Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Org Chem ; 71(19): 7133-45, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16958506

RESUMO

A multistep scalable synthesis of the clinically important hepatitis C virus (HCV) protease inhibitor BILN 2061 (1) is described. The synthesis is highly convergent and consists of two amide bond formations, one etherification, and one ring-closing metathesis (RCM) step, using readily available building blocks 2-5. The optimization of each step is described at length. The main focus of the paper is the study of the RCM step and the description of the main problems faced when scaling up to pilot scale this highly powerful but very challenging synthetic operation. Eventually, the RCM reaction was smoothly scaled up to produce >400 kg of cyclized product.


Assuntos
Antivirais/síntese química , Carbamatos/síntese química , Hepacivirus/enzimologia , Compostos Macrocíclicos/síntese química , Inibidores de Proteases/síntese química , Quinolinas/síntese química , Tiazóis/síntese química , Antivirais/química , Antivirais/farmacologia , Carbamatos/química , Carbamatos/farmacologia , Cromatografia Líquida de Alta Pressão , Ciclização , Hepacivirus/efeitos dos fármacos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Tiazóis/química , Tiazóis/farmacologia
2.
Org Biomol Chem ; 4(3): 416-23, 2006 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-16446799

RESUMO

A cyclic Leu-enkephalin mimetic containing a 7-membered ring, and two linear analogues, has been prepared on solid phase. In the cyclic mimetic the intramolecular (1-4) hydrogen bond found in crystalline Leu-enkephalin has been replaced by an ethylene bridge. In addition, the amide bond between Tyr1 and Gly2 has been replaced by a methylene ether isostere and Gly3 has been deleted. The two linear analogues both contain the methylene ether isostere instead of the Tyr1-Gly2 amide bond and the shorter of the two lacks Gly3. The three compounds, and a beta-turn mimetic analogous to the 7-membered turn mimetic but with Gly3 included, were evaluated for specific binding to micro- and delta-opioid receptors in rat brain membranes. With the exception of the beta-turn mimetic the three other Leu-enkephalin analogues all bound with varying affinity to the micro- and delta-opioid receptors. From the results it could be concluded that Leu-enkephalin binds in a turn conformation to the opiate receptors, but that this conformation is not a (1-4) beta-turn.


Assuntos
Materiais Biomiméticos/síntese química , Materiais Biomiméticos/farmacologia , Encefalina Leucina/análogos & derivados , Encefalina Leucina/química , Animais , Materiais Biomiméticos/química , Materiais Biomiméticos/metabolismo , Encéfalo/citologia , Ciclização , Ligantes , Estrutura Molecular , Ratos , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo
3.
J Org Chem ; 69(10): 3500-8, 2004 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-15132562

RESUMO

A beta-turn mimetic in which the four amino acids of a beta-turn have been replaced by a 10-membered ring has been designed, synthesized, and subjected to conformational studies. In the mimetic, the intramolecular CO(i)-HN(i)(+3) hydrogen bond that is often found in beta-turns has been replaced by an ethylene bridge. In addition, the amide bond between residues i and i + 1 was exchanged for a methylene ether isoster. Such a beta-turn mimetic, based on the first four residues of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu), was prepared in 15 steps. The synthesis relied on a beta-azido alcohol prepared in five steps from Cbz-Tyr(tBu)-OH as a key, i-position building block. tert-Butyl bromoacetate, glycine, and a Phe-Leu dipetide were then used as building blocks for positions i + 1, i + 2, and i + 3, respectively. Conformational studies based on (1)H NMR data showed that the beta-turn mimetic was flexible, but that it resembled a type-II beta-turn at low temperature. This low energy conformer closely resembled the structure determined for crystalline Leu-enkephalin.


Assuntos
Encefalina Leucina/síntese química , Aminoácidos/química , Encefalina Leucina/química , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Mimetismo Molecular , Estrutura Molecular , Conformação Proteica , Estrutura Secundária de Proteína
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...