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1.
Pharmaceuticals (Basel) ; 17(4)2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38675418

RESUMO

The synthesis of a series of new N-benzylidene derivatives of 3-amino-4-imino-3,5-dihydro-4H-chromeno[2,3-d]pyrimidine 10(a-l) bearing two points of molecular diversity is reported. These new compounds were synthesized in five steps including two steps under microwave dielectric heating. They were fully characterized using 1H and 13C NMR, FTIR and HRMS. The in silico physicochemical properties of compounds 10(a-l) were determined according to Lipinski's rules of five (RO5) associated with the prediction of their bioavailability. These new compounds 10(a-l) were tested for their antiproliferative activities in fibroblasts and eight representative human tumoral cell lines (Huh7 D12, Caco2, MDA-MB231, MDA-MB468, HCT116, PC3, MCF7 and PANC1). Among them, the compounds 10h and 10i showed sub-micromolar cytotoxic activity on tumor cell lines (0.23 < IC50 < 0.3 µM) and no toxicity on fibroblasts (IC50 > 25 µM). A dose-dependent inhibition of Store-Operated Ca+2 Entry (SOCE) was observed in the HEK293 cell line with 10h. In vitro embryotoxicity and angiogenesis on the mCherry transgenic zebrafish line showed that 10h presented no toxic effect and no angiogenic effect on embryos with a dose of 5 µM at 72 hpf.

2.
J Med Chem ; 65(2): 1396-1417, 2022 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-34928152

RESUMO

The protein kinase DYRK1A is involved in Alzheimer's disease, Down syndrome, diabetes, viral infections, and leukemia. Leucettines, a family of 2-aminoimidazolin-4-ones derived from the marine sponge alkaloid Leucettamine B, have been developed as pharmacological inhibitors of DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases). We report here on the synthesis and structure-activity relationship (SAR) of 68 Leucettines. Leucettines were tested on 11 purified kinases and in 5 cellular assays: (1) CLK1 pre-mRNA splicing, (2) Threonine-212-Tau phosphorylation, (3) glutamate-induced cell death, (4) autophagy and (5) antagonism of ligand-activated cannabinoid receptor CB1. The Leucettine SAR observed for DYRK1A is essentially identical for CLK1, CLK4, DYRK1B, and DYRK2. DYRK3 and CLK3 are less sensitive to Leucettines. In contrast, the cellular SAR highlights correlations between inhibition of specific kinase targets and some but not all cellular effects. Leucettines deserve further development as potential therapeutics against various diseases on the basis of their molecular targets and cellular effects.


Assuntos
Imidazóis/química , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Splicing de RNA , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Autofagia , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Fosforilação , Relação Estrutura-Atividade
3.
Pharmaceuticals (Basel) ; 14(11)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34832868

RESUMO

Here, we report on the synthesis of libraries of new 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones 3 (twenty-two compounds) and new 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones 5 (twenty-four compounds) with stereo controlled Z-geometry under microwave irradiation. The 46 designed final compounds were tested in order to determine their activity against four representative protein kinases (DYR1A, CK1, CDK5/p25, and GSK3α/ß). Among these 1,3-thiazolidin-4-ones, the molecules (5Z) 5-(4-hydroxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one 3e (IC50 0.028 µM) and (5Z)-5-benzo[1,3]dioxol-5-ylmethylene-2-(pyridin-2-yl)amino-1,3-thiazol-4(5H)-one 5s (IC50 0.033 µM) were identified as lead compounds and as new nanomolar DYRK1A inhibitors. Some of these compounds in the two libraries have been also evaluated for their in vitro inhibition of cell proliferation (Huh7 D12, Caco2, MDA-MB 231, HCT 116, PC3, and NCI-H2 tumor cell lines). These results will enable us to use the 1,3-thiazolidin-4-one core as pharmacophores to develop potent treatment for neurological or oncological disorders in which DYRK1A is fully involved.

