Synthesis of New 5′-Norcarbocyclic Aza/Deaza Purine Fleximers - Noncompetitive Inhibitors of E.coli Purine Nucleoside Phosphorylase

Abstract

A new series of flexible 5′-norcarbocyclic aza/deaza-purine nucleoside analogs were synthesized from 6-oxybicyclo[3.1.0.]hex-2-ene and pyrazole-containing fleximer analogs of heterocyclic bases using the Trost procedure. The compounds were evaluated as potential inhibitors of E. coli purine nucleoside phosphorylase. Analog 1-3 were found to be noncompetitive inhibitors with inhibition constants of 14–24 mM. From the data obtained, it can be assumed that the new 5′-norcarbocyclic nucleoside analogs interact with the active site of the PNP like natural heterocyclic bases. But at the same time the presence of a cyclopentyl moiety with 2′ and 3′ hydroxyls is necessary for the inhibitory properties, since compounds 8–10, without those groups did not exhibit an inhibitory effect under the experimental conditions.