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1.
Pestic Biochem Physiol ; 179: 104972, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34802522

RESUMO

Long non-coding RNAs (lncRNAs) represent the largest class of non-coding transcripts. They act a pivotal part in various insect developmental processes and stress responses. However, the investigation of lncRNA functions in insecticide resistant remains at an early phase. Herein, we conducted whole-transcriptome RNA sequencing for two cotton aphid (Aphis gossypii Glover) strains, i.e., insecticide-susceptible (SS) and spirotetramat-resistant (SR). We discovered 6059 lncRNAs in the RNA-Seq data, and 874 lncRNAs showed differential expression. In addition, 5 lncRNAs among 874 lncRNAs were predicted as targets of acetyl-CoA carboxylase (ACC). Reverse transcription real-time quantitative PCR (RT-qPCR) combined with RNA interference (RNAi) confirmed that selected ACC lncRNA was related to the expression of ACC. Moreover, we also identified two transcription factors, i.e., C/EBP and C/EBPzeta, that regulate the transcription level of ACC lncRNA. These results provide a good basis for the study of cotton aphid lncRNA functions in insecticide resistance development.


Assuntos
Afídeos , Compostos Aza , RNA Longo não Codificante , Acetil-CoA Carboxilase/genética , Animais , Afídeos/genética , Resistência a Inseticidas/genética , RNA Longo não Codificante/genética , Compostos de Espiro
3.
Angew Chem Int Ed Engl ; 60(38): 20744-20747, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34324230

RESUMO

Azadithiolate, a cofactor found in all [FeFe]-hydrogenases, is shown to undergo acid-catalyzed rearrangement. Fe2 [(SCH2 )2 NH](CO)6 self-condenses to give Fe6 [(SCH2 )3 N]2 (CO)17 . The reaction, which is driven by loss of NH4 + , illustrates the exchange of the amine group. X-ray crystallography reveals that three Fe2 (SR)2 (CO)x butterfly subunits interconnected by the aminotrithiolate [N(CH2 S)3 ]3- . Mechanistic studies reveal that Fe2 [(SCH2 )2 NR](CO)6 participate in a range of amine exchange reactions, enabling new methodologies for modifying the adt cofactor. Ru2 [(SCH2 )2 NH](CO)6 also rearranges, but proceeds further to give derivatives with Ru-alkyl bonds Ru6 [(SCH2 )3 N][(SCH2 )2 NCH2 ]S(CO)17 and [Ru2 [(SCH2 )2 NCH2 ](CO)5 ]2 S.


Assuntos
Compostos Aza/metabolismo , Complexos de Coordenação/metabolismo , Hidrogenase/metabolismo , Rubídio/metabolismo , Tolueno/análogos & derivados , Compostos Aza/química , Complexos de Coordenação/química , Modelos Moleculares , Estrutura Molecular , Rubídio/química , Tolueno/química , Tolueno/metabolismo
4.
J Med Chem ; 64(14): 10286-10296, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34253025

RESUMO

The neurotrophic receptor tyrosine kinase (NTRK) genes including NTRK1, NTRK2, and NTRK3 encode the tropomyosin receptor kinase (Trk) proteins TrkA, TrkB, and TrkC, respectively. So far, two TRK inhibitors, larotrectinib sulfate (LOXO-101 sulfate) and entrectinib (NMS-E628, RXDX-101), have been approved for clinical use in 2018 and 2019, respectively. To overcome acquired resistance, next-generation Trk inhibitors such as selitrectinib (LOXO-195) and repotrectinib (TPX-0005) have been developed and exhibit effectiveness to induce remission in patients with larotrectinib treatment failure. Herein, we report the identification and optimization of a series of macrocyclic compounds as potent pan-Trk (WT and MT) inhibitors that exhibited excellent physiochemical properties and good oral pharmacokinetics. Compound 10 was identified via optimization from the aspects of chemistry and pharmacokinetic properties, which showed good activity against wild and mutant TrkA/TrkC in in vitro and in vivo studies.


