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1.
Molecules ; 27(21)2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36364453

RESUMO

Sterically shielded nitroxides, which demonstrate high resistance to bioreduction, are the spin labels of choice for structural studies inside living cells using pulsed EPR and functional MRI and EPRI in vivo. To prepare new sterically shielded nitroxides, a reaction of cyclic nitrones, including various 1-pyrroline-1-oxides, 2,5-dihydroimidazole-3-oxide and 4H-imidazole-3-oxide with alkynylmagnesium bromide wereused. The reaction gave corresponding nitroxides with an alkynyl group adjacent to the N-O moiety. The hydrogenation of resulting 2-ethynyl-substituted nitroxides with subsequent re-oxidation of the N-OH group produced the corresponding sterically shielded tetraalkylnitroxides of pyrrolidine, imidazolidine and 2,5-dihydroimidazole series. EPR studies revealed large additional couplings up to 4 G in the spectra of pyrrolidine and imidazolidine nitroxides with substituents in 3- and/or 4-positions of the ring.


Assuntos
Brometos , Imidazolidinas , Óxidos N-Cíclicos/química , Óxidos de Nitrogênio/química , Marcadores de Spin , Óxidos , Pirrolidinas/química , Espectroscopia de Ressonância de Spin Eletrônica/métodos
2.
Eur J Med Chem ; 244: 114854, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36274279

RESUMO

Several lines of evidence indicated that generation of NADPH oxidase (Nox)-mediated reactive oxygen species are associated with neuronal inflammation, leading to Parkinson's disease (PD). Novel benzylidene-1-methyl-2-thioxoimidazolidin-one derivatives as Nox inhibitors were designed and synthesized in order to increase blood-brain barrier (BBB) permeability to target Nox in brain cells. In lucigenin chemiluminescence assay, eight compounds showed excellent inhibition activity against NADPH oxidases and parallel artificial membrane permeability assay (PAMPA) identified compound 11 with high passive permeability. To validate the effect of compound 11 on neuronal inflammation, we tested the regulatory activity of compound 11 in lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines in BV-2 microglial cells and LPS-mediated microglial migration. Treatment of BV2 cells with compound 11 resulted in suppressed production of pro-inflammatory cytokines and migration activity of BV2 cells in response to LPS. To evaluate the therapeutic efficacy of compound 11 in PD animal model, compound 11 was applied to MPTP-induced PD mouse model. Oral administration of compound 11 (30 mg/kg/daily, 4 weeks) into the mice resulted in suppression of dopaminergic neuronal death in substantia nigra (SN) and in striatum as well as inhibition of microglial migration into SN. These results implicate compound 11 as a novel therapeutic agent for the treatment of PD.


Assuntos
Antiparkinsonianos , Inibidores Enzimáticos , Imidazolidinas , NADPH Oxidases , Doença de Parkinson , Animais , Camundongos , Citocinas/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Inflamação/induzido quimicamente , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , NADPH Oxidases/antagonistas & inibidores , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/química , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Imidazolidinas/química , Imidazolidinas/farmacologia , Imidazolidinas/uso terapêutico
3.
Molecules ; 27(19)2022 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-36235245

RESUMO

Many heterocyclic compounds can be synthetized using diaza-1,3-butadienes (DADs) as key structural precursors. Isolated and in situ diaza-1,3-butadienes, produced from their respective precursors (typically imines and hydrazones) under a variety of conditions, can both react with a wide range of substrates in many kinds of reactions. Most of these reactions discussed here include nucleophilic additions, Michael-type reactions, cycloadditions, Diels-Alder, inverse electron demand Diels-Alder, and aza-Diels-Alder reactions. This review focuses on the reports during the last 10 years employing 1,2-diaza-, 1,3-diaza-, 2,3-diaza-, and 1,4-diaza-1,3-butadienes as intermediates to synthesize heterocycles such as indole, pyrazole, 1,2,3-triazole, imidazoline, pyrimidinone, pyrazoline, -lactam, and imidazolidine, among others. Fused heterocycles, such as quinazoline, isoquinoline, and dihydroquinoxaline derivatives, are also included in the review.


