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1.
J Colloid Interface Sci ; 607(Pt 1): 163-170, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34506998

RESUMO

HYPOTHESIS: Dynamic imine surfactants (DIS) can be constructed by the formation of dynamic imine bonds (Dibs) between aromatic aldehydes and aliphatic amines in water. Because of the nature of Dibs in water, a thermodynamic equilibrium state was achieved between the DIS and aldehyde and amine precursors to form a dynamic combinatorial library (DCL). When the DIS served as sole emulsifier to form oil-H2O emulsions, the precursors migrated between the H2O phase and the oil phase, which altered the DCL equilibrium. The DIS concentration and emulsion stability also changed. EXPERIMENTS: By mixing 4-(2-sulfobetaine-ethoxy)-benzaldehyde (SBBA) and aliphatic amines of CnH2n+1NH2 (n = 4, BA; n = 6, HA; n = 8, OA; n = 10, DA) in water, four amphoteric DIS (SBBA-BA/HA/OA/DA) were prepared. Dib formation was characterized using 1H NMR. The DIS surface activity was studied by surface tension and fluorescence probe methods. The reversible switching of DIS and its wormlike micelles were explored. FINDINGS: SBBA-OA (or SBBA-DA) DIS was not a suitable emulsifier for stable hydrocarbon (HC)-H2O emulsions. OA and DA were more soluble in the HC phase than the H2O phase. The precursors of OA and DA migrated from the H2O to the HC phase, and the thermodynamic equilibrium state of DCL shifted towards Dib dissociation. The Dib could be regenerated by HC phase removal. A novel strategy where volatile HC (such as pentane) was used as a trigger was developed to switch the DIS reversibly and its self-assemblies (such as wormlike micelles) in water without inorganic salt accumulation. The SBBA-HA (or SBBA-BA) DIS was a suitable emulsifier for stable emulsions because HA and BA were more soluble in the H2O phase.


Assuntos
Iminas , Tensoativos , Emulsões , Micelas , Água
2.
Anal Chim Acta ; 1188: 339191, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34794562

RESUMO

Lanthanide-functionalized porous organic materials have been the promising candidates in the chemical and biological sensing. Considering the superior thermal and solvent stability of covalent organic frameworks (COFs), the development of lanthanide ions-functionalized COFs based sensing platform is meaningful, while remains to be a challenge. In this work, a new imine-linked COF which provides suitable coordination sites for Tb3+ was constructed via the Schiff base reaction between P-phenylenediamine (Pda) and 2,6-Diformylpyridine (Dfp). Benefiting from its high signal-to-noise, the COF@Tb shows excellent ability to determinate ciprofloxacin (CIP) with a detection limit of 3.01 nM. The measurement can maintain good stability in the presence of potential interference or in actual sample. Being washed with ethanol after each measurement, COF@Tb can be recycled for five times. This work provides a novel alternative strategy for efficient construction of lanthanide-grafted COFs and may promote the development of porous organic materials based chemical sensing.


Assuntos
Estruturas Metalorgânicas , Antibacterianos , Iminas , Porosidade , Solventes
3.
Int J Mol Sci ; 22(19)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34639219

RESUMO

A five-step transformation of a spiroketal side chain of tigogenin into an indolizidine system present in solanidane alkaloids such as demissidine and solanidine was elaborated. The key intermediate in the synthesis was spiroimine 3 readily obtained from tigogenin by its RuO4 oxidation to 5,6-dihydrokryptogenin followed by amination with aluminum amide generated in situ from DIBAlH and ammonium chloride. The mild reduction of spiroimine to a 26-hydroxy-dihydropyrrole derivative and subsequent mesylation resulted in the formation of 25-epidemissidinium salt or 23-sulfone depending on reaction conditions.


Assuntos
Diosgenina/química , Iminas/química , Alcaloides de Solanáceas/química , Alcaloides de Solanáceas/síntese química , Espirostanos/química
4.
Molecules ; 26(19)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34641292

