose regime on OPFR removal was performed. Longer chain organophosphate flame retardants, TBP and TBEP, could be easily and completely removed by the fungus Ganoderma lucidum after only 4 days. This fungus also stood out as the sole organism capable of partially degrading TCEP (35% removal). The other chlorinated compound, TCPP, was more easily degraded and 70% of its main isomer was removed by T. versicolor. However, chlorinated compounds were only partially degraded under nutrient-limiting conditions. TEP was either not degraded or poorly degraded, and it is likely that it is a transformation product from another OPFR's degradation. These results suggest that degradation of chlorinated compounds is dependent on the concentration of the main carbon source and that more polar OPFRs are less susceptible to degradation, given that they are less accessible to radical removal by fungi. Overall, the findings of the present study pave the way for further planned research and a potential application for the degradation of these contaminants in real wastewaters.
Assuntos
Retardadores de Chama , Compostos Organofosforados , Fosfinas , Compostos Organofosforados/análise , Retardadores de Chama/análise , Cromatografia Gasosa-Espectrometria de Massas , Organofosfatos/análise , Águas Residuárias , Água , FosfatosRESUMO
Novel catalysts with multiple active sites and rapid separation are required to effectively activate peroxymonosulfate (PMS) for the removal of organic pollutants from water. Therefore, an integrated catalyst for PMS activation was developed by directly forming Co-Fe Prussian blue analogs on a three-dimensional porous nickel foam (NF), which were subsequently phosphorylated to obtain cobalt-iron bimetallic phosphide (FeCoP@NF). The FeCoP@NF/PMS system efficiently degraded dye wastewater within 20 min. The system exhibited excellent catalytic degradation over a broad pH range and at high dye concentrations due to the presence of unique asymmetrically charged Coa+ and Pb- dual active sites formed by cobalt phosphides within FeCoP@NF. These active sites significantly enhanced the catalytic activity of PMS. The activation mechanism of PMS involves phosphorylation that accelerates electron transfer from FeCoP@NF to PMS, to generate SO4·-, ·OH, O2·-, and 1O2 active species. Three-dimensional FeCoP@NF could be readily recycled and showed good stability for PMS activation. In this study, a highly efficient, stable, and readily recyclable integrated catalyst was developed. This catalyst system effectively resolves the separation and recovery issues associated with conventional powder catalysts and has a wide range of potential applications in wastewater treatment.
Assuntos
Cobalto , Corantes , Ferro , Níquel , Peróxidos , Poluentes Químicos da Água , Cobalto/química , Níquel/química , Ferro/química , Corantes/química , Peróxidos/química , Poluentes Químicos da Água/química , Catálise , Fosfinas/químicaRESUMO
Indium phosphide (InP) quantum dots (QDs) have recently garnered considerable interest in the design of bioprobes due to their non-toxic nature and excellent optical properties. Several attempts for the conjunction of InP QDs with various entities such as organic dyes and dye-labeled proteins have been reported, while that with fluorescent proteins remains largely uncharted. This study reports the development of a Förster resonance energy transfer pair comprising glutathione-capped InP/GaP/ZnS QDs [InP(G)] and the fluorescent protein mCherry. Glutathione on InP(G) undergoes effective bioconjugation with mCherry consisting of a hexahistidine tag, and the nonradiative energy transfer is investigated using steady-state and time-resolved measurements. Selective one-photon excitation of InP(G) in the presence of mCherry shows a decay of the emission of the QDs and a concomitant growth of acceptor emission. Time-resolved investigations prove the nonradiative transfer of energy between InP(G) and mCherry. Furthermore, the scope of two-photon-induced energy transfer between InP(G) and mCherry is investigated by exciting the donor in the optical transparency range. The two-photon absorption is confirmed by the quadratic relationship between the emission intensity and the excitation power. In general, near-infrared excitation provides a path for effective light penetration into the tissues and reduces the photodamage of the sample. The two-photon-induced energy transfer in such assemblies could set the stage for a wide range of biological and optoelectronic applications in the foreseeable future.