Assuntos
Imidazolidinas , Imidazolinas , Butadienos/química , Hidrazonas , Iminas/química , Indóis , Isoquinolinas , Lactamas , Pirazóis , Pirimidinonas , Quinazolinas , Triazóis
4.
Molecules ; 27(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36296503

RESUMO

Allyl halides with triflamide under oxidative conditions form halogen-substituted amidines. Allyl cyanide reacts with triflamide in acetonitrile or THF solutions in the presence of NBS to give the products of bromotriflamidation with a solvent interception, whereas in CH2Cl2 two regioisomers of the bromotriflamidation product without a solvent interception were obtained. The formed products undergo base-induced dehydrobromination to give linear isomers with the new C=C bond conjugated either with the nitrile group or the amidine moiety or alkoxy group. Under the same conditions, the reaction of allyl alcohol with triflamide gives rise to amidine, which was prepared earlier by the reaction of diallyl formal with triflamide. Unlike their iodo-substituted analogs, bromo-substituted amidines successfully transform into imidazolidines under the action of potassium carbonate.


Assuntos
Amidinas , Imidazolidinas , Amidinas/química , Solventes/química , Nitrilas , Acetonitrilas , Halogênios
5.
J Enzyme Inhib Med Chem ; 37(1): 2551-2565, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36120957

RESUMO

The molecular chaperone HSP90 plays an essential role in cancer occurrence and development. Therefore, it is an important target for the development of anticancer drugs. 1,3-Dibenzyl-2-aryl imidazolidine (8) is a previously reported inhibitor of HSP90; however, its anticancer activity is poor. In this work, chemical modification of 8 led to the discovery of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as two types of novel HSP90 N-terminal inhibitors. 16l and 22k exhibited antiproliferative activity against multiple breast cancer cell lines with IC50 values at the low micromolar level. 16l and 22k induced significant degradation of the client proteins AKT and ERK and a lower level of the heat shock response in comparison with tanespimycin (17-AAG). 22k exhibited a strong affinity for the HSP90α N-terminus with an IC50 value of 0.21 µM. A molecular docking study revealed that 16l and 22k successfully bind to the geldanamycin binding site at the N-terminus of HSP90α.


Assuntos
Antineoplásicos , Imidazolidinas , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzoquinonas , Proteínas de Choque Térmico HSP90 , Humanos , Lactamas Macrocíclicas , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-akt
6.
J Mol Model ; 28(10): 332, 2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36163521

RESUMO

Using metal substrates that are nanoscale in size, surface-enhanced Raman scattering (SERS) is a technique for enhancing the Raman signal of biomolecules. Numerous industries including sensing materials, adsorption and medical devices, use nanomaterials like nanocages and nanoclusters. To discover a possible novel sensor platform involving a small metal cluster and a curved rigid substrate, we used density functional theoretical (DFT) simulations to explore the adsorption of glycoluril (GLC), a prospective drug intermediate, on a pure magnesium oxide cage (Mg12O12). This well defined cage was used as (i) an exact probable structure that could be used as well as (ii) a general model for MgO nanostructures. We also investigated the mono Al-doped Mg12O12 nanocage version Mg11AlO12. All computations were performed at the M06-2X level of theory. The GLC binds to the Mg12O12 nanocage by way of strong donor-acceptor interactions. The adsorption is releasing - 45.80 kcal mol-1 of energy. Due to Al doping, the energy gap of GLC-Mg11AlO12 (1.91 eV) is reduced from that of GLC-Mg12O12 (4.28 eV) and hence there is an increase in electrical conductivity of GLC-Mg11AlO12. The electronic change in the nanocage's conductivity can be transformed into an electrical signal which can be used to detect the presence of the drug analyte. In addition, when a GLC molecule is present, the work function of the nanocage is also reduced. The MgO nanocage, we conclude, is a work function type as well as a possible electronic sensor for GLC drug detection. GLC desorption from the Mg11AlO12 surface recovers more quickly in comparison with Mg12O12 recovery time. The AIM and NCIs assessed in this study were performed to help analyze the electronic structures of the complexes. Our findings pave the possibility for Mg11AlO12 nanostructures to be used in drug recognition.