RESUMO

Dapsone (DDS) is an antibacterial drug with well-known antioxidant properties. However, the antioxidant behavior of its derivatives has not been well explored. In the present work, the antioxidant activity of 10 dapsone derivatives 4-substituted was determined by an evaluation in two in vitro models (DPPH radical scavenging assay and ferric reducing antioxidant power). These imine derivatives 1-10 were obtained through condensation between DDS and the corresponding aromatic aldehydes 4-substuited. Three derivatives presented better results than DDS in the determination of DPPH (2, 9, and 10). Likewise, we have three compounds with better reducing activity than dapsone (4, 9, and 10). In order to be more insight, the redox process, a conceptual DFT analysis was carried out. Molecular descriptors such as electronic distribution, the total charge accepting/donating capacity (I/A), and the partial charge accepting/donating capacity (ω+/ω-) were calculated to analyze the relative donor-acceptor capacity through employing a donor acceptor map (DAM). The DFT calculation allowed us to establish a relationship between GAPHOMO-LUMO and DAM with the observed antioxidant effects. According to the results, we concluded that compounds 2 and 3 have the lowest Ra values, representing a good antioxidant behavior observed experimentally in DPPH radical capturing. On the other hand, derivatives 4, 9, and 10 display the best reducing capacity activity with the highest ω- and Rd values. Consequently, we propose these compounds as the best antireductants in our DDS imine derivative series.


Assuntos
Antioxidantes/síntese química , Dapsona/química , Iminas/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Simulação por Computador , Teoria da Densidade Funcional , Iminas/química , Iminas/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
5.
J Org Chem ; 86(18): 12932-12944, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34482692

RESUMO

Although dynamic reactions of imines have been extensively studied, the dynamic behaviors manipulated by chirality remain nearly unexplored. In this work, enantioselective amine exchange reactions were demonstrated as a first example via the reaction of enantiomeric chiral amines such as natural amino acids with a series of innovative axially chiral 1,1'-binaphthyl-2,2'-diamine (BNDA)-based imines that were prepared from the condensation reactions between BNDA and salicylaldehyde (SA) or its derivatives. This enantioselective dynamic behavior can be directly indicated by the degree of the fluorescence response of the R-configuration of imines to the d-enantiomer of chiral amine, because the released BNDA can serve as the fluorescence signal output when the amine exchange reaction occurs, which is far higher than the response to its l-enantiomer under identical experimental conditions. For the S-configuration of chiral imines, the fluorescence response is the opposite. The enantioselective exchange reaction can be tuned by altering the electron-withdrawing or electron-donating capability of the substituent at position 4 or 5 of the SA part of chiral imines. Not only o-OH groups in SA-based imines but also protic solvents used as reaction media were found to be important to the dynamic behavior at high rates.


Assuntos
Aminas , Iminas , Catálise , Diaminas , Estereoisomerismo
6.
J Org Chem ; 86(19): 13454-13464, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34515479

RESUMO

A new type of diazo compounds, namely, CH-diazomethane sulfonamides (generated in situ from readily available α-acetyl-α-diazomethane sulfonamides), was employed in a 1,3-dipolar cycloaddition reaction with imines (also formed in situ from primary amines and aldehydes). The reaction gave hitherto undescribed 1,5-disubstituted 1,2,3-triazoline-4-sulfonamides, which were obtained in good to excellent yields with complete trans diastereoselectivity. These new sulfonamides based on the nonaromatic 1,2,3-triazoline core are rather attractive from a medicinal chemistry standpoint in light of the strong emphasis recently put on the nonflat, more saturated (higher Fsp3) scaffolds for lead-generation libraries. The oxidative aromatization of 1,2,3-triazoline-4-sulfonamides by manganese(IV) oxide gave nearly quantitative yields of 1,2,3-triazole-4-sulfonamides, of which only two examples have been reported in the literature.


Assuntos
Iminas , Sulfonamidas , Aldeídos , Compostos Azo , Estrutura Molecular
7.
J Org Chem ; 86(19): 13693-13701, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34529434

RESUMO

A transition-metal-free postmodification of the Groebke-Blackburn-Bienaymé (GBB) reaction for the synthesis of spiro[chromene-imidazo[1,2-a]pyridin]-3'-imine was discovered. The unusual transformation represents the first example of activation and the reaction of the imidazole carbon atom. In this postcondensational modification, KOt-Bu acts as a base, which, after the isomerization of an alkyne moiety to allene, causes the next unique nucleophilic reaction of the imidazole carbon atom that results in spirocyclic structures. The proposed reaction mechanism was confirmed based on the DFT calculations.


