Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Oncotarget ; 8(17): 28260-28277, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28423677

RESUMO

Leelamine is an anticancer chemotherapeutic agent inhibiting intracellular cholesterol transport. Cell death mediated by leelamine occurs due to the lysosomotropic property of the compound, its accumulation in the lysosome, and inhibition of cholesterol transport leading to lack of availability for key processes required for functioning of cancer cells. The present study dissects the structure-activity-relationship of leelamine using synthesized derivatives of leelamine and abietic acid, a structurally similar compound, to identify the moiety responsible for anti-cancer activity. Similar to leelamine, all active derivatives had an amino group or a similar moiety that confers a lysosomotropic property to the compound enabling its accumulation in the lysosome. Active derivatives inhibited intracellular cholesterol transport and hindered xenografted melanoma tumor development without obvious systemic toxicity. In silico studies suggested that active derivatives accumulating in lysosomes bound to NPC1, a protein responsible for cholesterol export from the lysosome, to inhibit its activity that then caused accumulation, and lack of cholesterol availability for other key cellular activities. Thus, active derivatives of leelamine or abietic acid maintained lysosomotropic properties, bound to NPC1, and disrupted cellular cholesterol transport as well as availability to retard tumor development.


Assuntos
Antineoplásicos Fitogênicos/química , Colesterol/química , Relação Estrutura-Atividade , Abietanos/química , Abietanos/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colesterol/metabolismo , Relação Dose-Resposta a Droga , Endocitose/efeitos dos fármacos , Humanos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/patologia , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Transdução de Sinais/efeitos dos fármacos
2.
Bioorg Med Chem Lett ; 23(24): 6747-54, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24231362

RESUMO

The design, synthesis and structure activity relationship studies of a series of compounds from benzo[d]imidazo[5,1-b]thiazole scaffold as phosphodiesterase 10A (PDE10A) inhibitors are discussed. Several potent analogs with heteroaromatic substitutions (9a-d) were identified. The anticipated binding mode of these analogs was confirmed by performing the in silico docking experiments. Later, the heteroaromatics were substituted with saturated heteroalkyl groups which provided a tool compound 9e with excellent PDE10A activity, PDE selectivity, CNS penetrability and with favorable pharmacokinetic profile in rats. Furthermore, the compound 9e was shown to be efficacious in the MK-801 induced psychosis model and in the CAR model of psychosis.


Assuntos
Imidazóis/química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/química , Tiazóis/química , Animais , Antipsicóticos/química , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Modelos Animais de Doenças , Maleato de Dizocilpina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Feminino , Meia-Vida , Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Transtornos Psicóticos/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/uso terapêutico
3.
Bioorg Med Chem Lett ; 23(4): 1104-9, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23294698

RESUMO

Substituted 1,4-dihydropyridines were discovered as a novel and potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationships within this series have been carried out and studies revealed that the dihydropyridine core, with indole moiety and 3,4-dimethoxybenzyl group, is a potent analogue for PDE4 inhibition. These novel series of compounds were prepared via a 3-component reaction in a single pot. In vitro biological activity, modeling studies and crystallography data are also reported.


Assuntos
Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Cristalografia por Raios X , Di-Hidropiridinas/síntese química , Descoberta de Drogas , Inibidores da Fosfodiesterase 4/síntese química , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 45(1): 98-105, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19850376

RESUMO

The Ser/Thr protein kinase MAPKAP kinase2 (MAPKAPK2 or MK2) plays an important role in inflammation. A comparison of several crystal structures of MK2 shows that differences in active and inactive conformations result in large part from structural variations within the conformations of the glycine rich loop (p-loop) regions. We propose the most preferred binding conformation of two classes of MK2 inhibitors and suggest plausible critical interactions with active site residues. The predicted binding conformations of the two classes of MK2 inhibitors depend upon their orientation in the active site and activities were well correlated with the sum of D and G scores. A qualitative relationship between the sum of D and G scores and the measured activities can be demonstrated.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/química , Modelos Moleculares , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Piridinas/metabolismo , Piridinas/farmacologia , Trifosfato de Adenosina/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Domínio Catalítico , Simulação por Computador , Sequência Conservada , Cristalografia por Raios X , Glicina , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ligantes , Ligação Proteica , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Secundária de Proteína , Pirazóis/química , Piridinas/química , Reprodutibilidade dos Testes
5.
Antimicrob Agents Chemother ; 53(4): 1427-33, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19075051

RESUMO

Oxazolidinones are known to inhibit protein biosynthesis and act against a wide spectrum of gram-positive bacteria. A new investigational oxazolidinone, ranbezolid, inhibited bacterial protein synthesis in Staphylococcus aureus and Staphylococcus epidermidis. In S. epidermidis, ranbezolid showed inhibition of cell wall and lipid synthesis and a dose-dependent effect on membrane integrity. A kill-kinetics study showed that ranbezolid was bactericidal against S. epidermidis. In vitro translation of the luciferase gene done using bacterial and mammalian ribosomes indicated that ranbezolid specifically inhibited the bacterial ribosome. Molecular modeling studies revealed that both linezolid and ranbezolid fit in similar manners the active site of ribosomes, with total scores, i.e., theoretical binding affinities after consensus, of 5.2 and 6.9, respectively. The nitrofuran ring in ranbezolid is extended toward C2507, G2583, and U2584, and the nitro group forms a hydrogen bond from the base of G2583. The interaction of ranbezolid with the bacterial ribosomes clearly helps to elucidate its potent activity against the target pathogen.


Assuntos
Antibacterianos/farmacologia , Furanos/farmacologia , Oxazóis/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Ribossomos/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Acetamidas/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Linezolida , Oxazolidinonas/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Ribossomos/metabolismo , Transcrição Gênica/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...