A chemoenzymatic process for the synthesis of acyclic nucleoside analogues involving the use of rabbit muscle aldolase (RAMA)

M. PALAZZOLO; A. IRIBARREN; E. LEWKOWICZ

Hamburgo

Congreso; biocat 2012; 2012

For more than 40 years, nucleoside analogues have shown to be a valuable source of antiviral and antitumor agents [1]. In particular, acyclic nucleosides received great interest –since the discovery of acyclovir in 1978- due to their extraordinary chemical and biological stability. Unlike natural nucleosides, the high flexibility of the C-C linkages enables the acyclic analogues to adopt conformations that favor the formation of complexes with the enzymes involved in their metabolism [2]. Often, the absolute configuration of the stereogenic centers plays an important role in determining both their biological activity and selectivity [3]. Aldolases are enzymes that catalyse stereospecific C-C bond condensation reactions. In general, they possess strong dependence on the donor compound but show low specificity towards the acceptor substrate [4]. Owing to these facts, they are a very interesting tool for the synthesis of a variety of chiral compounds. In this work, we describe a chemoenzymatic process for the preparation of thymidine and adenosine acyclic analogues (Figure 1). This strategy involved the suitable Nalkylation of the nucleosidic bases to generate the acceptors for the subsequent aldol condensation reaction biocatalysed by rabbit muscle aldolase (RAMA). The expected acyclic nucleoside analogues were obtained in moderate to high yields. [1] De Clercq, E. Annu. Rev. Pharmacol. Toxicol. (2011), 51, 1-24 [2] D’Alonzo, D.; Guaragna, A.; Palumbo, G. Chem. Biodiversity (2011), 8, 373-413 [3] Paju, A. et al. Nucleosides, Nucleotides Nucleic Acids (2010), 29, 707–720 [4] Clapés, P.; Fessner, W-D.; Sprenger, G. A.; Samland, A. K. Curr. Opin. Chem. Biol. (2010), 14, 154–167