Assuntos
Iminas , Elementos de Transição , Alcinos , Benzopiranos , Ciclização
8.
Int J Mol Sci ; 22(18)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34576025

RESUMO

Aziridination reactions represent a powerful tool in aziridine synthesis. Significant progress has been achieved in this field in the last decades, whereas highly functionalized aziridines including 3-arylated aziridine-2-carbonyl compounds play an important role in both medical and synthetic chemistry. For the reasons listed, in the current review we have focused on the ways to obtain 3-arylated aziridines and on the recent advances (mainly since the year 2000) in the methodology of the synthesis of these compounds via aziridination.


Assuntos
Aziridinas/química , Cetonas/química , Aziridinas/síntese química , Ácidos Carboxílicos/química , Iminas/química , Estrutura Molecular , Estereoisomerismo
9.
Anal Chim Acta ; 1181: 338886, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34556223

RESUMO

A facile and rapid strategy for preparation of covalent organic framework (COF) coated fibers at ambient temperature is urgently needed for solid-phase microextraction (SPME) technology. In this work, an in situ room-temperature rapid growth strategy was developed to high-efficiently fabricate imine-linked COF (TPB-DVA) coated fibers in as little as 30 min at room temperature, and the thickness of the coating reached 9 µm. The prepared TPB-DVA coated fiber offer high thermal and chemical stability, and outstanding service lifetime. Moreover, we generalize this strategy to other two imine-linked COF (TPB-DMTP and TFPB-TAPB) coated fibers and the fibers were fabricated at room temperature for 3 h and 12 h, respectively, which demonstrate the applicability of this strategy. Subsequently, a SPME-GC-MS/MS analytical method was developed for trace pyrethroids (PYs) detection, which exhibited high enhancement factors (EFs, 2700-13195), wide linear range (0.08-800 ng L-1), low limits of detection (LODs, 0.02-0.20 ng L-1), and good repeatability (RSD ≤ 8.5%, n = 6). Furthermore, the developed analytical method was applied to tea samples and trace PYs (1.31-4.32 ng L-1) were found with satisfactory recovery (80.2-119.8%). The above results demonstrated that the feasibility of the developed strategy for the facile and rapid fabrication of imine-linked COF coated fibers.


Assuntos
Estruturas Metalorgânicas , Piretrinas , Poluentes Químicos da Água , Iminas , Limite de Detecção , Microextração em Fase Sólida , Espectrometria de Massas em Tandem , Temperatura , Poluentes Químicos da Água/análise
10.
J Org Chem ; 86(18): 12840-12850, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34469687

RESUMO

Stereoselective synthesis of the C4-C16 polyketide fragment of portimines A and B is reported, enabled by our previously established method for the stereoselective synthesis of syn-α,α'-dihydroxyketones. The preparation of this advanced fragment provides insights useful for the total synthesis of portimines A and B. An asymmetric Evans aldol reaction was used to install the C10-C11 adjacent stereogenic centers before incorporation of indantrione, followed by epoxidation and epoxide opening to forge the challenging syn-α,α'-dihydroxyketone functionality.


Assuntos
Policetídeos , Compostos de Espiro , Compostos de Epóxi , Iminas
11.
Acc Chem Res ; 54(19): 3710-3719, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34565142

RESUMO

Redox reactions that take place in enzymes and on the surfaces of heterogeneous catalysts often require active sites that contain multiple metals. By contrast, there are very few homogeneous catalysts with multinuclear active sites, and the field of organometallic chemistry continues to be dominated by the study of single metal systems. Multinuclear catalysts have the potential to display unique properties owing to their ability to cooperatively engage substrates. Furthermore, direct metal-to-metal covalent bonding can give rise to new electronic configurations that dramatically impact substrate binding and reactivity. In order to effectively capitalize on these features, it is necessary to consider strategies to avoid the dissociation of fragile metal-metal bonds in the course of a catalytic cycle. This Account describes one approach to accomplishing this goal using binucleating redox-active ligands.In 2006, Chirik showed that pyridine-diimines (PDI) have sufficiently low-lying π* levels that they can be redox-noninnocent in low-valent iron complexes. Extending this concept, we investigated a series of dinickel complexes supported by naphthyridine-diimine (NDI) ligands. These complexes can promote a broad range of two-electron redox processes in which the NDI ligand manages electron equivalents while the metals remain in a Ni(I)-Ni(I) state.Using (NDI)Ni2 catalysts, we have uncovered cases where having two metals in the active site addresses a problem in catalysis that had not been adequately solved using single-metal systems. For example, mononickel complexes are capable of stoichiometrically dimerizing aryl azides to form azoarenes but do not turn over due to strong product inhibition. By contrast, dinickel complexes are effective catalysts for this reaction and avoid this thermodynamic sink by binding to azoarenes in their higher-energy cis form.Dinickel complexes can also activate strong bonds through the cooperative action of both metals. Norbornadiene has a ring-strain energy that is similar to that of cyclopropane but is not prone to undergoing C-C oxidative addition with monometallic complexes. Using an (NDI)Ni2 complex, norbornadiene undergoes rapid ring opening by the oxidative addition of the vinyl and bridgehead carbons. An inspection of the resulting metallacycle reveals that it is stabilized through a network of secondary Ni-π interactions. This reactivity enabled the development of a catalytic carbonylative rearrangement to form fused bicyclic dienones.These vignettes and others described in this Account highlight some of the implications of metal-metal bonding in promoting a challenging step in a catalytic cycle or adjusting the thermodynamic landscape of key intermediates. Given that our studies have focused nearly exclusively on the (NDI)Ni2 system, we anticipate that many more such cases are left to be discovered as other transition-metal combinations and ligand classes are explored.