Assuntos
Nanoestruturas , Materiais Inteligentes , Adsorção , Condutividade Elétrica , Compostos Heterocíclicos com 2 Anéis , Imidazolidinas , Óxido de Magnésio/química , Modelos Teóricos , Nanoestruturas/química
7.
Molecules ; 27(17)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36080213

RESUMO

Two new azobenzene heptamethine cyanine conjugates exist as dispersed monomeric molecules in methanol solution and exhibit near-infrared (NIR) cyanine absorption and fluorescence. Both conjugates form non-emissive cyanine H-aggregates in water, but the addition of cucurbit[7]uril (CB7) induces dye deaggregation and a large increase in cyanine NIR fluorescence emission intensity. CB7 encapsulates the protonated azonium tautomer of the 4-(N,N-dimethylamino)azobenzene component of each azobenzene-cyanine conjugate and produces a distinctive new absorption band at 534 nm. The complex is quite hydrophilic, which suggests that CB7 can be used as a supramolecular additive to solubilize this new family of NIR azobenzene-cyanine conjugates for future biomedical applications. Since many azobenzene compounds are themselves potential drug candidates or theranostic agents, it should be possible to formulate many of them as CB7 inclusion complexes with improved solubility, stability, and pharmaceutical profile.


Assuntos
Hidrocarbonetos Aromáticos com Pontes , Quinolinas , Compostos Azo , Corantes , Corantes Fluorescentes , Compostos Heterocíclicos com 2 Anéis , Imidazóis , Imidazolidinas , Compostos Macrocíclicos
8.
Anal Chim Acta ; 1226: 340262, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36068061

RESUMO

The efficient and selective detection of isomers is an attractive but challenging area. In this study, a supramolecular fluorescent probe based on cucurbit[8]uril (Q[8]) and a pyrene-based derivative (G) was prepared, which effectively recognized and removed o-nitrophenol (o-NP) from a mixture of nitrophenol isomers. The newly designed probe G@Q[8] was characterized by NMR spectroscopy, fluorescence emission and UV-Vis spectroscopy, and its host-guest properties in aqueous solution were investigated. The results revealed that the system forms a stable inclusion complex with a stoichiometric ratio of 1:1, which was accompanied by a distinct fluorescence enhancement of G. Moreover, it was employed for the rapid detection of nitrophenol isomers where o-NP showed a dramatical quenching efficiency with a detection limit of 1.53 × 10-7 mol·L-1. This highly efficient supramolecular fluorescent probe offers a new strategy for the convenient detection and removal of o-NP from mixtures in aqueous medium.


Assuntos
Corantes Fluorescentes , Nitrofenóis , Hidrocarbonetos Aromáticos com Pontes/química , Corantes Fluorescentes/química , Compostos Heterocíclicos com 2 Anéis , Imidazolidinas , Compostos Macrocíclicos , Espectroscopia de Ressonância Magnética , Água/química
9.
J Am Chem Soc ; 144(33): 15324-15332, 2022 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-35929817

RESUMO

Reactive sulfur species (RSS) play critical roles in diverse chemical environments. Molecules containing sulfane sulfur (S0) have emerged as key species involved in cellular redox buffering as well as RSS generation, translocation, and action. Using cucurbit[7]uril (CB[7]) as a model hydrophobic host, we demonstrate here that S8 can be encapsulated to form a 1:1 host guest complex, which was confirmed by solution state experiments, mass spectrometry, and X-ray crystallography. The solid state structure of CB[7]/S8 shows that the encapsulated S8 is available to nucleophiles through the carbonyl portals of the host. Treatment of CB[7]/S8 with thiols results in efficient reduction of S8 to H2S in water at physiological pH. We establish that encapsulated S8 is attacked by a thiol within the CB[7] host and that the resultant soluble hydropolysulfide is ejected into solution, where it reacts further with thiols to generate soluble sulfane sulfur carriers and ultimately H2S. The formation of these intermediate is supported by observed kinetic saturation behavior, competitive inhibition experiments, and alkylative trapping experiments. We also demonstrate that CB[7]/S8 can be used to increase sulfane sulfur levels in live cells using fluorescence microscopy. More broadly, this work suggests a general activation mechanism of S8 by hydrophobic motifs, which may be applicable to proteins, membranes, or other bimolecular compartments that could transiently bind and solubilize S8 to promote reaction with thiols to solubilize and shuttle S8 back into the redox labile sulfane sulfur pool. Such a mechanism would provide an attractive manifold in which to understand the RSS translocation and trafficking.