Assuntos
Antineoplásicos/farmacologia , Compostos Aza/farmacologia , Descoberta de Drogas , Compostos Macrocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Aza/síntese química , Compostos Aza/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Ratos , Ratos Sprague-Dawley , Receptor trkA/antagonistas & inibidores , Receptor trkA/metabolismo , Receptor trkB/antagonistas & inibidores , Receptor trkB/metabolismo , Receptor trkC/antagonistas & inibidores , Receptor trkC/metabolismo , Relação Estrutura-Atividade
5.
Chem Commun (Camb) ; 57(57): 6975-6978, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34219132

RESUMO

The first enantioselective carbometalation reaction of azabicycloalkenes has been achieved by iron catalysis to in situ form optically active organozinc intermediates, which are amenable to further synthetic elaborations. The observed chiral induction, along with the DFT and XAS analyses, reveals the direct coordination of the chiral phosphine ligand to the iron centre during the carbon-carbon and carbon-metal bond forming step. This new class of iron-catalysed asymmetric reaction will contribute to the synthesis and production of bioactive molecules.


Assuntos
Alcenos/química , Ferro/química , Alcenos/síntese química , Compostos Aza/química , Carbono/química , Catálise , Teoria da Densidade Funcional , Ligantes , Fosfinas/química , Estereoisomerismo , Espectroscopia por Absorção de Raios X
6.
Methods Enzymol ; 656: 169-190, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34325786

RESUMO

Azapeptides contain at least one aza-amino acid, where the α-carbon has been replaced by a nitrogen atom, and have found broad applicability in fields ranging from medicinal chemistry to biomaterials. In this chapter, we provide a step-by-step protocol for the solid phase submonomer synthesis of azapeptides, which includes three steps: (1) hydrazone activation and coupling onto a resin-bound peptide, (2) chemoselective semicarbazone functionalization for installation of the aza-amino acid side chain, and (3) orthogonal deprotection of the semicarbazone to complete the monomer addition cycle. We focus on semicarbazone functionalization by N-alkylation with primary alkyl halides, and describe conditions for coupling onto aza-amino acids. Such divergent methods accelerate the synthesis of peptidomimetics and allow the rapid introduction of a wide variety of natural and unnatural side chains directly on solid support using easily accessible submonomers.


Assuntos
Compostos Aza , Peptidomiméticos , Aminoácidos , Peptídeos , Técnicas de Síntese em Fase Sólida
7.
Eur J Med Chem ; 222: 113625, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34146914

RESUMO

Dicationic diamidines have been well established as potent antiparasitic agents with proven activity against tropical diseases like trypanosomiasis and malaria. This work presents the synthesis of new mono and diflexible triaryl amidines (6a-c, 13a,b and 17), their aza analogues (23 and 27) and respective methoxyamidine prodrugs (5, 7, 12a,b, 22 and 26). All diamidines were assessed in vitro against Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) where they displayed potent to moderate activities at the nanomolar level with IC50s = 11-378 nM for T. b. r. and 4-323 nM against P. f.. In vivo efficacy testing against T. b. r. STIB900 has shown the monoflexible diamidine 6c as the most potent derivative in this study eliciting 4/4 cures of infected mice for a treatment period of >60 days upon a 4 × 5 mg/kg dose i. p. treatment. Moreover, thermal melting analysis measurement ΔTm for this series of diamidines/poly (dA-dT) complexes fell between 0.5 and 19 °C with 6c showing the highest binding to the DNA minor groove. Finally, a 50 ns molecular dynamics study of an AT-rich DNA dodecamer with compound 6c revealed a strong binding complex supported by vdW and electrostatic interactions.