Assuntos
Complexos de Coordenação/química , Iminas/química , Níquel/química , Piridinas/química , Complexos de Coordenação/síntese química , Ligantes , Estrutura Molecular , Oxirredução
12.
J Org Chem ; 86(17): 11599-11607, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34351161

RESUMO

The mechanisms for the three- and four-component variants of the Castagnoli-Cushman reaction (CCR) have been investigated. A series of crossover experiments were conducted to probe the structure and reactivity of known amide-acid intermediates for the three- and four-component variants of the CCR (3CR and 4CR, respectively). Control experiments paired with in situ reaction monitoring with infrared spectroscopy for the 4CR align with a mechanism in which amide-acids derived from maleic anhydride can reversibly form free amine and cyclic anhydride. Although this equilibrium is unfavorable, the aldehyde present can trap the primary amine through imine formation and react with the enol form of the anhydride through a Mannich-like mechanism. This detailed mechanistic investigation coupled with additional crossover experiments supports an analogous mechanism for the 3CR and has led to the elucidation of new 3CR conditions with homophthalic anhydride, amines, and aldehydes for the formation of dihydroisoquinolones in good yields and excellent diastereoselectivity. This work represents the culmination of more than a decade of mechanistic speculation for the 3- and 4CR, enabling the design of new multicomponent reactions that exploit this novel mechanism.


Assuntos
Aldeídos , Aminas , Amidas , Anidridos , Iminas
13.
Biomolecules ; 11(8)2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34439823

RESUMO

Alveolar osteitis (AO) is a common complication following the extraction of the teeth, particularly the lower third molars. It starts within a few days after the extraction and manifests mainly as pain in the extraction site. Several strategies of treatment are available in order to relieve pain and heal the extraction wound. Recently, a novel medical device combining hyaluronic acid (HA) and octenidine (OCT) was introduced for the treatment of AO. This series of case reports aims to summarize the initial clinical experiences with this new device and to highlight factors possibly interfering with this treatment. The medical documentation of five patients with similar initial situations treated for AO with HA + OCT device was analyzed in detail. Smoking and previous treatment with Alveogyl (Septodont, Saint-Maur-des-Fossés, France) were identified as factors interfering with the AO treatment with the HA + OCT device. In three patients without these risk factors, the treatment led to recovery within two or three days. The patient pretreated with Alveogyl and the smoker required six and seven applications of the HA + OCT device, respectively. According to these initial observations, it seems smoking and previous treatment with Alveogyl prolong the treatment of AO using the HA + OCT device that, in turn, shows a rapid effect if these risk factors are not present.


Assuntos
Alvéolo Seco/tratamento farmacológico , Ácido Hialurônico/uso terapêutico , Iminas/uso terapêutico , Dor/tratamento farmacológico , Piridinas/uso terapêutico , Cicatrização/efeitos dos fármacos , Adolescente , Adulto , Creosoto/efeitos adversos , Combinação de Medicamentos , Alvéolo Seco/etiologia , Alvéolo Seco/fisiopatologia , Alvéolo Seco/cirurgia , Equipamentos e Provisões , Feminino , Humanos , Hidrocarbonetos Iodados/efeitos adversos , Pessoa de Meia-Idade , Dente Molar/cirurgia , Dor/etiologia , Dor/fisiopatologia , Dor/cirurgia , Fatores de Risco , Fumar/efeitos adversos , Extração Dentária/efeitos adversos , Resultado do Tratamento , Cicatrização/fisiologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-34343946