Assuntos
Sulfeto de Hidrogênio , Compostos de Sulfidrila , Compostos Heterocíclicos com 2 Anéis , Sulfeto de Hidrogênio/química , Imidazolidinas , Compostos Macrocíclicos , Piperidinas , Enxofre/metabolismo , Água
10.
J Am Chem Soc ; 144(31): 14363-14379, 2022 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-35913703

RESUMO

In a three-dimensional (3D) representation, each protein molecule displays a specific pattern of chemical and topological features, which are altered during its misfolding and aggregation pathway. Generating a recognizable fingerprint from such features could provide an enticing approach not only to identify these biomolecules but also to gain clues regarding their folding state and the occurrence of pathologically lethal misfolded aggregates. We report here a universal strategy to generate a fluorescent fingerprint from biomolecules by employing the pan-selective molecular recognition feature of a cucurbit[7]uril (CB[7]) macrocyclic receptor. We implemented a direct sensing strategy by covalently tethering CB[7] with a library of fluorescent reporters. When CB[7] recognizes the chemical and geometrical features of a biomolecule, it brings the tethered fluorophore into the vicinity, concomitantly reporting the nature of its binding microenvironment through a change in their optical signature. The photophysical properties of the fluorophores allow a multitude of probing modes, while their structural features provide additional binding diversity, generating a distinct fluorescence fingerprint from the biomolecule. We first used this strategy to rapidly discriminate a diverse range of protein analytes. The macrocyclic sensor was then applied to probe conformational changes in the protein structure and identify the formation of oligomeric and fibrillar species from misfolded proteins. Notably, the sensor system allowed us to differentiate between different self-assembled forms of the disease-specific amyloid-ß (Aß) aggregates and segregated them from other generic amyloid structures with a 100% identification accuracy. Ultimately, this sensor system predicted clinically relevant changes by fingerprinting serum samples from a cohort of pregnant women.


Assuntos
Peptídeos beta-Amiloides , Hidrocarbonetos Aromáticos com Pontes , Amiloide , Peptídeos beta-Amiloides/química , Hidrocarbonetos Aromáticos com Pontes/química , Feminino , Corantes Fluorescentes/química , Compostos Heterocíclicos com 2 Anéis , Humanos , Imidazóis/química , Imidazolidinas , Compostos Macrocíclicos , Gravidez
11.
Org Lett ; 24(35): 6443-6448, 2022 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-36017905

RESUMO

Reported herein are the unprecedented copper-catalyzed formal [n + 1]/[n + 3] (n = 5, 6) cycloadditions of diazo compounds with imidazolidines/hexahydropyrimidines, thus providing a general, economical, and efficient route to construct different sized (six- to nine-membered) diaza-heterocycles in moderate to excellent yields under mild reaction conditions. This strategy features the use of copper catalyst to accomplish such diverse annulations and the utilization of imidazolidines/hexahydropyrimidines as stable 1,5-/1,6-dipoles.


