RESUMO
SAR investigations of the 4- and 5-positions of a series of 4-amino-4H-pyran-2-carboxylic acid 6-carboxamides are reported. Potent inhibitors of influenza A sialidase with marked selectivity over the influenza B enzyme were obtained when the basic 4-amino substituent was replaced by hydroxyl or even deleted. Modifications at the 5-position exhibited a tight steric requirement, with trifluoroacetamide being optimal.
Assuntos
Antivirais/química , Inibidores Enzimáticos/química , Nylons/química , Piranos/química , Ácidos Siálicos/química , Antivirais/síntese química , Antivirais/farmacologia , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Guanidinas , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/enzimologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/enzimologia , Modelos Moleculares , Estrutura Molecular , Neuraminidase/antagonistas & inibidores , Neuraminidase/metabolismo , Nylons/farmacologia , Piranos/farmacologia , Ácidos Siálicos/metabolismo , Relação Estrutura-Atividade , Ensaio de Placa Viral , ZanamivirRESUMO
Recombinant fusion proteins containing human atrial natriuretic factor, ANF(1-28) joined to chloramphenicol acetyltransferase (CAT) via cleavable linker sequences have been produced in Escherichia coli. The linker sequences were designed to allow the release of authentic ANF(1-28) following proteolytic cleavage by enterokinase or thrombin, or chemical cleavage with 2-(2-nitrophenylsulphenyl)-3-methyl-3'-bromoindolenine. Proteins, containing ANF(1-28) fused to the carboxyl-terminal region of CAT (using the ScaI restriction site in the cat gene), were largely soluble in E. coli and were obtained in higher yield than analogues containing ANF(1-28) linked to shorter CAT sequences. The longer derivatives also retained CAT activity allowing subsequent purification by affinity chromatography.
Assuntos
Acetiltransferases/isolamento & purificação , Fator Natriurético Atrial/biossíntese , Escherichia coli/enzimologia , Regulação da Expressão Gênica , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes/isolamento & purificação , Sequência de Aminoácidos , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/isolamento & purificação , Sequência de Bases , Cloranfenicol O-Acetiltransferase , Enteropeptidase/metabolismo , Escherichia coli/metabolismo , Vetores Genéticos , Hidrólise , Dados de Sequência Molecular , Plasmídeos , Escatol/análogos & derivados , Trombina/metabolismo , Transcrição GênicaRESUMO
Anion exchange HPLC purification of synthetic oligonucleotides with a high guanosine content is difficult. This study has demonstrated that these sequences can be successfully purified by anion exchange HPLC using standard conditions provided that the base protecting groups (isobutyryl[ib] and benzoyl[bz]) are retained on the otherwise deprotected oligomer.
Assuntos
Guanosina , Oligodesoxirribonucleotídeos/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia por Troca Iônica/métodos , Indicadores e ReagentesRESUMO
With the aim of finding an antidysrhythmic agent suitable for intravenous or oral administration we have examined a range of steroids carrying basic substituents. The primary screen involved control of cardiac dysrhythmias induced by intravenous infusion of aconitine into pentobarbitone-anaesthetised artificially-respired rats. The best activity was found among a series of 11 alpha-alkylamino steroids and structure-activity studies included modification of the alkylamino group and variation of substituents in ring A and at the 17-position. Good oral and intravenous activity was found among 17 beta-methoxycarbonyl-5 alpha-androstanes and methyl 2 beta-ethoxy-3 alpha-hydroxy-11 alpha-(3-methylbutylamino)-5 alpha-androstane-17 beta-carboxylate hydrochloride (CCI 22277) was selected for more detailed pharmacological study.