RESUMO

A single laboratory method performance verification is reported for a rapid sensitive UHPLC-MS/MS method for the quantification of eight cyclic imine and two brevetoxin analogues in two bivalve shellfish matrices: mussel (Mytilus edulis) and Pacific oyster (Crassostrea gigas). Targeted cyclic imine analogues were from the spirolide, gymnodimine and pinnatoxin groups, namely 20-Me-SPX-C, 13-desMe-SPX-C, 13,19-didesMe-SPX-C, GYM-A, 12-Me-GYM, PnTx-E, PnTx-F and PnTx-G. Brevetoxin analogues consisted of the shellfish metabolites BTX-B5 and S-desoxy-BTX-B2. A rapid dispersive extraction was used as well as a fast six-minute UHPLC-MS/MS analysis. Mobile phase prepared using ammonium fluoride and methanol was optimised for both chromatographic separation and MS/MS response to suit all analytes. Method performance verification checks for both matrices were carried out. Matrix influence was acceptable for the majority of analogues with the MS response for all analogues being linear across an appropriate range of concentrations. In terms of limits of detection and quantitation the method was shown to be highly sensitive when compared with other methods. Acceptable recoveries were found with most analogues, with laboratory precision in terms of intra- and inter-batch precision deemed appropriate. The method was applied to environmental shellfish samples with results showing low concentrations of cyclic imines to be present. The method is fast and highly sensitive for the detection and quantification of all targeted analogues, in both mussel and oyster matrices. Consequently, the method has been shown to provide a useful tool for simultaneous monitoring for the presence or future emergence of these two toxin groups in shellfish.


Assuntos
Bivalves/química , Cromatografia Líquida de Alta Pressão/métodos , Toxinas Marinhas/análise , Ostreidae/química , Espectrometria de Massas em Tandem/métodos , Animais , Iminas/análise , Iminas/química , Iminas/isolamento & purificação , Limite de Detecção , Modelos Lineares , Extração Líquido-Líquido , Toxinas Marinhas/química , Toxinas Marinhas/isolamento & purificação , Oxocinas/análise , Oxocinas/química , Oxocinas/isolamento & purificação , Reprodutibilidade dos Testes
15.
Chemistry ; 27(58): 14461-14471, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34327737

RESUMO

Pnictinidenes are an increasingly relevant species in main group chemistry and generally exhibit proclivity for the triplet electronic ground state. However, the elusive singlet electronic states are often desired for chemical applications. We predict the singlet-triplet energy differences (ΔEST =ESinglet -ETriplet ) of simple group 15 and 16 substituted pnictinidenes (Pn-R; Pn=P, As, Sb, or Bi) with highly reliable focal-point analyses targeting the CCSDTQ/CBS level of theory. The only cases we predict to have favorable singlet states are P-PH2 (-3.2 kcal mol-1 ) and P-NH2 (-0.2 kcal mol-1 ). ΔEST trends are discussed in light of the geometric predictions as well as qualitative natural bond order analysis to elucidate some of the important electronic structure features. Our work provides a rigorous benchmark for the ΔEST of fundamental Pn-R moieties and provides a firm foundation for the continued study of heavier pnictinidenes.


Assuntos
Iminas , Teoria Quântica
16.
Sci Total Environ ; 797: 149004, 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34293608

RESUMO

Trifloxystrobin is a new type of fungicide, which is extensively used due to its excellent antifungal activity. In this study, oxidative stress and DNA damage induced by trifloxystrobin exposure was evaluated using Eisenia fetida at subchronic toxicity concentrations in artificial soil and brown soil (0.1-2.5 mg/kg). Throughout the exposure period (days 7, 28 and 56), six biochemical indicators including reactive oxygen species (ROS), antioxidant enzymes (SOD and CAT), glutathione S-transferase (GST), lipid peroxidation and DNA damage (8-hydroxydeoxyguanosine) were measured. In addition, the integrated biomarker response (IBR) index was calculated to make comparison of toxicological response between artificial and brown soils. Results indicated that trifloxystrobin can induce oxidative stress and DNA damage to earthworms with subchronic toxicity greater in brown soil compared to artificial soil as determined through integrated calculations for six biochemical indicators. Trifloxystrobin toxicological experiments in artificial soil may not accurately evaluate its toxicity in natural soil ecosystems, as the toxicity of trifloxystrobin to Eisenia fetida was underestimated.