Assuntos
Amidinas/farmacologia , Antiparasitários/farmacologia , Compostos Aza/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Pró-Fármacos/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Amidinas/síntese química , Amidinas/química , Antiparasitários/síntese química , Antiparasitários/química , Compostos Aza/síntese química , Compostos Aza/química , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/enzimologia
8.
J Chromatogr A ; 1651: 462296, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34144400

RESUMO

A 34-membered tetraazahexaphenylmacrocycle (N4Ph6) with a rigid π-conjugated moiety was chemically bonded to silica gel with 3-chloropropyltrimethoxysilane as the coupling agent to prepare a novel SiO2@N4Ph6 stationary phase. Several common organic analytes, including alkylbenzenes, polycyclic aromatic hydrocarbons, anilines, phenols, phthalates, and folic acid, were selected as probes to investigate its chromatographic performance. The as-developed SiO2@N4Ph6 stationary phase showed superiority retention and high selectivity for probe molecules through multiple interactions, including hydrophobic, π-π, hydrogen-bonding, and steric interactions. Density functional theory calculation results using folic acid as model solute provided an intuitive and a quantitative description of the multiple retention mechanisms.


Assuntos
Compostos Aza/química , Compostos Macrocíclicos/química , Teoria da Densidade Funcional , Interações Hidrofóbicas e Hidrofílicas , Fenóis/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Padrões de Referência , Reprodutibilidade dos Testes , Dióxido de Silício/química , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Termodinâmica
9.
Environ Pollut ; 287: 117649, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34182397

RESUMO

Gabapentin-lactam (GBP-L) is a transformation product (TP) of gabapentin (GBP), a widely used anti-epileptic pharmaceutical. Due to its high persistence, GBP-L has been frequently detected in the surface water. However, the effects of GBP-L on aquatic organisms have not been thoroughly investigated. In the present study, zebrafish (Danio rerio) embryos as a model organism were used to study the impacts of GBP-L in terms of embryos LC50, spontaneous movement at 24 hpf (hours post fertilization), heartbeat rates at 48 hpf, and body length at 72 hpf, with the concentrations of GBP-L down to 0.01 µg/L, covering its environmental concentrations. Various biomarkers from nervous, antioxidant and immune systems of zebrafish larvae were analyzed, including acetylcholinesterase, acetylcholine, dopamine, gamma-aminobutyric acid, superoxide dismutase, catalase, glutathione S-transferase, C reactive protein, and lysozyme, to assess its toxicity on these systems. RT-qPCR was then used to further verify the results and explain the toxicological mechanism at the gene level. The results demonstrated that GBP-L is much more toxic than its parent compound, and could lead to adverse impacts on the aquatic organisms even at every low concentrations.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Animais , Compostos Aza , Embrião não Mamífero/metabolismo , Larva , Estresse Oxidativo , Compostos de Espiro , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/toxicidade
10.
J Natl Compr Canc Netw ; 19(5): 478-482, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34030125

RESUMO

NTRK gene fusions are found in <1% of all cancers but are uniformly present in mammary analog secretory carcinomas (MASC) of the salivary glands. Two selective histology-agnostic tropomyosin receptor kinase (TRK) inhibitors are currently approved for malignancies with these oncogenic fusions. Resistance to TRK inhibition has been recognized, and the mediating mechanisms are presently being studied. This report describes a patient diagnosed with an MASC of the parotid gland who after undergoing multiple lines of treatment was found to have an ETV6-NTRK3 fusion and initiated TRK-targeted therapy using entrectinib. Upon disease progression, we performed tumor genetic sequencing that showed a secondary resistance mutation. The patient subsequently responded to selitrectinib, a next-generation TRK inhibitor.