4.
Phytochem Anal ; 32(4): 592-600, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33150689

RESUMO

INTRODUCTION: Pseudevernia furfuracea, a lichen used classically for cosmetic applications, contains interesting metabolites possessing antimicrobial and anti-inflammatory or antioxidant properties. OBJECTIVES: Ionic liquid combined to microwave-assisted extraction (IL-MAE) was successfully applied for metabolites extraction from Pseudevernia furfuracea. MATERIALS AND METHODS: Three imidazolium and pyridinium-based ionic liquids (ILs): 1,3-dimethylimidazolium methylsulphate [C1 C1 Im][MeSO4 ], 1-ethyl-3-methylimidazolium ethylsulphate [C2 C1 Im][EtSO4 ], and N-ethylpyridinium ethylsulphate [C2 Py][EtSO4 ] were assessed for this process. The efficiency of the extraction method was evaluated using thin-layer chromatography (TLC) coupled to a Camag® spectrophotodensitometer and using high-performance liquid chromatography (HPLC) analysis. RESULTS: ILs under MAE showed extraction time efficiency (15 min vs. 24 h for conventional heating) and high selectivity in extracting the targeted metabolites: atranorin (AT), methyl-ß-orcinol carboxylate (MOC), fumarprotocetraric acid (Fum. Ac.), and physodic acid (Phys. Ac.) despite the increased degradation of AT under MAE. We showed a tunable selectivity of ILs towards extracting metabolites by changing anion or cation due to the modification of the interaction between the IL and the metabolites. While [C2 Py][EtSO4 ] was the most efficient IL and could extract all the targeted metabolites, [C2 C1 Im][EtSO4 ] was the most selective. It fully extracted AT and partially Fum. Ac. Moreover, the lichen prepared by mixing procedure provided AT and Fum. Ac. more than the milled one. A 100 times scale-up extraction was successfully performed on mixed samples with full IL recycling after back extraction. CONCLUSION: IL-MAE is reliable for lichen metabolites extraction. The method is reproducible, scalable, with possible IL recycling, opening the door for potential industrial applications.


Assuntos
Líquidos Iônicos , Líquens , Cromatografia Líquida de Alta Pressão , Micro-Ondas , Parmeliaceae
5.
Eur J Pharmacol ; 881: 173137, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32380016

RESUMO

The current study was aimed to assess the protective effect of a new molecule (E)-N'-(1-(3-oxo-3H-benzo[f]chromen-2-yl)ethylidene)benzohydrazide, denoted 1c, against cardiac remodeling process in isoproterenol (Isop) induced myocardial infarction (MI) in rats. Male Wistar rats were randomly divided into four groups, control, Isop (85 mg/kg body weight was injected subcutaneously into rats at an interval of 24 h for 2 days (6th and 7th day) to induce MI and pretreated animals with acenocoumarol (Ace) (150 µg/kg bw) and 1c (150 µg/kg bw) by oral administration during 7 days and injected with isoproterenol (Isop + Ace) and (Isop + 1c) groups. Results in vitro showed that 1c is endowed with potent inhibition of angiotensin-converting enzyme (ACE) with an IC50 39.12 µg/ml. The in vivo exploration evidenced alteration in the ECG pattern, notable cardiac hypertrophy and increase in plasma level of fibrinogen, troponin-T, CK-MB and LDH, AST and ALT by 171%, 300%, 50%, 64% and 75% respectively with histological myocardium necrosis and cells inflammatory infiltration. However, pre-treatment with 1c improved the ECG pattern reduced significantly the cardiac dysfunction markers and ameliorated the thrombolytic process by decreasing fibrinogen level as compared to untreated infracted rats. Overall, (E)-N'-(1-(3-oxo-3H-benzo[f]chromen-2-yl)ethylidene)benzohydrazide 1c could be used as anticoagulant agent to prevent thrombosis in acute myocardial infarction.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Fibrinolíticos/farmacologia , Hidrazonas/farmacologia , Infarto do Miocárdio/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/síntese química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Biomarcadores/sangue , Cardiotoxicidade , Modelos Animais de Doenças , Fibrinogênio/metabolismo , Fibrinolíticos/síntese química , Frequência Cardíaca/efeitos dos fármacos , Hidrazonas/síntese química , Isoproterenol , Lipídeos/sangue , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Necrose , Ratos Wistar , Remodelação Ventricular/efeitos dos fármacos
6.
Acta Neuropathol Commun ; 7(1): 46, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30885273

