INVESTIGADORES
ZÍGOLO MarÍa Antonela
congresos y reuniones científicas
Título:
Bile acid derivatives as potent inhibitors of T. cruzi proliferation. Enzymatic synthesis, biological evaluation and docking study
Autor/es:
MARÍA ANTONELA ZÍGOLO; ALICIA BALDESSARI; GUADALUPE E. GARCÍA LIÑARES
Reunión:
Simposio; 1º Simposio Latinoamericano de Biocatálisis y Biotransformaciones; 2014
Resumen:
Bile acids (BAs) are widely distributed in nature as oxygenated metabolites of steroids. They are also powerful biological detergents that aid in the solubilization and absorption of fats, fatty acids and lipid soluble vitamins. As amphiphilic compounds, they show two different faces: a hydrophobic face (β) containing angular methyl groups and a hydrophilic face (α) with hydroxyl groups. The ratio of the hydrophobic to the hydrophilic surface area of BAs determines their broad biological activity. With the aim of getting a variation in the above mentioned ratio, in this work we are reporting the enzymatic synthesis of a series of derivatives involving the modification of the hydroxyl (R1, R2, R3: OAc) and the carboxyl (R4: alkyl) groups, which were biologically evaluated against T. cruzi. On the other hand, a docking study was carried out in order to shed light to the molecular determinants of the enzyme activity. RESULTS AND DISCUSSION In order to find an increase in lipophilicity and enhance permeability features, we prepared derivatives containing an acyl group at the C-3 or C-7 position and/or alkyl groups in the acid moiety. In steroid chemistry, it is difficult to achieve reactions in a regioselective way and protection and deprotection steps are required in order to obtain only the desired product. To avoid this problem we have used lipases and fungi as reaction catalysts, due to their good performance in steroid transformations1,2. We have been carried out enzyme-catalyzed acetylation, deacetylation and alcoholysis reactions performed on chenodeoxycholic, deoxycholic and lithocholic acids. We have studied the influence of various reaction parameters in the enzymatic reactions, such as lipase source, acylating agent/ or alcohol /substrate ratio, enzyme/substrate ratio, solvent and temperature. The lipases showed to be very efficient affording most of products in high yield (77-98%) and with high regioselectivity. In addition, in order to establish a more complete understanding of enzymatic reactions, a docking study showed how different substrates are arranged differently in the catalytic site of the enzymes used thus achieving the observed regioselectivities. It was also studied the effect of different concentrations of bile acids derivatives on epimastigote form of Trypanosoma cruzi growth was studied during 12 days. In some cases, a significant inhibition of growth was observed. CONCLUSION This work describes a enzymatic strategy for the synthesis of twelve mono-, diacetyl and ester derivatives of deoxycholic, chenodeoxycholic and lithocholic acid which were completely spectroscopically characterized. All compounds were biologically evaluated against epimastigote form of T. cruzi; some of them showed to be very effective as inhibitors of parasite growth with low IC50. The advantages showed by the enzymatic methodology, such as mild reaction conditions and low environmental impact, make biocatalysis a convenient way to prepare these derivatives of bile acids with application as potential drugs for chemotherapy of Chagas disease. ACKNOWLEDGEMENTS We thank UBA, CONICET, ANPCyT and Bunge y Born Foundation for partial financial support. REFERENCES [1] Quintana, P.G.; Guillén, M.; Marciello, M. ; Valero, F.; Palomo, J.M.; Baldessari, A. Eur. J. Org. Chem, 2012, 4306-12. [2] Quintana, P.G.; Romero, S.M.; Vaamonde, G.; Baldessari, A. J. Mol. Cat. B : Enzymatic 2013, 97, 110-17.