Highly regioselectively enzymatic acylation and deacylation reactions to obtain potential prodrugs of the antileukemic fludarabine

MARÍA B. SABAINI; ADOLFO M. IRIBARREN; LUIS E. IGLESIAS

Hamburgo

Congreso; 7th International Congress on Biocatalysis; 2014

Highly regioselective enzymatic deacylation and acylation reactions to obtain potential prodrugs of the antileukemic fludarabine    M. B. Sabaini1, A. M. Iribarren1,2  and L. E. Iglesias1  1Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Roque Sáenz Peña 352 - (1876) Bernal,  Buenos Aires, Argentina;  2INGEBI (CONICET) ? Vuelta de Obligado 2490 ? (1428) Buenos Aires, Argentina. Fludarabine (9-b-D-arabinofuranosyl-2-fluoroadenine) is a powerful drug [1] applied in chronic lymphocytic leukaemia. To get agents with enhanced therapeutic efficacy, the delivery of nucleosides can be improved using prodrugs, which are derivatives with better pharmacokinetic properties and increased metabolical stability [2]. Synthesis of nucleoside prodrugs requires the troublesome regioselective derivatisation of furanosic hydroxyls; this aim can be simplified by applying biocatalytic tools [3]. Continuing our previous works [4], we have now obtained partially acylated derivatives of fludarabine (Figure 1). The regioselectivity of lipase B from Candida antarctica (CAL-B) in deacylation reactions was modulated by choice of the reaction medium: in buffer, 2´,3´-di-O-acylated products (3a-c) were obtained while in alcohol, monoacylated derivatives at 2? (4a-c) were formed. CAL-B-catalysed acetylations gave regioselectively 5´-O-acetyl- (5a) and 2´,5´-di-O-acetylfludarabine (6a), providing regioisomers of 4a and 3a, respectively. The acyl moiety affected the conversion of the studied biotransformations and trioleylated 2d was unreactive in the assayed deacylations. The set of biotransformations in Figure 1 is a simple, highly regioselective and versatile procedure to prepare potential prodrugs of cytarabine, shortening conventional synthetic strategies based on protective groups. The financial support of UNQ and CONICET (PIP11-172) is acknowledged. [1] C.Galmarini, J.Mackey, C.Dumontet, Lancet 2002, 3, 415. [2] F.Li, H.Maag, T.Alfredson, J.Pharm. Sci. 2008, 97, 1109. [3] (a) M.Ferrero, V.Gotor, Chem. Rev. 2000, 100, 4319. (b) N.Li, T.Smith, M.Zong, Biotechnol. Adv. 2010, 28, 348. [4] (a) M.Sabaini, M.Zinni, M.Mohorcic, J.Friedrich, A.Iribarren, L.Iglesias, J. Mol. Catal. B: Enzym. 2010, 62, 225. (b) C.Palacio, M.Sabaini, A.Iribarren, L.Iglesias, J. Biotechnol. 2013, 165, 99