RESUMEN
A series of branched-chain sugar isonucleosides was synthesized and evaluated for antiviral activity against herpesviruses. The preparation of homochiral [3S-(3 alpha, 4 beta, 5 alpha)]-2-amino-1, 9-dihydro-9-[tetrahydro-4,5-bis(hydroxymethyl)-3-furanyl]-6H-purin-6-one (7, BMS-181,164) and related compounds was stereospecifically achieved starting from 1,2-isopropylidene-D-xylofuranose (10). An efficient two-step reduction of the anomeric center of bis-acetate 18 involved formation of the chloride intermediate 19, followed by diisobutylaluminum hydride reduction. Tosylation of the resulting alcohol 20 provided the key intermediate 21, which was coupled with a variety of nucleobase anions. Several members of this new class of compounds possess activity against herpes simplex virus types 1 and 2 (HSV-1 and -2), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV). Compound 7 exhibits potent and selective activity against thymidine kinase encoding herpesviruses, in particular, HSV-1 and HSV-2. Evaluation of compound 7 for inhibition of WI-38 cell growth indicated an ID50 of > 700 microM. Although the antiherpetic activity in vitro of 7 is less than that of acyclovir (1), compound 7 displays superior efficacy in mouse model infections. The (bromovinyl)uridine analog 8 (BMS-181,165) also exhibits selective activity against HSV-1 and VZV, with no cytostatic effect on WI-38 cell growth at > 800 microM. Compound 8 is active against simian varicella virus and is efficacious in the corresponding monkey model.
Asunto(s)
Antivirales/síntesis química , Guanosina/análogos & derivados , Herpesviridae/efectos de los fármacos , Uridina/análogos & derivados , Animales , Línea Celular , Varicela/tratamiento farmacológico , Citomegalovirus/efectos de los fármacos , Femenino , Guanosina/síntesis química , Guanosina/farmacología , Guanosina/uso terapéutico , Herpes Simple/tratamiento farmacológico , Herpesviridae/enzimología , Herpesvirus Humano 3/efectos de los fármacos , Ratones , Estructura Molecular , Simplexvirus/efectos de los fármacos , Relación Estructura-Actividad , Timidina Quinasa/antagonistas & inhibidores , Uridina/síntesis química , Uridina/farmacología , Uridina/uso terapéutico , Virus Vaccinia/efectos de los fármacos , Ensayo de Placa ViralRESUMEN
A series of novel aminodiol inhibitors of HIV protease based on the lead compound 1 with structural modifications at P1' were synthesized in order to reduce the cytotoxicity of 1. We have observed a high degree of correlation between the lipophilicity and cytotoxicity of this series of inhibitors. It was found that appropriate substitution at the para position of the P1' phenyl group of 1 resulted in the identification of equipotent (both against the enzyme and in cell culture) compounds (10l, 10m, 10n, and 15c) which possess significantly decreased cytotoxicity.