Assuntos
Compostos Aza/uso terapêutico , Carcinoma Secretor Análogo ao Mamário , Neoplasias das Glândulas Salivares/tratamento farmacológico , Benzamidas , Resistencia a Medicamentos Antineoplásicos , Humanos , Indazóis , Carcinoma Secretor Análogo ao Mamário/tratamento farmacológico , Carcinoma Secretor Análogo ao Mamário/genética , Proteínas de Fusão Oncogênica/genética , Glândula Parótida/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias das Glândulas Salivares/genética
11.
Bioorg Chem ; 113: 104992, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34051415

RESUMO

Bacterial infections are still the main significant problem of public health in the world, and their elimination will greatly rely on the discovery of antibacterial drugs. In the processes of our searching for novel macrolide derivatives with excellent activity against sensitive and resistant bacteria, three series of novel N11-, C12- and C13-substituted 15-membered homo-aza-clarithromycin derivatives were designed and synthesized as Series A, B and C by creatively opening the lactone ring of clarithromycin (CAM), introducing various 4-substituted phenyl-1H-1,2,3-triazole side chains at the N11, C12 or C13 position of CAM and macrolactonization. The results from their in vitro antibacterial activity demonstrated that compounds 20c, 20d and 20f displayed not only the most potent activity against S. aureus ATCC25923 with the MIC values of 0.5, 0.5 and 0.5 µg/mL, but also greatly improved activity against B. subtilis ATCC9372 with the MIC values of less than or equal to 0.25, 0.25 and 0.25 µg/mL, respectively. In particular, compound 11g exhibited the strongest antibacterial effectiveness against all the tested resistant bacterial strains and had well balanced activity with the MIC values of 4-8 µg/mL. Further study on minimum bactericidal concentration and kinetics confirmed that compound 11g possessed a bacteriostatic effect on bacterial proliferation. Moreover, the results of molecular docking revealed an potential additional binding force between compound 11g and U790 in addition to the normal binding force of macrolide skeleton, which may explain why this compound performed the most potent activity against resistant bacteria. The results of cytotoxic assay indicated that compounds 20c, 20d and 20f were non-toxic to human breast cancer MCF-7 cells at its effective antibacterial concentration.


Assuntos
Antibacterianos/farmacologia , Compostos Aza/farmacologia , Bacillus subtilis/efeitos dos fármacos , Claritromicina/farmacologia , Desenho de Fármacos , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Compostos Aza/síntese química , Compostos Aza/química , Claritromicina/síntese química , Claritromicina/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
12.
Chem Commun (Camb) ; 57(43): 5254-5257, 2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-33973595

RESUMO

The first photoinduced synthesis of polyfunctionalized 3-aza[n.1.0]bicycles from readily available ene-ynamides and 2,6-lutidine N-oxide using an organic acridinium photocatalyst is reported. Applying a photocatalytic strategy to the reactive distonic cation vinyl radical intermediate from ynamide, a series of bio-valuable 3-azabicycles, including diverse 3-azabicyclio[4.1.0]heptanes and 3-azabicyclo[5.1.0]octanes that are challenging to accomplish using traditional methods, have been successfully synthesized in good to high yields under mild and metal-free conditions. Mechanistic studies are consistent with the photocatalyzed single-electron oxidation of ene-ynamide and the intermediacy of a putative cationic vinyl radical in this transformation. Importantly, this strategy provides new access to the development of photocatalytic vinyl radical cascades for the synthesis of structurally sophisticated substrates.


Assuntos
Alcinos/química , Amidas/química , Compostos Aza/síntese química , Compostos Bicíclicos com Pontes/síntese química , Ciclopropanos/química , Compostos Aza/química , Compostos Bicíclicos com Pontes/química , Estrutura Molecular , Oxirredução , Processos Fotoquímicos
13.
Eur J Med Chem ; 220: 113483, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33915372

