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

Anastasia Khandazhinskaya; Ilja Fateev; Irina Konstantinova; Roman Esipov; Konstantin Polyakov; Katherine Seley-Radtke; Sergey Kochetkov; Elena Matyugina

doi:10.3389/fchem.2022.867587

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

Front Chem. 2022 May 4:10:867587. doi: 10.3389/fchem.2022.867587. eCollection 2022.

Authors

Anastasia Khandazhinskaya¹, Ilja Fateev², Irina Konstantinova², Roman Esipov², Konstantin Polyakov¹, Katherine Seley-Radtke³, Sergey Kochetkov¹, Elena Matyugina¹

Affiliations

¹ Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, Moscow, Russia.
² Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
³ Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD, United States.

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.

Keywords: 5'-norcarbocyclic nucleoside analogs; fleximers; inhibitor; purine nucleoside phosphorylase; pyrazole derivatives.