Assuntos
Oligoquetos , Poluentes do Solo , Acetatos , Animais , Catalase/metabolismo , Dano ao DNA , Ecossistema , Iminas , Malondialdeído , Oligoquetos/metabolismo , Estresse Oxidativo , Solo , Poluentes do Solo/toxicidade , Estrobilurinas , Superóxido Dismutase/metabolismo
17.
Chemistry ; 27(53): 13457-13467, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34270124

RESUMO

Despite their intrinsic hydrolysable character, imine bonds can become remarkably stable in water when self-assembled in amphiphilic micellar structures. In this work, we systematically studied some of these structures and the influence of various parameters that can be used to take control of their hydrolysis, including pH, concentration, the position of the imine function in the amphiphilic structure, relative lengths of the linked hydrophilic and hydrophobic moieties. Thermodynamic and kinetic data led us to the rational design of stable imines in water, partly based on the location of the imine function within the hydrophobic part of the amphiphile and on a predictable quantitative term that we define as the total hydrophilic-lipophilic balance (HLB). In addition, we show that such stable systems are also stimuli-responsive and therefore, of potential interest in trapping and releasing micellar components on demand.


Assuntos
Iminas , Micelas , Hidrólise , Interações Hidrofóbicas e Hidrofílicas , Água
18.
Biomolecules ; 11(7)2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209460

RESUMO

High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. PTP4A3 mRNA levels were 5-20 fold higher in drug resistant or high grade serous OvCa cell lines compared to nonmalignant cells. JMS-053 is a potent allosteric small molecule PTP4A3 inhibitor and to explore further the role of PTP4A3 in OvCa, we synthesized and interrogated a series of JMS-053-based analogs in OvCa cell line-based phenotypic assays. While the JMS-053 analogs inhibit in vitro PTP4A3 enzyme activity, none were superior to JMS-053 in reducing high grade serous OvCa cell survival. Because PTP4A3 controls cell migration, we interrogated the effect of JMS-053 on this cancer-relevant process. Both JMS-053 and CRISPR/Cas9 PTP4A3 depletion blocked cell migration. The inhibition caused by JMS-053 required the presence of PTP4A3. JMS-053 caused additive or synergistic in vitro cytotoxicity when combined with paclitaxel and reduced in vivo OvCa dissemination. These results indicate the importance of PTP4A3 in OvCa and support further investigations of the lead inhibitor, JMS-053.


Assuntos
Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Proteínas Tirosina Fosfatases/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Bases de Dados Genéticas , Feminino , Humanos , Iminas/química , Iminas/farmacologia , Proteínas de Neoplasias/fisiologia , Neoplasias Ovarianas/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Monoéster Fosfórico Hidrolases/fisiologia , Proteínas Tirosina Fosfatases/fisiologia , Piridinas/química , Piridinas/farmacologia
19.
J Org Chem ; 86(15): 10665-10671, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34255506

RESUMO

The mechanism of the Kinugasa reaction, that is, the copper-catalyzed formation of ß-lactams from nitrones and terminal alkynes, is re-evaluated by means of density functional theory calculations and in light of recent experimental findings. Different possible mechanistic scenarios are investigated using phenanthroline as a ligand and triethylamine as a base. The calculations confirm that after an initial two-step cycloaddition promoted by two copper ions, the resulting five-membered ring intermediate can undergo a fast and irreversible cycloreversion to generate an imine and a dicopper-ketenyl intermediate. From there, the reaction can proceed through a nucleophilic attack of a ketenyl copper intermediate on the imine and an intramolecular cyclization, rather than through the previously suggested (2 + 2) Staudinger synthesis.


Assuntos
Alcinos , Iminas , Cobre , Ciclização , Reação de Cicloadição
20.
J Org Chem ; 86(15): 10555-10567, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34283591

RESUMO

The efficient assembly of complex aromatic structures from simple acyclic building blocks is reported. An anion-cascade union of an enoate and a conjugated imine affords cyclohexenone products, which are readily aromatized to phenols. By engaging the intermediate cyclohexenones with Grignard reagents, a facile addition/elimination proceeds yielding chiral cyclohexadienes, which are then aromatized. In a complementary approach, the cyclohexenone products are converted into enol triflates, which provides a gateway to diverse aromatic architectures following cross-couplings and aromatization steps.


Assuntos
Cicloexenos , Iminas , Fenóis
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