Bile acids derivatives as potent inhibitors of T.cruzy proliferation. Enzymatic synthesis, biological evaluation and docking study

GUADALUPE E. GARCÍA LIÑARES; MARÍA ANTONELA ZÍGOLO; ALICIA BALDESSARI

Buzios

Simposio; Primer Simposio Latinoamericano de Biocatálsis y Biotransformaciones VII Workshop on Biocatalysis and Biotransformations; 2014

Universidad de Rio de Janeiro

INTRODUCTION 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 spite of the broad activity spectrum of bile acids, the potential use is sometimes difficult because of the low solubility in both hydrophilic and hydrophobic media of these compounds. In order to find an increase in lipophilicity and enhance permeability features, we planned to modify the structure of some bile acids. For example, the presence of a acyl group at the C-3 or C-7 positions or esterification of acid moiety could be to bile acid more lipophilic. . 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. 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 of the compounds were biological 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 the 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 Foundationfor 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.