Enzymatic regioselectively preparation of potential prodrugs of the antileukemic agent cytarabine

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

Manchester

Simposio; 11th International Symposium on Biocatalysis and Biotransformation; 2013

University of Manchester

Cytarabine (1-beta-D-arabinofuranosylcytosine, Ara-C), a drug widely employed against acute myeloid leucemia, is a highly polar compound, a feature limiting bioavailability and therapeutic efficacy. These pharmacological properties can be improved by the use of prodrugs1, what requires efficient regioselective hydroxyl derivatisation; this aim can be achieved nowadays by biocatalytic methodologies2. Taking into account our antecedents on the chemo-3a and regioselective Candida antarctica B lipase (CAL-B) catalysed deacetylation of nucleosides3b, we have studied the preparation of a set of Ara-C partially acylated derivatives. Starting from tri-O- (1, Figure 1) and N,O-tetraacetylated Ara-C (2), and by proper choice of the deacetylation medium (alcohol or buffer), it was possible to obtain regioselectively acetylated isomers (e.g. 4 and 8; 5 and 11) and derivatives bearing different degree of acetylation (e.g. 4, 5, 7). For products 10 and 11, a deacetylation followed by a subsequent acetylation was applied, both steps being catalysed by the same enzyme. The reactions outlined in Figure 1, which were not restricted to acetyl moieties (6 and 9 are hexanoylated derivatives), took place in good and high yields, providing a simple, highly regioselective and versatile procedure to prepare potential prodrugs of cytarabine. The financial support of Universidad Nacional de Quilmes and CONICET (PIP11-172) is acknowledged. [1]         K. Huttunen, J. Rautio, Curr. Top. Med. Chem. 2011, 11, 2265. [2]       (a) M. Ferrero, V. Gotor, Chem. Rev. 2000, 100, 4319. (b) N. Li, T. J. Smith, M. H. Zong, Biotechnol. Adv. 2010, 28, 348. [3]       (a) C. M. Palacio, M. B. Sabaini, A. M. Iribarren, L. E. Iglesias, J. Biotechnol. 2013, 165, 99. (b) M. B. Sabaini, M. A. Zinni, M. Mohorcic, J. Friedrich, A. M. Iribarren, L. E. Iglesias, J. Mol. Catal. B: Enzym. 2010, 62, 225. The financial support of Universidad Nacional de Quilmes and CONICET (PIP11-172) is acknowledged. [1]         K. Huttunen, J. Rautio, Curr. Top. Med. Chem. 2011, 11, 2265. [2]       (a) M. Ferrero, V. Gotor, Chem. Rev. 2000, 100, 4319. (b) N. Li, T. J. Smith, M. H. Zong, Biotechnol. Adv. 2010, 28, 348. [3]       (a) C. M. Palacio, M. B. Sabaini, A. M. Iribarren, L. E. Iglesias, J. Biotechnol. 2013, 165, 99. (b) M. B. Sabaini, M. A. Zinni, M. Mohorcic, J. Friedrich, A. M. Iribarren, L. E. Iglesias, J. Mol. Catal. B: Enzym. 2010, 62, 225. The financial support of Universidad Nacional de Quilmes and CONICET (PIP11-172) is acknowledged. [1]         K. Huttunen, J. Rautio, Curr. Top. Med. Chem. 2011, 11, 2265. [2]       (a) M. Ferrero, V. Gotor, Chem. Rev. 2000, 100, 4319. (b) N. Li, T. J. Smith, M. H. Zong, Biotechnol. Adv. 2010, 28, 348. [3]       (a) C. M. Palacio, M. B. Sabaini, A. M. Iribarren, L. E. Iglesias, J. Biotechnol. 2013, 165, 99. (b) M. B. Sabaini, M. A. Zinni, M. Mohorcic, J. Friedrich, A. M. Iribarren, L. E. Iglesias, J. Mol. Catal. B: Enzym. 2010, 62, 225. The financial support of Universidad Nacional de Quilmes and CONICET (PIP11-172) is acknowledged. [1]         K. Huttunen, J. Rautio, Curr. Top. Med. Chem. 2011, 11, 2265. [2]       (a) M. Ferrero, V. Gotor, Chem. Rev. 2000, 100, 4319. (b) N. Li, T. J. Smith, M. H. Zong, Biotechnol. Adv. 2010, 28, 348. [3]       (a) C. M. Palacio, M. B. Sabaini, A. M. Iribarren, L. E. Iglesias, J. Biotechnol. 2013, 165, 99. (b) M. B. Sabaini, M. A. Zinni, M. Mohorcic, J. Friedrich, A. M. Iribarren, L. E. Iglesias, J. Mol. Catal. B: Enzym. 2010, 62, 225.