RESUMO

Three near-infrared (NIR-I) optical theranostic systems were synthesized, characterized and studied in vitro and in vivo. These original homo-bimetallic gold(I)-based aza-BODIPY complexes proved to be trackable through near-infrared optical imaging in cells and in mice. They display anti-proliferative properties in micromolar range against human and murine cancer cell lines (4T1, MDA-MB-231, CT26, and SW480). Moreover, the injection of the most promising theranostic agent in CT26 tumor-bearing BALB/c mice induced a significant anti-cancer activity.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Corantes Fluorescentes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Aza/química , Compostos Aza/farmacologia , Compostos de Boro/química , Compostos de Boro/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Ouro/química , Ouro/farmacologia , Humanos , Raios Infravermelhos , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Imagem Óptica , Relação Estrutura-Atividade , Células Tumorais Cultivadas
14.
J Am Chem Soc ; 143(15): 5622-5628, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33830738

RESUMO

A cross-selective aza-pinacol coupling of aldehydes and imines has been developed to afford valuable ß-amino alcohols. This strategy enables chemoselective conversion of aliphatic aldehydes to ketyl radicals, in the presence of more easily reduced imines and other functional groups. Upon carbonyl-specific activation by AcI, a photoinitiated Mn catalyst selectively reduces the resulting α-oxy iodide by an atom transfer mechanism. The ensuing ketyl radical selectively couples to imines, precluding homodimerization by a classical reductive approach. In this first example of reductive, ketyl coupling by atom transfer catalysis, Zn serves as a terminal reductant to facilitate Mn catalyst turnover. This new strategy also enables ketyl radical couplings to alkenes, alkynes, aldehydes, propellanes, and chiral imines.


Assuntos
Compostos Aza/química , Oligopeptídeos/química , Aldeídos/química , Amino Álcoois/química , Catálise , Radicais Livres/química , Iminas/química , Magnésio/química , Oxirredução , Estereoisomerismo
15.
Molecules ; 26(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921479

RESUMO

Synthetic and natural ionophores have been developed to catalyze ion transport and have been shown to exhibit a variety of biological effects. We synthesized 24 aza- and diaza-crown ethers containing adamantyl, adamantylalkyl, aminomethylbenzoyl, and ε-aminocaproyl substituents and analyzed their biological effects in vitro. Ten of the compounds (8, 10-17, and 21) increased intracellular calcium ([Ca2+]i) in human neutrophils, with the most potent being compound 15 (N,N'-bis[2-(1-adamantyl)acetyl]-4,10-diaza-15-crown-5), suggesting that these compounds could alter normal neutrophil [Ca2+]i flux. Indeed, a number of these compounds (i.e., 8, 10-17, and 21) inhibited [Ca2+]i flux in human neutrophils activated by N-formyl peptide (fMLF). Some of these compounds also inhibited chemotactic peptide-induced [Ca2+]i flux in HL60 cells transfected with N-formyl peptide receptor 1 or 2 (FPR1 or FPR2). In addition, several of the active compounds inhibited neutrophil reactive oxygen species production induced by phorbol 12-myristate 13-acetate (PMA) and neutrophil chemotaxis toward fMLF, as both of these processes are highly dependent on regulated [Ca2+]i flux. Quantum chemical calculations were performed on five structure-related diaza-crown ethers and their complexes with Ca2+, Na+, and K+ to obtain a set of molecular electronic properties and to correlate these properties with biological activity. According to density-functional theory (DFT) modeling, Ca2+ ions were more effectively bound by these compounds versus Na+ and K+. The DFT-optimized structures of the ligand-Ca2+ complexes and quantitative structure-activity relationship (QSAR) analysis showed that the carbonyl oxygen atoms of the N,N'-diacylated diaza-crown ethers participated in cation binding and could play an important role in Ca2+ transfer. Thus, our modeling experiments provide a molecular basis to explain at least part of the ionophore mechanism of biological action of aza-crown ethers.


