ACYCLIC NUCLEOSIDE ANALOGUES SYNTHESIS THROUGH BIOCATALYSED ALDOL REACTION

MARIANO NIGRO; ISRAEL SANCHEZ MORENO; RAUL BENITO ARENAS; PILAR MONTERO CALLE; AGATHA BASTIDA; ADOLFO IRIBARREN; ELIZABETH LEWKOWICZ; EDUARDO GARCÍA JUNCEDA

Budapest

Simposio; XI Simposio Internacional de Biocatalisis y Biotransformaciones; 2017

Hungarian Chemical Society and Budapest University of Technology and Economics

Nucleosideanalogues are a family of compounds widely used as antiviral and anticancerdrugs. Among them, acyclic nucleoside analogues (ANs) possess a branched or linear alkyl chain substitutedwith at least one hydroxyl group that mimics the pentofuranose ring in naturalnucleosides. The flexibility of the alkyl chain enables ANs to adopt a suitableconformation to fit in the active site of the enzymes involved in theirmetabolisms, conferring higher therapeutic activity. Additionally, theirbioavailability can be increased by introducing phosphate moieties. On theother hand, the stereochemistry of the ANs often plays an important role indetermining their biological activity and selectivity.A number of synthetic routes to prepare ANs inenantiomerically pure form have been reported. The only antecedent of abiocatalytic approach is their synthesis using aldolases. The potential of DHAP-dependentaldolases for the preparation of different stereoisomers of ANs, was studiedemploying commercially available fructose-1,6-biphosphate aldolase (RAMA) andrecombinants L-rhamnulosa-1-fosfatoaldolase (Rhu1PA) from Thermotogamaritima and L-fuculosa-1-fosfatoaldolase (Fuc1PA) from E. coli. The aldehydes containing cytosine or thymine asbase were condensed by the corresponding aldolase with in situ prepared DHAP. Aldol formation was confirmed by NMR afterpurification by HPLC with conversions between 80-90%.