Aldolase cascade reaction for the synthesis of acyclic nucleoside analogues

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

Murcia

Congreso; Biotech 2017; 2017

Sociedad Española de Biotecnología

Nucleosideanalogues are a family of compounds widely used as antiviral and anticancerdrugs. Among them, acyclic nucleoside analogues (ANs) possess a branched orlinear alkyl chain substituted with at least one hydroxyl group that mimics thepentofuranose ring in natural nucleosides. The flexibility of the alkyl chainenables ANs to adopt a suitable conformation to fit in the active site of theenzymes involved in their metabolisms, conferring higher therapeutic activity.Additionally, their bioavailability can be increased by introducing phosphatemoieties. On the other hand, the stereochemistry of the ANs often plays animportant role in determining their biological activity and selectivity.A number ofsynthetic routes to prepare ANs in enantiomerically pure form have beenreported. The only antecedent of a biocatalytic approach is their synthesisusing aldolases. The potential of DHAP-dependent aldolases for the preparationof different stereoisomers of ANs, was studied employing commercially availablefructose-1,6-biphosphate aldolase (RAMA) and recombinantsL-rhamnulosa-1-fosfato aldolase (Rhu1PA) from Thermotoga maritima and L-fuculosa-1-fosfato aldolase (Fuc1PA) fromE. coli.Thealdehydes containing cytosine or thymine as base (1) were condensed by the corresponding aldolase with in situ prepared DHAP4. NMRconfirmed aldol (2-4) formation after purification by HPLCwith conversions between 80-90%.