Assuntos
Cobre , Imidazolidinas , Compostos Azo , Catálise , Reação de Cicloadição
12.
J Colloid Interface Sci ; 627: 942-955, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35901573

RESUMO

Pressure ulcer is a common chronic injury in the bedridden population. The wound is easily subjected to secondary pressure injury due to the inconvenient mobility of patients, which greatly prolongs the hospital stay of patients and is highly prone to wound infection or other complications. It is urgent to develop a multifunctional wound dressing with pressure sensing, real-time monitoring, and wound therapy to overcome the secondary pressure injury during treatment. Here, a polyvinyl alcohol/acrylamide-ionic liquid hydrogel dressing is designed based on the antibacterial property and electrical conductivity of imidazolidine ionic liquids. Compared with existing pressure-sensing hydrogels, the hydrogel exhibits extremely high pressure sensitivity (9.19 kPa-1). Meanwhile, the good real-time responsiveness, stable signal output as well as excellent mechanical properties enable the hydrogel to monitor human movement on a large scale, and transmit the pressure status of patient wounds to nursing staff in a timely manner to avoid secondary pressure injuries. In addition, this hydrogel dressing exhibits a wide range of antibacterial activities against Gram-negative and Gram-positive bacteria as well as fungi, and has a significant therapeutic effect on full-thickness skin wounds by inhibiting wound infection, rapidly eradicating inflammation, promoting proliferation and tissue remodeling. This multifunctional hydrogel dressing opens a therapeutic and regulatory two-pronged strategy avenue through chronic wound management and pressure sensing monitoring.


Assuntos
Imidazolidinas , Líquidos Iônicos , Infecção dos Ferimentos , Acrilamidas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bandagens , Humanos , Hidrogéis/farmacologia , Álcool de Polivinil , Cicatrização
13.
Org Biomol Chem ; 20(29): 5796-5802, 2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35833381

RESUMO

The supramolecular complexation of doxepin (DOX) with cucurbit[7]uril (CB7) was investigated in aqueous solution. The results indicated the formation of a host-guest complex, as verified by complexation-induced chemical shifts in the NMR experiments and supported by quantum-chemical calculations, in which the alkylammonium tail of DOX was found to be encapsulated inside the CB7 cavity, while the tricyclic moiety remained exposed to bulk water. Isothermal titration calorimetry and dye-displacement experiments provided a moderate binding affinity (104 M-1). Interestingly, the partial encapsulation of DOX by the CB7 macrocycle led to the development of a supramolecular assembly at a low millimolar concentration, as verified by NMR and dynamic light scattering (DLS) measurements, which showed homogeneous size distributions with an average diameter of 1700 nm.


Assuntos
Hidrocarbonetos Aromáticos com Pontes , Doxepina , Hidrocarbonetos Aromáticos com Pontes/química , Calorimetria , Compostos Heterocíclicos com 2 Anéis , Imidazóis/química , Imidazolidinas , Compostos Macrocíclicos , Água/química
14.
Int J Pharm ; 625: 122048, 2022 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-35902054

RESUMO

Precise delivery of hydrophobic drugs has always been a great challenge for drug delivery systems. To overcome this problem, we designed and synthesized a novel supramolecular host biotin-acyclic cucurbituril (ACBB) at the first time, and we have developed a host-guest amphiphilic complex based on ACBB and amantadine-conjugated cannabinoids (AD-CBD) that self-assembles to form functionalized supramolecular micelles (FSMs) for cell-targeted drug delivery. The 1:1 stoichiometric ratio of the amphiphilic complex and its possible host-guest inclusion behaviors are obtained by fluorescence titration, nuclear magnetic resonance (NMR), Fourier transform-infrared spectroscopy (FT-IR) and thermal analysis (TGA and DSC). Using transmission electron microscope (TEM) and dynamic light scattering (DLS), we have observed that the shape of FSMs was spherical and size was 137-192 nm. In addition, MTT test results show that FSMs have good antitumor activity, taking MCF-7 as an example, the in vitro half-maximal inhibitory concentration (IC50) values of FSMs were 1.53 µM and 5.02 µM, which were better than 30.83 µM of cisplatin. Confocal laser scanning microscopy (CLSM) results showed that FSMs loaded with Rhodamine B can specifically aggregate on the surface of tumor cells and the targeting ability has been directly verified. Flow cytometry results showed that FSMs could promote tumor cell apoptosis. All results indicated that FSMs had high bioavailability, stability, accurate targeting and excellent delivery efficiency, which had great application potential in the field of drug delivery.