RESUMO

Recent evidences suggest the involvement of DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1 A) in Alzheimer's disease (AD). Here we showed that DYRK1A undergoes a proteolytic processing in AD patients hippocampus without consequences on its kinase activity. Resulting truncated forms accumulate in astrocytes and exhibit increased affinity towards STAT3ɑ, a regulator of inflammatory process. These findings were confirmed in APP/PS1 mice, an amyloid model of AD, suggesting that this DYRK1A cleavage is a consequence of the amyloid pathology. We identified in vitro the Leucettine L41 as a compound able to prevent DYRK1A proteolysis in both human and mouse protein extracts. We then showed that intraperitoneal injections of L41 in aged APP/PS1 mice inhibit STAT3ɑ phosphorylation and reduce pro-inflammatory cytokines levels (IL1- ß, TNF-ɑ and IL-12) associated to an increased microglial recruitment around amyloid plaques and decreased amyloid-ß plaque burden. Importantly, L41 treatment improved synaptic plasticity and rescued memory functions in APP/PS1 mice. Collectively, our results suggest that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. Further evaluation of inhibitors of DYRK1A truncation promises a new therapeutic approach for AD.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Fenótipo , Presenilina-1/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Proteólise , Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Animais , Hipocampo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Quinases Dyrk
7.
Dis Model Mech ; 11(9)2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-30115750

RESUMO

Growing evidence supports the implication of DYRK1A in the development of cognitive deficits seen in Down syndrome (DS) and Alzheimer's disease (AD). We here demonstrate that pharmacological inhibition of brain DYRK1A is able to correct recognition memory deficits in three DS mouse models with increasing genetic complexity [Tg(Dyrk1a), Ts65Dn, Dp1Yey], all expressing an extra copy of Dyrk1a Overexpressed DYRK1A accumulates in the cytoplasm and at the synapse. Treatment of the three DS models with the pharmacological DYRK1A inhibitor leucettine L41 leads to normalization of DYRK1A activity and corrects the novel object cognitive impairment observed in these models. Brain functional magnetic resonance imaging reveals that this cognitive improvement is paralleled by functional connectivity remodelling of core brain areas involved in learning/memory processes. The impact of Dyrk1a trisomy and L41 treatment on brain phosphoproteins was investigated by a quantitative phosphoproteomics method, revealing the implication of synaptic (synapsin 1) and cytoskeletal components involved in synaptic response and axonal organization. These results encourage the development of DYRK1A inhibitors as drug candidates to treat cognitive deficits associated with DS and AD.


Assuntos
Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Dioxóis/farmacologia , Dioxóis/uso terapêutico , Síndrome de Down/complicações , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Biocatálise , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Disfunção Cognitiva/patologia , Citoplasma/metabolismo , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Dioxóis/química , Modelos Animais de Doenças , Síndrome de Down/patologia , Imidazóis/química , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiopatologia , Fosforilação , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteômica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapsinas/química , Sinapsinas/metabolismo , Quinases Dyrk
8.
Mol Divers ; 22(3): 685-708, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29623536

RESUMO

A series of 16 new ethyl [Formula: see text]-amino benzimidazole acrylate derivatives 12(a-p) with a (2E)-s-cis/trans conformation and bearing two points of diversity was designed and synthesized by using a multi-step strategy (reductive amination, deprotection in acidic media and transamination) in moderate to good yields from ethyl 3-dimethylamino-2-(1H-benzimidazol-2-yl)acrylate (5) and monosubstituted N-Boc diamines (7a,7b) as starting building blocks. Products 12 were evaluated for their in vitro cytotoxic potential against six selected human cell lines (Huh7-D12, Caco2, MDA-MB231, HCT116, PC3 and NCI-H727). Compounds 12a, 12e and 12l exhibited selective and micromolar antitumor activities against Huh7-D12 and Caco2 cell lines.