Assuntos
Corantes , Transferência Ressonante de Energia de Fluorescência , Índio , Fosfinas , Glutationa , FótonsRESUMO
Exposure routes are important for health risk assessment of chemical risks. The application of physiologically based toxicokinetic (PBTK) models to predict concentrations in vivo can determine the effects of harmful substances and tissue accumulation on the premise of saving experimental costs. In this study, Tri(2-chloroethyl) phosphate (TCEP), an organophosphate ester (OPE), was used as an example to study the PBTK model of mice exposed to different exposure doses by multiple routes. Different routes of exposure (gavage and intradermal injection) can cause differences in the concentration of chemicals in the organs. TCEP that enters the body through the mouth is mainly concentrated in the gastrointestinal tract and liver. However, the concentrations of chemicals that enter the skin into the mice are higher in skin, rest of body, and blood. In addition, TCEP was absorbed and accumulated very rapidly in mice, within half an hour after a single exposure. We have successfully established a mouse PBTK model of the TCEP accounting for multiple exposure Routes and obtained a series of kinetic parameters. The model includes blood, liver, kidney, stomach, intestine, skin, and rest of body compartments. Oral and dermal exposure route was considered for PBTK model. The PBTK model established in this study has a good predictive ability. More than 70% of the predicted values deviated from the measured values by less than 5-fold. In addition, we extrapolated the model to humans. A human PBTK model is built. We performed a health risk assessment for world populations based on human PBTK model. The risk of TCEP in dust is greater through mouth than through skin. The risk of TCEP in food of Chinese population is greater than dust.
Assuntos
Fosfatos , Fosfinas , Pele , Camundongos , Humanos , Animais , Toxicocinética , Poeira , Modelos BiológicosRESUMO
Organophosphorus flame retardants (OPFRs) have been frequently detected with relatively high concentrations in various environmental media and are considered emerging environmental pollutants. However, their biological effect and underlying mechanism is still unclear, and whether chlorinated OPFRs (Cl-OPFRs) cause adverse outcomes with the same molecular initial events or share the same key events (KEs) remains unknown. In this study, in vitro bioassays were conducted to analyze the cytotoxicity, mitochondrial impairment, DNA damage and molecular mechanisms of two Cl-OPFRs. The results showed that these two Cl-OPFRs, which have similar structures, induced severe cellular and molecular damages via different underlying mechanisms. Both tris(2-chloroethyl) phosphate (TCEP) and tris(1-chloro-2-propyl) (TCPP) induced oxidative stress-mediated mitochondrial impairment and DNA damage, as shown by the overproduction of intracellular reactive oxygen species (ROS) and mitochondrial superoxide. Furthermore, the DNA damage caused by TCPP resulted in p53/p21-mediated cell cycle arrest, as evidenced by flow cytometry and real-time PCR. At the cellular and molecular levels, TCPP increased the sub-G1 apoptotic peak and upregulated the p53/Bax apoptosis pathway, possibly resulted in apoptosis associated with its stronger cytotoxicity. Although structurally similar to TCPP, TCEP did not induce mitochondrial impairment and DNA damage by the same KEs. These results provide insight into the toxicity of Cl-OPFRs with similar structures but different mechanisms, which is of great significance for constructing adverse outcome pathways or determining intermediate KEs.
Assuntos
Retardadores de Chama , Compostos Organofosforados , Fosfinas , Compostos Organofosforados/toxicidade , Retardadores de Chama/toxicidade , Proteína Supressora de Tumor p53/genética , Organofosfatos/toxicidade , Dano ao DNARESUMO
As a typical organophosphorus flame retardant, tris(2-chloroethyl) phosphate (TCEP) is refractory in aqueous environment. The application of TAP is a promising method for removing pollutants. Herein, the removal of TCEP using TAP was rigorously investigated, and the effects of some key variables were optimized by the one-factor-at-a-time approach. To further evaluate the interactions among variables, the response surface methodology (RSM) based on central composite design was employed. Under optimized conditions (pH 5, [PS]0: [TCEP]0 = 500:1), the maximum removal efficiency (RE) of TCEP reached up to 90.6%. In real-world waters, the RE of TCEP spanned the range of 56%- 65% in river water, pond water, lake water and sanitary sewage. The low-concentration Cl- (0.1 mM) promoted TCEP degradation, but the contrary case occurred when the high-concentration Cl-, NO3-, CO32-, HCO3-, HPO42-, H2PO4-, NH4+ and humic acid were present owing to their prominently quenching effects on SO4â¢-. Both EPR and scavenger experiments revealed that the main radicals in the TAP system were SO4â¢- and â¢OH, in which SO4â¢- played the most crucial role in TCEP degradation. GC-MS/MS analysis disclosed that two degradation products appeared, sourcing from the replacement, oxidation, hydroxylation and water-molecule elimination reactions. The other two products were inferred from the comprehensive literature. As for acute toxicity to fish, daphnid and green algae, product A displayed the slightly higher toxicity, whereas other three products exhibited the declining toxicity as compared to their parent molecule. These findings offer a theoretical/practical reference for high-efficiency removal of TCEP and its ecotoxicological risk evaluation.
