Síntesis quimio-enzimática de fosfatos y fosfotriésteres de nucleósidos

ESTEBAN GUDIÑO; LUCAS DETTORRE; LUIS IGLESIAS; ELIZABETH LEWKOWICZ; ADOLFO IRIBARREN

Biocatálise e Biotransformaçao, fundamentos e aplicaçoes.

Editorial Schoba

Lugar: Salto; Año: 2014; p. 103 - 132

Many of the commercially available antiviral and antitumor drugs are nucleoside analogues. However, these compounds show poor bioavailability, are catabolically inactivated and in some cases the first phosphorylation needed to generate the active drug, the nucleoside 5´- monophosphates, is the limiting metabolic step . One way to partially avoid these problems is by the use of prodrugs. In this regard , the regioselective synthesis of 5´-phosphatidylnucleosides catalyzed by phospholipase D (PLD) can produce potential prodrugs with a nontoxic structure and with high affinity for the cell membrane. Subsequent enzymatic hydrolysis with phospholipase C using these derivatives allows to obtain the corresponding nucleoside 5´- monophosphates by a simple purification step . On the other hand, dialkylphosphotriesters are potential lipophilic prodrugs which would avoid the first step of phosphorylation in vivo releasing the corresponding nucleoside monophosphate. These derivatives can be regioselectively obtained through a transesterification reaction catalyzed by phosphotriesterases ( PTE ) carried out in anhydrous medium. To improve yields of these reactions, medium engineering studies and expression of the enzyme is in progress.