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1.
Neuropharmacology ; 164: 107902, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31811873

RESUMO

Vesicular glutamate transporters (VGLUT1-3) mediate the uptake of glutamate into synaptic vesicles. VGLUTs are pivotal actors of excitatory transmission and of almost all brain functions. Their implication in various pathologies has been clearly documented. Despite their functional importance, the pharmacology of VGLUTs is limited to a few dyes such as Trypan Blue, Rose Bengal or Brilliant Yellow type. Here, we report the design and evaluation of new potent analogs based on Trypan Blue scaffold. Our best compound, named LSP5-2157, has an EC50 of 50 nM on glutamate vesicular uptake. Using a 3D homology model of VGLUT1 and docking experiments, we determined its putative binding subdomains within vesicular glutamate transporters and validated the structural requirement for VGLUT inhibition. To better estimate the specificity and potency of LSP5-2157, we also investigated its ability to block glutamatergic transmission in autaptic hippocampal cells. Neither glutamate receptors nor GABAergic transmission or transmission machinery were affected by LSP5-2157. Low doses of compound reversibly reduce glutamatergic neurotransmission in hippocampal autpases. LSP5-2157 had a low and depressing effect on synaptic efficacy in hippocampal slice. Furthermore, LSP5-2157 had no effect on NMDA-R- mediated fEPSP but reduce synaptic plasticity induced by 3 trains of 100 Hz. Finally, LSP5-2157 had the capacity to inhibit VGLUT3-dependent auditory synaptic transmission in the guinea pig cochlea. In this model, it abolished the compound action potential of auditory nerve at high concentration showing the limited permeation of LSP5-2157 in an in-vivo model. In summary, the new ligand LSP5-2157, has a high affinity and specificity for VGLUTs and shows some permeability in isolated neuron, tissue preparations or in vivo in the auditory system. These findings broaden the field of VGLUTs inhibitors and open the way to their use to assess glutamatergic functions in vitro and in vivo.


Assuntos
Proteínas Vesiculares de Transporte de Glutamato/antagonistas & inibidores , Potenciais de Ação/efeitos dos fármacos , Animais , Cóclea/efeitos dos fármacos , Nervo Coclear/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Cobaias , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Neurônios/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Proteínas Vesiculares de Transporte de Glutamato/metabolismo
2.
J Org Chem ; 77(18): 8294-302, 2012 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-22931204

RESUMO

A series of dicarboxylic quinoline derivatives bearing electron-releasing or -withdrawing substituents have been synthesized using mono- or/and biphasic methodologies. By controlling the regioselectivity of addition into our electrophilic intermediate, we also characterized by which mechanism the Doebner-Miller cyclization step occurred. As anticipated, electron-releasing substituents induce a red shift of the low-energy absorption allowing excitation in the visible region. In addition, by playing on the strength and position of the electron-releasing substituents, chromophore having interesting fluorescent properties such as large Stoke shifts, good fluorescent quantum yields, emission in the visible green-yellow region and reasonable two-photon absorption in the NIR region have been obtained. These small-size fluorophores, which can be made water-soluble and have been shown to be non-toxic, can be hetero- and/or polyfunctionalized and thus represent promising key units for fluorescence-based physiological experiments with low background interactions.


Assuntos
Ácidos Dicarboxílicos/síntese química , Corantes Fluorescentes/síntese química , Quinolinas/síntese química , Absorção , Ácidos Dicarboxílicos/química , Elétrons , Ésteres , Corantes Fluorescentes/química , Estrutura Molecular , Quinolinas/química , Espectrometria de Fluorescência
3.
Eur J Med Chem ; 45(2): 623-38, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19931949

RESUMO

A series of twenty six 8-hydroxyquinoline substituted amines, structurally related to compounds 2 and 3, were synthesized to evaluate the effects of structural changes on antitumor activity and understand their mechanism of action. The studies were performed on a wide variety of cancer cell lines within glioma and carcinoma models. The results obtained from chemical models and biological techniques such as microarrays suggest the following hypothesis that a quinone methide intermediate which does not react with DNA but which gives covalent protein thiol adducts. Micro-array analysis showed that the drugs induce the expression of a variety of stress related genes responsible for the cytotoxic and cytostatic effects in carcinoma and glioblastoma cells respectively. The described analogues could represent new promising anti-cancer candidates with specific action mechanisms, targeting accessible thiols from specific proteins and inducing potent anti-cancer effects.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzilaminas/química , Benzilaminas/farmacologia , Oxiquinolina/química , Antineoplásicos/metabolismo , Benzoquinonas/química , Benzilaminas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , DNA/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Concentração Inibidora 50 , Nucleotídeos/metabolismo , Estresse Fisiológico/genética , Relação Estrutura-Atividade
4.
J Med Chem ; 52(14): 4358-69, 2009 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-19537799

