RESUMEN
Previous investigations identified 2'-C-Me-branched ribo-C-nucleoside adenosine analogues, 1, which contains a pyrrolo[2,1-f][1,2,4]triazin-4-amine heterocyclic base, and 2, which contains an imidazo[2,1-f][1,2,4]triazin-4-amine heterocyclic base as two compounds with promising anti-HCV in vitro activity. This Letter describes the synthesis and evaluation of a series of novel analogues of these compounds substituted at the 2-, 7-, and 8-positions of the heterocyclic bases. A number of active new HCV inhibitors were identified but most compounds also demonstrated unacceptable cytotoxicity. However, the 7-fluoro analogue of 1 displayed good potency with a promising cytotherapeutic margin.
Asunto(s)
Antivirales/farmacología , Proliferación Celular/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Imidazoles/química , Nucleósidos/farmacología , Pirroles/química , Triazinas/química , Replicación Viral/efectos de los fármacos , Antivirales/química , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Estructura Molecular , Nucleósidos/química , ARN Viral/genética , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Chalcone derivatives of the natural product khellinone were synthesised and screened for bioactivity against the voltage-gated potassium channel Kv1.3. X-ray crystallography was employed to investigate relationships between the structure and function of a selection of the reported chalcones.
Asunto(s)
Chalconas/síntesis química , Chalconas/farmacología , Canal de Potasio Kv1.3/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/farmacología , Benzofuranos/farmacología , Chalconas/química , Cristalografía por Rayos X , Electrofisiología , Humanos , Canal de Potasio Kv1.3/metabolismo , Modelos Químicos , Estructura Molecular , Bloqueadores de los Canales de Potasio/química , Relación Estructura-ActividadRESUMEN
Factor Xa is a central protease in the coagulation cascade and the target for many anticoagulant compounds currently under development. The preferences of the enzyme for substrates incorporating residues N-terminal to the cleavage site (P1, P2, etc.) have been elucidated, but little is known of its preferences for residues C-terminal to the cleavage site (P1', P2', etc.). The preferences of bovine factor Xa for substrate residues in the P1', P2' and P3' positions were mapped using fluorescence-quenched substrates. Bovine factor Xa, often used as a model for factor Xa, was most selective for the P2' position, less selective at the P1' position and almost completely non-selective at the P3' position. It appears that while the prime side subsites of factor Xa impose some selectivity towards substrates, the influence of these sites on factor Xa cleavage specificity is relatively low in comparison to related enzymes such as thrombin.
Asunto(s)
Factor Xa/metabolismo , Animales , Bovinos , Factor Xa/química , Fluorescencia , Cinética , Biblioteca de Péptidos , Péptidos/química , Péptidos/metabolismo , Especificidad por SustratoRESUMEN
The preparation and characterization by LCMS of a library of 55 fluorescence- quenched peptides is described. The peptides bear a terminal anthranilamide fluorophore and a penultimate 2,4-dinitrophenyl-L-lysine quencher, and will be used to probe the substrate binding domain of the human blood coagulation enzyme, factor Xa.