Assuntos
Compostos Aza/síntese química , Compostos Aza/farmacologia , Éteres de Coroa/síntese química , Éteres de Coroa/farmacologia , Modelos Moleculares , Cálcio/metabolismo , Quimiotaxia/efeitos dos fármacos , Teoria da Densidade Funcional , Células HL-60 , Humanos , Ligantes , Neutrófilos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores de Formil Peptídeo/metabolismo , Análise de Regressão , Eletricidade Estática , Termodinâmica
16.
Molecules ; 26(5)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33801330

RESUMO

The aza-vinylogous Povarov reaction between aromatic amines, α-ketoaldehydes or α-formylesters and α,ß-unsaturated dimethylhydrazones was carried out in a sequential three-component fashion under mechanochemical conditions. Following extensive optimization work, the reaction was performed on a vibratory ball mill operating at 20 Hz and using zirconium oxide balls and milling jar, and afforded 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro- 1,5-naphthyridines functionalized at C-2, C-4 and also at C-6, in the latter case. This protocol generally afforded the target compounds in good to excellent yields and diastereoselectivities. A comparison of representative examples with the results obtained under conventional conditions revealed that the mechanochemical protocol affords faster Povarov reactions in comparable yields using a solvent-less environment.


Assuntos
Compostos Aza/química , Fenômenos Mecânicos , Naftiridinas/química , Quinolinas/química , Catálise , Estrutura Molecular , Estereoisomerismo
17.
Chem Biol Interact ; 343: 109478, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33905741

RESUMO

7-Azaindole has been labelled a privileged scaffold for the design of new potent inhibitors of protein kinases. In this paper, we determined the inhibition profiles of novel mono- and disubstituted derivatives of 7-azaindole-coumaranone hybrids on various disease-related protein kinases. Eight hit compounds were identified, including a potent Haspin inhibitor with an IC50 value of 0.15 µM. An interesting observation was that all active monosubstituted compounds displayed dual inhibition for Haspin and GSK-3ß, while disubstituted derivatives inhibited GSK-3ß and LmCK1 from Leishmania major parasite. Analyses of structure activity relationships (SARs) also revealed that mono-substitution with para-fluorobenzyloxy ring produced an equipotent inhibition of Haspin and GSK-3ß. Haspin and GSK-3ß are relevant targets for developing new anticancer agents while LmCK1 is an innovative target for leishmanicidal drugs. Novel compounds reported in this paper constitute promising starting points for the development of new anticancer and leishmanicidal drugs.


Assuntos
Compostos Aza/química , Benzofuranos/química , Indóis/química , Inibidores de Proteínas Quinases/química , Animais , Compostos Aza/síntese química , Compostos Aza/farmacocinética , Benzofuranos/síntese química , Benzofuranos/farmacocinética , Ensaios Enzimáticos , Humanos , Indóis/síntese química , Indóis/farmacocinética , Leishmania major/enzimologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Células Sf9 , Spodoptera , Relação Estrutura-Atividade
18.
Exp Neurol ; 341: 113703, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33745919

RESUMO

OBJECTIVE: Glucocorticoid levels rise rapidly following status epilepticus and remain elevated for weeks after the injury. To determine whether glucocorticoid receptor activation contributes to the pathological sequelae of status epilepticus, mice were treated with a novel glucocorticoid receptor modulator, C108297. METHODS: Mice were treated with either C108297 or vehicle for 10 days beginning one day after pilocarpine-induced status epilepticus. Baseline and stress-induced glucocorticoid secretion were assessed to determine whether hypothalamic-pituitary-adrenal axis hyperreactivity could be controlled. Status epilepticus-induced pathology was assessed by quantifying ectopic hippocampal granule cell density, microglial density, astrocyte density and mossy cell loss. Neuronal network function was examined indirectly by determining the density of Fos immunoreactive neurons following restraint stress. RESULTS: Treatment with C108297 attenuated corticosterone hypersecretion after status epilepticus. Treatment also decreased the density of hilar ectopic granule cells and reduced microglial proliferation. Mossy cell loss, on the other hand, was not prevented in treated mice. C108297 altered the cellular distribution of Fos protein but did not restore the normal pattern of expression. INTERPRETATION: Results demonstrate that baseline corticosterone levels can be normalized with C108297, and implicate glucocorticoid signaling in the development of structural changes following status epilepticus. These findings support the further development of glucocorticoid receptor modulators as novel therapeutics for the prevention of brain pathology following status epilepticus.