RESUMO

The ganglioside GM1 has neuroprotective effects but is not of therapeutic value because of its lack of bioavailability. Thus, molecules that mimic GM1 represent a novel approach to neuroprotection. We have synthesized 19 small GM1-like analogues whose simplified structure includes a hydrophobic saturated or unsaturated moiety linked to a hydrophilic moiety. We report their neuroprotective effects in two distinct models of nerve cell death using hippocampus-derived HT22 cells. We found that several analogues protected the HT22 cells from death at concentrations ranging from 2 to 5 microM. Additional neuroprotective assays using cortical slices injured by glutamate confirmed these results. Since members of the MAP kinase family are known to be key players in nerve cell survival and death, we characterized the role of these kinases in the neuroprotective mechanisms of the GM1-like analogues. Interestingly, the results indicate that the compounds provide neuroprotection through distinct mechanisms of action.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Ácidos Graxos Insaturados/química , Gangliosídeo G(M1)/análogos & derivados , Interações Hidrofóbicas e Hidrofílicas , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Isquemia Encefálica/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/uso terapêutico , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 44(2): 558-67, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18485536

RESUMO

Bis-8-hydroxyquinoline substituted benzylamines have been synthesized and screened for their antitumor activity on KB3 cell line model. Synthesis of this series of new analogues was accomplished using a one pot specific methodology which allows the synthesis of both bis- and mono-8-hydroxyquinoline substituted benzylamines. Among the synthesized compounds two compounds (4a and 5a), respectively, named JLK 1472 and JLK 1486, were particularly potent on KB3 cell line. Their CC(50) values being, respectively, 2.6 and 1.3 nM. Screened on a panel of cell lines showing various phenotype alterations, both compounds were found inactive on some cell lines such as PC3 (prostate cell line) and SF268 (neuroblastoma cell line) while highly active on other different cell lines. Mechanistic studies reveal that these two analogues did not affect tubulin and microtubules neither they exert a proteasomal inhibition effect. In contrast 4a and 5a activate specifically caspase 3/7 and not caspase 8 and 9, suggesting that their biological target should be located upstream from caspase 3/7. Moreover their cytotoxic effect is potentiated by the pro-apoptotic effects of TRAIL.


Assuntos
Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Benzilaminas/síntese química , Antineoplásicos/farmacologia , Benzilaminas/farmacologia , Caspases/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Hidroxiquinolinas , Masculino , Relação Estrutura-Atividade , Ligante Indutor de Apoptose Relacionado a TNF
6.
Bioorg Med Chem Lett ; 18(1): 169-74, 2008 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-18024032

RESUMO

Using SVZ (subventricular zone) tissue explants from one-day-old mice, we investigated the activity of new amino aromatic disulfide analogues and polyazamacrocycles on the migration of SVZ cells (neuroblasts). We found that among the tested analogues, non-peptidic disulfide derivative 8 significantly decreases the migration of neuroblasts from SVZ cells, and antagonized the stimulating activity of disulfide cyclic peptide 1. Discovery of compounds 1 and 8 constitutes new chemical tools which could be used to understand the mechanism of neuroblast migration during neurogenesis and eventually to identify specific genes involved in the neurogenesis.


Assuntos
Compostos Aza/farmacologia , Movimento Celular/efeitos dos fármacos , Dissulfetos/farmacologia , Compostos Macrocíclicos/farmacologia , Neurônios/efeitos dos fármacos , Poliaminas/farmacologia , Animais , Compostos Aza/síntese química , Compostos Aza/química , Dissulfetos/síntese química , Dissulfetos/química , Desenho de Fármacos , Ventrículos Laterais/citologia , Ventrículos Laterais/efeitos dos fármacos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Camundongos , Neurônios/citologia , Peptídeos Cíclicos/química , Poliaminas/síntese química , Poliaminas/química
7.
Bioorg Med Chem Lett ; 16(23): 5988-92, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-17000109

RESUMO

To find new derivatives that block different virus strains entry in cells bearing specific surface receptors represent an interesting challenge for medicinal chemists. Here, we report the synthesis and the anti-HIV properties of a new series of analogues based on the introduction of quinoline moiety on various polyamine backbones, including polyazamacrocycles. Three compounds 7, 8, and 10 of this series were found active on PBMCs cells infected by HIV-1 LAV or by HIV-1 BaL, in contrast the well-known reference compound 1a (AMD 3100) was found only active on HIV-1 LAV strain.


Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Hidroxiquinolinas/química , Poliaminas/química , Poliaminas/farmacologia , Fármacos Anti-HIV/química , Estrutura Molecular , Poliaminas/síntese química , Relação Estrutura-Atividade
8.
J Med Chem ; 49(14): 4275-85, 2006 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-16821787

RESUMO

Twenty novel beta-secretase inhibitors containing biarylpiperazine moieties belonging to naphthyl and coumarinyl series were designed for their potential use in Alzheimer's disease therapy. Enzymatic and cell-based assays have been carried out. The biological results clearly demonstrate that specific substituents located at the N(4)-position of the piperazine ring result in excellent in vitro inhibitory potency (IC(50) values ranging between 40 and 70 nM). Variable temperature NMR and modeling studies are consistent with the obtained biological data, since these studies confirmed that introduction at the N(4)-position of the piperazine ring allows productive interactions within the BACE-1 active site, which appear to be determinative for high BACE-1 inhibitory activity. These results are of particular interest since some of the new analogues belonging to the naphthyl series are almost one log more active than the best inhibitor of the similar family recently reported.


Assuntos
Cumarínicos/síntese química , Endopeptidases/metabolismo , Naftalenos/síntese química , Piperazinas/síntese química , Inibidores de Proteases/síntese química , Secretases da Proteína Precursora do Amiloide , Animais , Ácido Aspártico Endopeptidases , Linhagem Celular , Cumarínicos/química , Cumarínicos/farmacologia , Desenho de Fármacos , Endopeptidases/química , Transferência Ressonante de Energia de Fluorescência , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Naftalenos/química , Naftalenos/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 16(12): 3298-301, 2006 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-16581247

RESUMO

Dysfunction of copper metabolism leading to its excess or deficiency results in severe ailments. Recently, neurodegenerative disorders such as Alzheimer's disease have been associated with copper metabolism. Compounds having the ability to reduce copper levels in brain or to affect its distribution could have neuroprotective effects, mainly through a downregulation of the transcription of amyloid peptide precursor (APP). We report here the biological effect of compound 1,1'-xylyl bis-1,4,8,11-tetraaza cyclotetradecane, which specifically affects copper concentration in the brain cortex region. Its copper homeostatic activity is compared with that of clioquinol, a well-known drug, which has been recently reported as an active A beta-peptide clearance drug in vivo for Alzheimer's patients.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Quelantes/farmacologia , Clioquinol/farmacocinética , Cobre/metabolismo , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/farmacologia , Doença de Alzheimer/líquido cefalorraquidiano , Animais , Quelantes/farmacocinética , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 16(7): 1995-9, 2006 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-16412632

RESUMO

The protease beta-secretase plays a central role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease. Here, we report a new series of analogues based on the phenyl-piperazine scaffold coupled to various heterocyclic moieties, which demonstrate improved inhibitory activities on BACE-1 (FRET assay) compared to already known naphthyl counterparts. The obtained results suggest further structural modifications to access to more potent BACE-1 inhibitors.


Assuntos
Benzopiranos/química , Cumarínicos/química , Endopeptidases/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Piperazinas/farmacologia , Quinolinas/química , Secretases da Proteína Precursora do Amiloide , Piperazinas/química
11.
Curr Pharm Des ; 11(24): 3077-90, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16178746

RESUMO

One of the major challenges raised by HIV chemotherapy is the insurgence of viral resistance to drugs. Resistance to antiviral therapy has been observed for each of the different classes of anti-viral drugs: nucleoside reverse-transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. The crucial question for AIDS drug research community is: Should we continue the search of new anti-HIV drugs which can overcome HIV resistance insurgence or should we consider resistance to anti-HIV drugs as a futile challenge? This review, focussed specifically on HIV antiprotease drugs, highlights the different strategies which have been developed to design new anti-protease drugs which could overcome HIV resistance, and also reviews the different classes of compounds (peptidomimetic or non-peptidomimetic) actually under investigation in order to face the problem of HIV resistance to drug.


Assuntos
Desenho de Fármacos , Farmacorresistência Viral , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , Estrutura Molecular
12.
Org Biomol Chem ; 3(13): 2450-7, 2005 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-15976862

RESUMO

Inhibition of gamma-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce pathogenic Abeta peptides, is an attractive approach for the treatment of Alzheimer's disease. We designed a gamma-secretase inhibitor bearing an ascorbic acid moiety which allows a specific delivery of the drug to the brain. Through, on the one hand, Abeta peptide production measurements by specific in vitro assays (gamma-secretase cell free assay and cell based assay on HEK 293 APP transfected cells) and on the other hand through pharmacokinetic studies on animal models, the new inhibitor shows a good pharmacokinetic profile as well as a potent gamma-secretase inhibitory activity in vitro. From the obtained results, it is expected that drug will be mainly delivered to the CNS with a low diffusion in the peripheral tissues. Consequently the side effects of this gamma-secretase inhibitor on the immune cells could be reduced.


