RESUMEN
Novel purine nucleosides functionalized at the 2-position have been prepared using new applications of synthetic methodology. The target molecules were designed as potential inhibitors (as their monophosphates) of the enzyme, inosine monophosphate dehydrogenase (IMPDH), and representative inhibition data are presented. Antiviral data of the compounds are discussed.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , IMP Deshidrogenasa/antagonistas & inhibidores , Nucleósidos de Purina/síntesis química , Antivirales/síntesis química , Antivirales/farmacología , Catálisis , Inhibidores Enzimáticos/farmacología , Modelos Químicos , Fosforilación , Nucleósidos de Purina/antagonistas & inhibidores , Nucleósidos de Purina/farmacologíaRESUMEN
A new enzyme-mediated synthesis of 2-vinylinosine, a compound with broad-spectrum RNA antiviral activity, is described. In order to understand the mechanism of action of this compound, we synthesized its monophosphate and investigated the behavior of that compound toward the enzyme, inosine monophosphate dehydrogenase (IMPDH), a key enzyme involved in the biosynthesis of nucleotides. 2-Vinylinosine monophosphate is a potent inhibitor of IMPDH with a K(i) of 3.98 microM (k(inact)=2.94 x 10(-2) s(-1)). The antiviral activity of 2-vinylinosine may be explained by its cellular conversion to the monophosphate through the sequential action of PNP and HGPRT and subsequent inhibition of IMPDH by the cellularly produced 2-vinylinosine 5'-monophosphate.