N-Acetylneuraminic acid aldolase-catalyzed synthesis of acyclic nucleoside analogues carrying 2-keto-4-hydroxy moieties

PALAZZOLO, M. A.; IRIBARREN, A. M.; LEWKOWICZ, E. S.

Manchester

Simposio; 11th International Symposium on Biocatalysis and Biotransformation (Biotrans 2013); 2013

N-Acetylneuraminic acid aldolase-catalyzed synthesis of acyclic nucleoside analogues carrying 2-keto-4-hydroxy moieties Martín A. Palazzoloa, Adolfo M. Iribarrena,b, Elizabeth S. Lewkowicza aLaboratorio de Biocatálisis y Biotransformaciones, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Roque Sáenz Peña 352, Bernal (CP 1876), Argentina; bLaboratorio de Química de Ácidos Nucleicos, INGEBI-CONICET, Vuelta de Obligado 2490, Ciudad Autónoma de Buenos Aires (CP 1428), Argentina E-mail: elewko@unq.edu.ar Nucleoside analogues are a valuable source of antiviral agents. Since the discovery of acyclovir in 1978, acyclic nucleosides (ANs) have become target of intense research and a number of outstanding drugs have been marketed to treat viral diseases including herpes, hepatitis and AIDS, among others(1). Aldolases are useful enzymatic tools to catalyze stereoselective aldol C-C additions. In quest of  new active ANs, we have recently employed rabbit muscle aldolase to prepare acyclic analogues of vidarabine, an active nucleoside currently used against herpes simplex and varicella zoster viruses(2). In the present work, we explored the production of novel nucleoside derivatives bearing a 2-keto-4-hydroxybutyrate skeleton by means of N-acetylneuraminic acid (NeuAc) aldolase, an enzyme which has been thoroughly used in the carbohydrate field to synthesize a variety of sugar mimetics displaying different biological activities(3). Based on the known relaxed specificity of the enzyme for the acceptor aldehyde, we prepared a range of 2-oxoethyl purinic and pyrimidinic compounds to be tested as substrates in condensation reactions with pyruvate. We observed that NeuAc aldolase was an efficient biocatalyst for the synthesis of ANs, since products were successfully obtained in up to 94% conversion (Figure 1). Furthermore, it was evidenced that the enzyme was capable of performing the desired reactions with a two-fold excess of either the heterocyclic aldehydes or pyruvate, thus making possible the choice of the limiting reagent depending on cost and easy of work-up. In addition, the obtained 2-keto-4-hydroxybutyrate blocks could be further (bio)chemically transformed to get other compounds of potential biological interest.     Figure 1. Chemoenzymatic production of novel ANs by means of NeuAc aldolase. (1)           De Clercq, E. Med. Res. Rev. 2013, DOI 10.1002/med.21283. (2) Palazzolo, M.A.; Iribarren, A.M.; Lewkowicz, E.S. 2013. To be submitted. (3)           Clapés, P.; Fessner, W.-D.; Sprenger, G. A.; Samland, A. K. Curr. Opin. Chem. Biol. 2010, 14, 154–167.