Assuntos
Acrilatos , Antineoplásicos , Benzimidazóis , Citotoxinas , Acrilatos/síntese química , Acrilatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/síntese química , Citotoxinas/farmacologia , Humanos
9.
Int J Mol Sci ; 19(3)2018 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-29538341

RESUMO

From a series of (1R, 1S)-1[ß-(phenylalkoxy)-(phenetyl)]-1H-pyrazolium hydrochloride as new analogues of SKF-96365, one has an interesting effect for endoplasmic reticulum (ER) Ca2+ release and store-operated Ca2+ entry (SOCE) (IC50 25 µM) on the PLP-B lymphocyte cell line. A successful resolution of (±) 1-phenyl-2-(1H-pyrazol-1-yl)ethan-1-ol has been developed by using the method of "half-concentration" in the presence of (+)-(1S)- or (-)-(1R)-CSA.


Assuntos
Bloqueadores dos Canais de Cálcio/síntese química , Sinalização do Cálcio/efeitos dos fármacos , Imidazóis/química , Relação Quantitativa Estrutura-Atividade , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Linhagem Celular Tumoral , Humanos , Imidazóis/farmacologia
10.
Mar Drugs ; 15(10)2017 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-29039762

RESUMO

A large diversity of 2-aminoimidazolone alkaloids is produced by various marine invertebrates, especially by the marine Calcareous sponges Leucetta and Clathrina. The phylogeny of these sponges and the wide scope of 2-aminoimidazolone alkaloids they produce are reviewed in this article. The origin (invertebrate cells, associated microorganisms, or filtered plankton), physiological functions, and natural molecular targets of these alkaloids are largely unknown. Following the identification of leucettamine B as an inhibitor of selected protein kinases, we synthesized a family of analogues, collectively named leucettines, as potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) and potential pharmacological leads for the treatment of several diseases, including Alzheimer's disease and Down syndrome. We assembled a small library of marine sponge- and ascidian-derived 2-aminoimidazolone alkaloids, along with several synthetic analogues, and tested them on a panel of mammalian and protozoan kinases. Polyandrocarpamines A and B were found to be potent and selective inhibitors of DYRKs and CLKs. They inhibited cyclin D1 phosphorylation on a DYRK1A phosphosite in cultured cells. 2-Aminoimidazolones thus represent a promising chemical scaffold for the design of potential therapeutic drug candidates acting as specific inhibitors of disease-relevant kinases, and possibly other disease-relevant targets.


Assuntos
Alcaloides/farmacologia , Imidazóis/farmacologia , Poríferos/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Urocordados/química , Alcaloides/síntese química , Alcaloides/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Aminas/síntese química , Aminas/farmacologia , Aminas/uso terapêutico , Animais , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Síndrome de Down/tratamento farmacológico , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/uso terapêutico , Fosforilação , Filogenia , Poríferos/genética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Infecções por Protozoários/tratamento farmacológico , Proteínas de Protozoários/antagonistas & inibidores , Relação Estrutura-Atividade , Quinases Dyrk
11.
Mol Phylogenet Evol ; 114: 401-414, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28694102

RESUMO

DMSP (dimethylsulfoniopropionate) is an ecologically important sulfur metabolite commonly produced by marine algae and by some higher plant lineages, including the polyploid salt marsh genus Spartina (Poaceae). The molecular mechanisms and genes involved in the DMSP biosynthesis pathways are still unknown. In this study, we performed comparative analyses of DMSP amounts and molecular phylogenetic analyses to decipher the origin of DMSP in Spartina that represents one of the major source of terrestrial DMSP in coastal marshes. DMSP content was explored in 14 Spartina species using 1H Nuclear Magnetic Resonance (NMR) spectroscopy and Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). Putative genes encoding the four enzymatic steps of the DMSP biosynthesis pathway in Spartina were examined and their evolutionary dynamics were studied. We found that the hexaploid lineage containing S. alterniflora, S. foliosa and S. maritima and their derived hybrids and allopolyploids are all able to produce DMSP, in contrast to species in the tetraploid clade. Thus, examination of DMSP synthesis in a phylogenetic context implicated a single origin of this physiological innovation, which occurred in the ancestor of the hexaploid Spartina lineage, 3-6MYA. Candidate genes specific to the Spartina DMSP biosynthesis pathway were also retrieved from Spartina transcriptomes, and provide a framework for future investigations to decipher the molecular mechanisms involved in this plant phenotypic novelty that has major ecological impacts in saltmarsh ecosystems.


