Bio- and Organocatalytic methods in the synthesis of nucleoside-based antiviral drugs

MARTÍN PALAZZOLO; MARÍA PÉREZ-SÁNCHEZ; ADOLFO IRIBARREN; PABLO DOMÍNGUEZ DE MARÍA; ELIZABETH LEWKOWICZ

Hamburgo

Congreso; 6th international congress on biocatalysis (BIOCAT 12); 2012

Hamburg University of Technology

The use of nucleoside-based compounds as antiviral drugs has been widely established during the last decades. Their mechanisms of action lie either on the specific inhibition of constitutive enzymes, or as interrupter agents within the RNA or DNA biosyntheses of viruses. Several nucleoside-based drugs have been approved by the OMS, and are currently being used worldwide. In this area, nucleoside derivatives in which the sugar part is substituted by an acyclic, functionalized chain are of particular interest. In its proper conformation, these drugs mimic real nucleosides, selectively inhibiting the DNA polymerase from viruses, and thus hampering their replication and propagation. In virtue of their importance, some of them (e.g. acyclovir and ganciclovir) are actively being used in therapies against, e.g., herpes virus. Several biocatalytic approaches for the synthesis of nucleosides have been successfully reported. A novel biocatalytic approach in the production of nucleoside-based acyclic antiviral drugs would involve the use of aldolases as biocatalysts. Aldolases (e.g. rabbit muscle aldolase, RAMA) are enzymes of the group of lyases that catalyze the aldol reaction between carbonylic compounds (e.g. aldehydes and ketones), to afford 1,3-hydroxy-ketones. Aldolases can provide a promising framework for the development of novel nucleoside-based acyclic antiviral drugs (Figure 1). Additionally, organocatalysis provides a complementary strategy to the aforementioned aldolase route. Organocatalysis has emerged in the last decade as a powerful and promising alternative to perform important organic reactions under very mild process conditions, often with high selectivity and reduced waste formation. In this area, pyrrolidine-based aldol reactions are efficiently conducted with high yields and selectivity. Thus, it would be of importance to explore (and compare) both catalytic routes (aldolase-based and organocatalyst-based) to provide a broader and complementary scope of mild and green technologies for synthetic purposes in the area of nucleosides (Figure 2). To this end, two model substrates as nitrogenated bases (N-alkyl derivatives of adenine and thymidine) were selected. The reaction biocatalysed by RAMA, using dihydroxyacetone phosphate as donor, afforded moderate to high yields. On the other hand, when pyrrolidine was used as organocatalyst and acetone and diethyl-2-oxopropylphosphonate were evaluated as acceptors, acyclic nucleosides analogs were obtained in 100% yield.