Assuntos
Retardadores de Chama , Fosfinas , Poluentes Químicos da Água , Retardadores de Chama/toxicidade , Espectrometria de Massas em Tandem , Compostos Organofosforados , Organofosfatos/toxicidade , Organofosfatos/química , Oxirredução , Água , Fosfatos , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/químicaRESUMO
The reaction of (ortho-acetalaryl)arylmethanols with various phosphines PR1R2R3 (R1 = R2 = R3 = Ph; R1 = R2 = Ph, R3 = Me and R1 = R2 = Me, R3 = Ph) under acidic conditions (e.g., HCl, HBF4, TsOH) unexpectedly led to the formation of (10-hydroxy-9,10-dihydroanthr-9-yl)phosphonium salts instead of the corresponding anthryl phosphonium salts. The cyclization occurred according to the Friedel-Crafts mechanism but without the usually observed Bradsher dehydration, giving cyclic products in the form of cis/trans isomers and their conformers. In case of electron-rich and less-hindered dimethylphenylphosphine, all four stereoisomers were recorded in 31P{1H} NMR spectra, while for the other phosphines, only the two most stable cis/trans stereoisomers were detected. This study was supported by DFT and NCI calculations in combination with FT-IR analysis.
Assuntos
Fosfinas , Sais , Humanos , Estrutura Molecular , Ciclização , Desidratação , Espectroscopia de Infravermelho com Transformada de Fourier , Fosfinas/químicaRESUMO
3,4-disubstituted maleimides find wide applications in various pharmacologically active compounds. This study presents a highly effective approach for synthesizing derivatives of 3,4-disubstituted maleimides through the direct isomerization of α-succinimide-substituted allenoates, followed by a cascade γ'-addition and aryl imines using PR3 as a catalyst. The resulting series of 3,4-disubstituted maleimides exhibited excellent stereoselectivities, achieving yields of up to 86%. To our knowledge, the phosphine-mediated γ'-addition reaction of allenoates is seldom reported.
Assuntos
Iminas , Maleimidas , Fosfinas , Succinimidas , Maleimidas/química , Maleimidas/síntese química , Fosfinas/química , Catálise , Iminas/química , Succinimidas/química , Estereoisomerismo , Estrutura Molecular , IsomerismoRESUMO
Gastric cancer prognosis is still notably poor despite efforts made to improve diagnosis and treatment of the disease. Chemotherapy based on platinum agents is generally used, regardless of the fact that drug toxicity leads to limited clinical efficacy. In order to overcome these problems, our group has been working on the synthesis and study of trans platinum (II) complexes. Here, we explore the potential use of two phosphine-based agents with the general formula trans-[Pt(amine)Cl2(PPh3)], called P1 and P2 (with dimethylamine or isopropylamine, respectively). A cytotoxicity analysis showed that P1 and especially P2 decrease cell viability. Specifically, P2 exhibits higher activity than cisplatin in gastric cancer cells while its toxicity in healthy cells is slightly lower. Both complexes generate Reactive Oxygen Species, produce DNA damage and mitochondrial membrane depolarization, and finally lead to induced apoptosis. Thus, an intrinsic apoptotic pathway emerges as the main type of cell death through the activation of BAX/BAK and BIM and the degradation of MCL1. Additionally, we demonstrate here that P2 produces endoplasmic reticulum stress and activates the Unfolded Protein Response, which also relates to the impairment observed in autophagy markers such as p62 and LC3. Although further studies in other biological models are needed, these results report the biomolecular mechanism of action of these Pt(II)-phosphine prototypes, thus highlighting their potential as novel and effective therapies.
Assuntos
Apoptose , Estresse do Retículo Endoplasmático , Retículo Endoplasmático , Mitocôndrias , Espécies Reativas de Oxigênio , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/química , Dano ao DNA/efeitos dos fármacos , Fosfinas/farmacologia , Fosfinas/química , Resposta a Proteínas não Dobradas/efeitos dos fármacosRESUMO
A series of optically pure aziridine phosphines and their corresponding phosphine oxides were synthesized through established chemical methodologies. The compounds were systematically investigated for their biological properties. Notably, all synthesized compounds demonstrated moderate antibacterial activity only against the reference strain of Staphylococcus aureus. However, compounds 5 and 7 exhibited noteworthy cell viability inhibition of human cervical epithelioid carcinoma HeLa cells and endometrial adenocarcinoma Ishikawa cells. Further studies of these compounds revealed additional biological effects, including disruption of the cell membrane in high concentrations, cell cycle arrest in the S phase, and the induction of reactive oxygen species (ROS). Comparative analysis of the two classes of chiral organophosphorus derivatives of aziridines indicated that chiral phosphine oxides displayed significantly higher biological activity. Consequently, these findings suggest that chiral phosphine oxides may be potential candidates for the development of anticancer drugs. In light of the significant interest in preparations whose structure is based on a three-membered aziridine ring in terms of potential anticancer therapy, this research fits into the current research trend and should constitute a valuable addition to the current state of knowledge and the existing library of aziridine derivatives with anticancer properties.