Assuntos
Evolução Molecular , Poaceae/metabolismo , Compostos de Sulfônio/metabolismo , Aldeído Desidrogenase/classificação , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Carboxiliases/classificação , Carboxiliases/genética , Carboxiliases/metabolismo , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Metiltransferases/classificação , Metiltransferases/genética , Metiltransferases/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/classificação , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Filogenia , Poaceae/classificação , Poaceae/genética , Poliploidia , Compostos de Sulfônio/análise
12.
Talanta ; 150: 525-30, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26838439

RESUMO

Lichens are symbiotic organisms known for producing unique secondary metabolites with attractive cosmetic and pharmacological properties. In this paper, we investigated three standard methods of preparation of Pseudevernia furfuracea (blender grinding, ball milling, pestle and mortar). The materials obtained were characterized by electronic microscopy, nitrogen adsorption and compared from the point of view of extraction. Their microscopic structure is related to extraction efficiency. In addition, it is shown using thalline reactions and mass spectrometry mapping (TOF-SIMS) that these metabolites are not evenly distributed throughout the organism. Particularly, atranorin (a secondary metabolite of interest) is mainly present in the cortex of P. furfuracea. Finally, using microwave assisted extraction (MAE) we obtained evidence that an appropriate preparation can increase the extraction efficiency of atranorin by a factor of five.


Assuntos
Misturas Complexas/normas , Hidroxibenzoatos/análise , Hidroxibenzoatos/isolamento & purificação , Líquens/química , Manejo de Espécimes/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
13.
Eur Neuropsychopharmacol ; 25(11): 2170-82, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26381812

RESUMO

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) are implicated in the onset and progression of Down syndrome (DS) and Alzheimer's disease (AD). DYRK1A has emerged as a possible link between amyloid-ß (Aß) and Tau, the major pathological proteins in AD. We here assessed the neuroprotective potential of a novel inhibitor of DYRKs/CLKs. The Leucettine L41, acting preferentially on DYRK1A, was tested in Aß25-35-treated mice, a nontransgenic model of AD-like toxicity. We co-injected intracerebroventricularly oligomeric Aß25-35 peptide and L41 in Swiss male mice. After 7 days, they were submitted to behavioral tests addressing spatial and non-spatial, short- and long-term memories. The oxidative stress, apoptotic markers, kinases involved in Tau phosphorylation, and synaptic integrity were analyzed by Western blot and ELISA in the hippocampus. L41, tested at 0.4, 1.2, 4 µg, prevented the Aß25-35-induced memory deficits in the Y-maze, passive avoidance and water-maze tests, with the most active dose being 4 µg. The inhibitor prevented the Aß25-35-induced oxidative stress, as revealed by measures of lipid peroxidation levels and reactive oxygen species accumulation, and abolished Aß25-35-induced expression of pro-apoptotic markers. L41 prevented the Aß25-35-induced decrease of AKT activation and increase of glycogen synthase kinase-3ß (GSK-3ß) activation, resulting in a decrease of Tau phosphorylation. Finally, L41 restored Aß25-35-reduced levels of synaptic markers. The novel DYRK1A-preferential inhibitor L41 therefore prevented Aß25-35-induced memory impairments and neurotoxicity in the mouse hippocampus. These in vivo data highlighted particularly DYRK1A as a major kinase involved in Aß pathology and suggested therapeutic developments for DYRK1A inhibitors in AD.