Assuntos
Canabidiol , Micelas , Biotina , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Compostos Heterocíclicos com 2 Anéis , Imidazolidinas , Compostos Macrocíclicos , Espectroscopia de Infravermelho com Transformada de Fourier
15.
Toxicol Appl Pharmacol ; 450: 116156, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35803438

RESUMO

Anaplastic lymphoma kinase (ALK) belongs to the family of receptor tyrosine kinases. Recently, the incidence of anaplastic large cell lymphoma (ALCL) with ALK rearrangement has raised considerably. The application of ALK-targeted inhibitors such as ceritinib provides an effective therapy for the treatment of ALK-positive cancers. However, with the prolongation of treatment time, the emergence of resistance is inevitable. We found that 1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3-(2-(dimethylamino)ethyl)imidazolidin-2-one (ZX-42), a novel ceritinib derivative, could inhibit the proliferation of ALK-positive ALCL cells, induce the apoptosis of Karpas299 cells through the mitochondrial pathway in a caspase-dependent manner. In addition, ZX-42 could suppress ALK and downstream pathways including PI3K/Akt, Erk and JAK3/STAT3 and reduce the nuclear translocation of NFκB by inhibiting TRAF2/IKK/IκB pathway. Taken together, our findings indicate that ZX-42 shows more effective activity than ceritinib against ALK-positive ALCL. We hope this study can provide a direction for the structural modification of ceritinib and lay the foundation for the further development of clinical research in ALK-positive ALCL.


Assuntos
Apoptose , Fosfatidilinositol 3-Quinases , Quinase do Linfoma Anaplásico , Linhagem Celular Tumoral , Proliferação de Células , Imidazolidinas , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/farmacologia
16.
J Am Chem Soc ; 144(29): 13084-13095, 2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35850489

RESUMO

Insufficient binding selectivity of chemosensors often renders biorelevant metabolites indistinguishable by the widely used indicator displacement assay. Array-based chemosensing methods are a common workaround but require additional effort for synthesizing a chemosensor library and setting up a sensing array. Moreover, it can be very challenging to tune the inherent binding preference of macrocyclic systems such as cucurbit[n]urils (CBn) by synthetic means. Using a novel cucurbit[7]uril-dye conjugate that undergoes salt-induced adaptation, we now succeeded in distinguishing 14 bioorganic analytes from each other through the facile stepwise addition of salts. The salt-specific concentration-resolved emission provides additional information about the system at a low synthetic effort. We present a data-driven approach to translate the human-visible curve differences into intuitive pairwise difference measures. Ion mobility experiments combined with density functional theory calculations gave further insights into the binding mechanism and uncovered an unprecedented ternary complex geometry for CB7. TThis work introduces the non-selectively binding, salt-adaptive cucurbit[n]uril system for sensing applications in biofluids such as urine, saliva, and blood serum.


Assuntos
Hidrocarbonetos Aromáticos com Pontes , Imidazóis , Compostos Heterocíclicos com 2 Anéis , Humanos , Imidazolidinas , Compostos Macrocíclicos
17.
J Am Chem Soc ; 144(31): 14235-14247, 2022 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-35895999

RESUMO

Photoswitchable fluorophores─proteins and synthetic dyes─whose emission is reversibly switched on and off upon illumination, are powerful probes for bioimaging, protein tracking, and super-resolution microscopy. Compared to proteins, synthetic dyes are smaller and brighter, but their photostability and the number of achievable switching cycles in aqueous solutions are lower. Inspired by the robust photoswitching system of natural proteins, we designed a supramolecular system based on a fluorescent diarylethene (DAE) and cucurbit[7]uril (CB7) (denoted as DAE@CB7). In this assembly, the photoswitchable DAE molecule is encapsulated by CB7 according to the host-guest principle, so that DAE is protected from the environment and its fluorescence brightness and fatigue resistance in pure water improved. The fluorescence quantum yield (Φfl) increased from 0.40 to 0.63 upon CB7 complexation. The photoswitching of the DAE@CB7 complex, upon alternating UV and visible light irradiations, can be repeated 2560 times in aqueous solution before half-bleaching occurs (comparable to fatigue resistance of the reversibly photoswitchable proteins), while free DAE can be switched on and off only 80 times. By incorporation of reactive groups [maleimide and N-hydroxysuccinimidyl (NHS) ester], we prepared bioconjugates of DAE@CB7 with antibodies and demonstrated both specific labeling of intracellular proteins in cells and the reversible on/off switching of the probes in cellular environments under irradiations with 355 nm/485 nm light. The bright emission and robust photoswitching of DAE-Male3@CB7 and DAE-NHS@CB7 complexes (without exclusion of air oxygen and addition of any stabilizing/antifading reagents) enabled confocal and super-resolution RESOLFT (reversible saturable optical fluorescence transitions) imaging with apparent 70-90 nm optical resolution.