Assuntos
Compostos Aza/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Receptores de Glucocorticoides/metabolismo , Estado Epiléptico/metabolismo , Estado Epiléptico/patologia , Animais , Compostos Aza/farmacologia , Relação Dose-Resposta a Droga , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Camundongos , Pilocarpina/toxicidade , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/antagonistas & inibidores , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico
19.
Invest Ophthalmol Vis Sci ; 62(3): 16, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33704359

RESUMO

Purpose: Aurora kinase B (AURKB) plays a pivotal role in the regulation of mitosis and is gaining prominence as a therapeutic target in cancers; however, the role of AURKB in retinoblastoma (RB) has not been studied. The purpose of this study was to determine if AURKB plays a role in RB, how its expression is regulated, and whether it could be specifically targeted. Methods: The protein expression of AURKB was determined using immunohistochemistry in human RB patient specimens and immunoblotting in cell lines. Pharmacological inhibition and shRNA-mediated knockdown were used to understand the role of AURKB in cell viability, apoptosis, and cell cycle distribution. Cell viability in response to AURKB inhibition was also assessed in enucleated RB specimens. Immunoblotting was employed to determine the protein levels of phospho-histone H3, p53, p21, and MYCN. Chromatin immunoprecipitation-qPCR was performed to verify the binding of MYCN on the promoter region of AURKB. Results: The expression of AURKB was found to be markedly elevated in human RB tissues, and the overexpression significantly correlated with optic nerve and anterior chamber invasion. Targeting AURKB with small-molecule inhibitors and shRNAs resulted in reduced cell survival and increased apoptosis and cell cycle arrest at the G2/M phase. More importantly, primary RB specimens showed decreased cell viability in response to pharmacological AURKB inhibition. Additional studies have demonstrated that the MYCN oncogene regulates the expression of AURKB in RB. Conclusions: AURKB is overexpressed in RB, and targeting it could serve as a novel therapeutic strategy to restrict tumor cell growth.


Assuntos
Aurora Quinase B/genética , Regulação Enzimológica da Expressão Gênica/fisiologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/farmacologia , Neoplasias da Retina/enzimologia , Retinoblastoma/enzimologia , Apoptose/efeitos dos fármacos , Compostos Aza/farmacologia , Benzamidas/farmacologia , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Immunoblotting , Imuno-Histoquímica , Indóis/farmacologia , Organofosfatos/farmacologia , Quinazolinas/farmacologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Células Tumorais Cultivadas
20.
Bioorg Med Chem Lett ; 39: 127871, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33662539

RESUMO

3,7-Diazabicyclo[3.3.1]nonane scaffold can serve as a basis for the design of molecular switches stimulating the fast release of water soluble compounds under the influence of external factors from the liposomal containers having those switches incorporated into the lipid bilayer. It was demonstrated that liposomes having 3,7-dihexadecyl-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one (3) incorporated into the liposomal membrane sharply increase the permeability upon pH decrease from 7.4 to 6.5, and compound 3 can serve as a pH-sensitive agent in the bilayer of liposomal nanocontainers. Similar but less pronounced effect was shown for liposomes modified with 3,7-bis(methyldodecylaminoacetyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane (5) and 3,7-didodecylsulfonyl-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one (4). The structure (morphology) and size of modified liposomes were studied with scanned transmission electron microscopy.


Assuntos
Compostos Aza/química , Compostos Aza/síntese química , Bicamadas Lipídicas/química , Lipossomos/química , Microscopia Eletrônica de Transmissão , Estrutura Molecular
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