Assuntos
Dioxóis/farmacologia , Imidazóis/farmacologia , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Peptídeos beta-Amiloides , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/patologia , Masculino , Transtornos da Memória/enzimologia , Transtornos da Memória/patologia , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Fragmentos de Peptídeos , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/enzimologia , Sinapses/patologia , Proteínas tau/metabolismo , Quinases Dyrk
14.
Molecules ; 20(7): 12412-35, 2015 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-26184130

RESUMO

A new route to 3-(4-arylmethylamino)butyl-5-arylidene-2-thioxo-1,3-thiazolidine-4-one 9 was developed in six steps from commercial 1,4-diaminobutane 1 as starting material. The key step of this multi-step synthesis involved a solution phase "one-pot two-steps" approach assisted by microwave dielectric from N-(arylmethyl)butane-1,4-diamine hydrochloride 6a-f (as source of the first point diversity) and commercial bis-(carboxymethyl)-trithiocarbonate reagent 7 for construction of the rhodanine platform. This platform was immediately functionalized by Knoevenagel condensation under microwave irradiation with a series of aromatic aldehydes 3 as second point of diversity. These new compounds were prepared in moderate to good yields and the fourteen synthetic products 9a-n have been obtained with a Z-geometry about their exocyclic double bond. These new 5-arylidene rhodanines derivatives 9a-n were tested for their kinase inhibitory potencies against four protein kinases: Human cyclin-dependent kinase 5-p25, HsCDK5-p25; porcine Glycogen Synthase Kinase-3, GSK-3α/ß; porcine Casein Kinase 1, SsCK1 and human HsHaspin. They have also been evaluated for their in vitro inhibition of cell proliferation (HuH7 D12, Caco 2, MDA-MB 231, HCT 116, PC3, NCI-H727, HaCat and fibroblasts). Among of all these compounds, 9j presented selective micromolar inhibition activity on SsCK1 and 9i exhibited antitumor activities in the HuH7 D12, MDA-MBD231 cell lines.


Assuntos
Antineoplásicos Alquilantes/síntese química , Inibidores de Proteínas Quinases/síntese química , Tiazolidinas/síntese química , Aldeídos/química , Animais , Antineoplásicos Alquilantes/farmacologia , Células CACO-2 , Caseína Quinase I/antagonistas & inibidores , Caseína Quinase I/genética , Caseína Quinase I/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/metabolismo , Expressão Gênica , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Células HCT116 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Micro-Ondas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Putrescina/química , Relação Estrutura-Atividade , Suínos , Tiazolidinas/farmacologia , Tionas/química
15.
Molecules ; 20(6): 11617-31, 2015 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-26111185

RESUMO

We here disclosed a new protocol for the condensation of acetophenone derivatives and active methylene compounds with aldehydes in the presence of boric acid under microwave conditions. Implementation of the reaction is simple, healthy and environmentally friendly owing to the use of a non-toxic catalyst coupled to a solvent-free procedure. A large variety of known or novel compounds have thus been prepared, including with substrates bearing acid or base-sensitive functional groups.


Assuntos
Acetofenonas/química , Aldeídos/química , Ácidos Bóricos/química , Catálise , Química Verde , Metano/análogos & derivados , Metano/química , Micro-Ondas , Solventes/química
16.
Mol Divers ; 18(2): 375-88, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24584455

RESUMO

A practical approach for the preparation of (5Z) 5-ylidene rhodanine derivatives bearing the (4,5-dihalogeno-pyrrol-2-yl)carbamoyl fragment of dispacamide A is reported. The new compounds were obtained in good yields (19-88 %) by Knoevenagel condensation according to a solution-phase microwave dielectric heating protocol in the presence of organic bases (piperidine, TEA, and AcONa) from a set of N-substituted rhodanines 2(a-i). The ten synthetic products 3(a-j) have been synthesized with a Z-geometry about their exocyclic double bond and the structure of one of these compounds (3) was confirmed by a single X-ray diffraction analysis. The new (5Z) 5-ylidene rhodanine derivatives 3(a-j) were tested against eight protein kinases.


Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Pirróis/química , Rodanina/análogos & derivados , Rodanina/química , Rodanina/síntese química , Técnicas de Química Sintética
17.
Mol Pharmacol ; 85(3): 441-50, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24366666