Assuntos
Ácido Ascórbico/química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Encéfalo/metabolismo , Dipeptídeos/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Secretases da Proteína Precursora do Amiloide , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Células Cultivadas , Sistema Nervoso Central/metabolismo , Dipeptídeos/síntese química , Sistemas de Liberação de Medicamentos , Endopeptidases , Inibidores Enzimáticos/síntese química , Humanos , Farmacocinética
13.
Bioorg Med Chem Lett ; 15(6): 1561-4, 2005 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-15745797

RESUMO

Starting from various cyclic or bicyclic ketones, we have synthesized novel Pifithrin-alpha analogues bearing different methyl substituted phenyl ketone groups at the N3-position of the 2-iminothiazole heterocycle. From stability studies in a biological medium as well as under specific chemical conditions, we have shown by NMR techniques that through a dehydration process, some derivatives can generate their corresponding cyclized analogues. All of the new analogues, Pifithrin-like and polycyclic dehydrated derivatives were assessed for their p53 inactivation potency by measuring survival of cortical neurons, whose death was induced by the DNA-damaging agent etoposide. Pifithrin-alpha like 2f as well as the cyclic dehydrated 6b analogue were found to be one log more potent p53 inactivators than reference compound Pft-alpha, with EC50 values ranging around 30 nM. These results support the finding that p53 inactivation by Pft-alpha analogues could be also due to the presence of the cyclic dehydrated Pft-alpha forms, generated in situ in the biological assay incubation medium.


Assuntos
Tiazóis/química , Tolueno/análogos & derivados , Tolueno/química , Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Benzotiazóis , Córtex Cerebral/citologia , Estabilidade de Medicamentos , Etoposídeo/farmacologia , Camundongos , Modelos Químicos , Estrutura Molecular , Neurônios/efeitos dos fármacos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia , Tolueno/síntese química , Tolueno/farmacologia
14.
Org Biomol Chem ; 3(4): 612-8, 2005 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-15703796

RESUMO

Inhibition of gamma-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce pathogenic A beta peptides, is an attractive approach for the treatment of Alzheimer's disease. We have designed a new gamma-secretase thiazolamide inhibitor bearing a dihydronicotinoyl moiety as Redox Delivery System which allows specific delivery of the drug to the brain. Through, on the one hand, A beta peptide production measurements by specific in vitro assays (gamma-secretase Cell Free assay and Cell Based assay on HEK 293 APP transfected cells) and, on the other hand, pharmacokinetic studies on animal models, the new inhibitor shows a good pharmacokinetic profile as well as a potent gamma-secretase inhibitory activity in vitro. From the obtained results, it is expected that drug will be mainly delivered to the CNS with low diffusion in the peripheral tissues. Consequently the side effects of this gamma-secretase inhibitor on the immune cells could be reduced.


Assuntos
Amidas/síntese química , Endopeptidases/química , Inibidores Enzimáticos/síntese química , Tiazóis/síntese química , Doença de Alzheimer/tratamento farmacológico , Amidas/química , Amidas/farmacocinética , Secretases da Proteína Precursora do Amiloide , Animais , Ácido Aspártico Endopeptidases , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Di-Hidropiridinas/química , Sistemas de Liberação de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Masculino , Estrutura Molecular , Ácidos Nicotínicos/química , Oxirredução , Ratos , Ratos Sprague-Dawley , Tiazóis/química , Tiazóis/farmacocinética
15.
Bioorg Med Chem Lett ; 15(1): 135-8, 2005 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-15582426

RESUMO

New 2-bromomethyl-8-substituted-benzo[c]chromen-6-ones have been synthesized and their bioactive properties have been evaluated on different enzymatic models: serine proteases (trypsin and alpha-chymotrypsin), HIV aspartyl protease, nitric oxide synthase and a panel of protein kinases. These new derivatives can provide upon chemical or enzymatic attack, very reactive quinonimine methide intermediates, which could be utilized for the design of enzyme inhibitors. We found that some of these new derivatives exhibit modest inhibitory activities on the studied enzyme models, but it could be improved after structure optimization.


Assuntos
Benzopiranos/síntese química , Benzopiranos/farmacologia , Ácido Aspártico Endopeptidases/metabolismo , Benzopiranos/química , Quimotripsina/metabolismo , HIV/enzimologia , Estrutura Molecular , Óxido Nítrico Sintase/metabolismo , Proteínas Quinases/metabolismo , Tripsina/metabolismo
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