Assuntos
Hidrocarbonetos Aromáticos com Pontes , Imidazóis , Fluorescência , Corantes Fluorescentes , Compostos Heterocíclicos com 2 Anéis , Imidazolidinas , Compostos Macrocíclicos , Água
18.
Anal Chem ; 94(24): 8715-8723, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35671188

RESUMO

The target of typical PCR analysis is restricted to nucleic acids. To this end, we report here a novel strategy to simultaneously detect genetic and metabolic markers using commercial PCR kits with cucurbit[8]urils (CB[8]) implemented to manipulate the activity of Taq DNA polymerase. CB[8] binds with the nonionic surfactants and displaces them from the polymerase surface, resulting in decreased enzyme activity. Meanwhile, the inhibited enzyme can be reversibly activated when spermine, the downstream metabolite of ornithine decarboxylase (ODC), is present in the sample, which competitively binds to CB[8] and recovers polymerase activity. CB[8] was implemented in conventional PCR kits not only to reduce false-positive results but also to extend the detection range of PCR technology. With this novel method to detect ODC in cell lysates containing both the nucleotides and intracellular metabolites, positive results were only observed in highly active HEK 293T cells, whereas silent cells treated with ODC inhibitor showed negative readouts, therefore providing a simple but elegant dual-modality PCR method for precision diagnosis.


Assuntos
Inibidores da Ornitina Descarboxilase , Ornitina Descarboxilase , Compostos Heterocíclicos com 2 Anéis , Imidazolidinas , Compostos Macrocíclicos , Nucleotidiltransferases/genética , Ornitina Descarboxilase/genética , Ornitina Descarboxilase/metabolismo , Reação em Cadeia da Polimerase , Transcrição Genética
19.
Methods Mol Biol ; 2487: 177-187, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35687236

RESUMO

Self-assembly is a phenomenon that governs molecular structural organization in nature, therefore raising research interest for the fabrication of novel nanomaterials with diverse applications in biocatalysis, biomedicine, material templating, and biosensor development. In this chapter we provide protocols for the development of supramolecular protein complexes based on host-guest interactions in the presence of the macrocyclic host, cucurbit[8]uril (CB[8]). CB[8] is reported to exhibit high binding affinity towards the tripeptide Phe-Gly-Gly (FGG), therefore it can be utilized as a selective adhesive of protein molecules, after fusion of FGG to an accessible protein surface.


Assuntos
Hidrocarbonetos Aromáticos com Pontes , Nanoestruturas , Compostos Heterocíclicos com 2 Anéis , Imidazóis/química , Imidazolidinas , Compostos Macrocíclicos , Nanoestruturas/química , Proteínas/química
20.
J Am Chem Soc ; 144(25): 11364-11376, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35687857

RESUMO

Pd-catalyzed sequential hydroamination of readily available 1,3-enynes is reported. The redox-neutral process provides an efficient route to synthesize a broad scope of imidazolidinones, thiadiazolidines, and imidazolidines. Asymmetric sequential hydroamination generates a series of synthetically valuable, enantioenriched imidazolidinones. Mechanistic studies revealed that the transformation occurred via an intermolecular enyne hydroamination pathway to give an allene intermediate. Subsequent intramolecular hydroamination of the allene intermediate proceeded under the Curtin-Hammett principle to provide enantioenriched imidazolidinone products.


Assuntos
Imidazolidinas , Paládio , Aminação , Catálise , Estereoisomerismo
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