RESUMO

Leucettines, a family of pharmacological inhibitors of dual-specificity tyrosine phosphorylation regulated kinases and cdc-like kinases (CLKs), are currently under investigation for their potential therapeutic application to Down syndrome and Alzheimer's disease. We here report that leucettine L41 triggers bona fide autophagy in osteosarcoma U-2 OS cells and immortalized mouse hippocampal HT22 cells, characterized by microtubule-associated protein light chain 3 membrane translocation and foci formation. Leucettine L41-triggered autophagy requires the Unc-51-like kinase and is sensitive to the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and 3-methyladenine, suggesting that it acts through the mammalian target of rapamycin (mTOR)/PI3K-dependent pathway. Leucettine L41 does not act by modifying the autophagic flux of vesicles. Leucettine L41-induced autophagy correlates best with inhibition of CLKs. Leucettine L41 modestly inhibited phosphatidylinositol-3-phosphate 5-kinase, FYVE domain-containing activity as tested both in vitro and in vivo, which may also contribute to autophagy induction. Altogether these results demonstrate that leucettines can activate the autophagic mTOR/PI3K pathway, a characteristic that may turn advantageous in the context of Alzheimer's disease treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Autofagia/efeitos dos fármacos , Dioxóis/farmacologia , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Fosforilação/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Tirosina/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Autofagia/genética , Autofagia/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação/genética , Fosforilação/imunologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Serina-Treonina Quinases TOR/genética , Tirosina/genética , Quinases Dyrk
18.
Eur J Med Chem ; 62: 728-37, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23454515

RESUMO

Leucettines, a family of marine sponge-derived 2-aminoimidazolone alkaloids, are potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases). They constitute promising pharmacological leads for the treatment of several diseases, including Alzheimer's disease and Down syndrome. In order to investigate the scope of potential targets of Leucettine L41, a representative member of the chemical class, we designed an affinity chromatography strategy based on agarose-immobilized leucettines. A synthesis protocol for the attachment of a polyethylene (3 or 4 units) linker to L41 was first established. The linker attachment site on L41 was selected on the basis of the co-crystal structure of L41 with several kinases. L41 was then covalently bound to agarose beads through the primary amine located at the end of the linker. Control, kinase inactive Leucettine was also immobilized, as well as free linker devoid of ligand. Extracts of several mouse tissues revealed a complex pattern of interacting proteins, some of which probably resulting from non-specific, hydrophobic binding, while others representing bona fide Leucettine-interacting proteins. DYRK1A and GSK-3 (glycogen synthase kinase-3) were confirmed as interacting targets by Western blotting in various mouse tissues. The Leucettine affinity chromatography resin constitutes a powerful tool to purify and identify the targets of this new promising therapeutic class of molecules.


Assuntos
Dioxóis/farmacologia , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Animais , Dioxóis/síntese química , Dioxóis/química , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Suínos
19.
Sci Pharm ; 80(4): 825-36, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23264934

RESUMO

New N,N'-bis(5-arylidene-4-oxo-4,5-dihydrothiazoline-2-yl)diamine derivatives 5 were prepared in two steps from rhodanine and piperazine, or 1,4-bis(3-amino-propyl)piperazine, under microwave reaction conditions with retention of configuration. Some of these compounds were tested for in vitro antiproliferative activities and for their kinase inhibitory potencies towards six kinases (CDK5/p25, GSK3α/ß, DYRK1A, DYRK2, CLK1, and CLK2). The compound 5d showed nanomolar activity towards DYRK1A kinase (IC(50) = 0.041 µM).

20.
Eur J Med Chem ; 58: 581-90, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23174317

RESUMO

The synthesis in 4 steps of new N,N'-bis(5-arylidene-4-oxo-3,5-dihydro-4H-imidazol-2-yl)diamines issued from various symmetric primary diamines as linkers was reported. The key step of our strategy has been the sulphur/nitrogen displacement of (5Z)-5-arylidene-2-ethylsulfanyl-3,5-dihydro-4H-imidazol-4-ones 6 with respectively ethylenediamine 7a, piperazine 7b and N,N'-bis(3-aminopropyl)piperazine 7c using solvent-free reaction conditions under microwave irradiation with retention of configuration. These compounds were tested for their kinase inhibitory potencies toward four kinases (GSK-3α/ß, DYRK1A, CLK1 and CLK3).


Assuntos
Diaminas/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Diaminas/síntese química , Diaminas/química , Relação Dose-Resposta a Droga , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Camundongos , Micro-Ondas , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ratos , Relação Estrutura-Atividade , Suínos , Quinases Dyrk
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