title: Enzymatic synthesis of bile acid derivatives and biological evaluation against Trypanosoma cruzi.
abstract: Enzyme catalysis was applied to synthesize derivatives of three bile acids and their biological activity was evaluated as growth inhibitors of the protozoan Trypanosoma cruzi. Twelve mono-, diacetyl and ester derivatives of deoxycholic, chenodeoxycholic and lithocholic acid, seven of them new compounds, were obtained through lipase-catalyzed acetylation, esterification and alcoholysis reactions in very good to excellent yield and a highly regioselective way. Among them, acetylated ester products, in which the lipase catalyzed both reactions in one-pot, were obtained. The influence of various reaction parameters in the enzymatic reactions, such as enzyme source, acylating agent/substrate ratio, enzyme/substrate ratio, solvent and temperature, was studied. Some of the evaluated compounds showed a remarkable activity as Trypanosoma cruzi growth inhibitors, obtaining the best results with ethyl chenodeoxycholate 3-acetate and chenodeoxycholic acid 3,7-diacetate, which showed IC50: 8.6 and 22.8 μM, respectively. In addition, in order to shed light to bile acids behavior in enzymatic reactions, molecular modeling was applied to some derivatives. The advantages showed by the enzymatic methodology, such as mild reaction conditions and low environmental impact, make the biocatalysis a convenient way to synthesize these bile acid derivatives with application as potential antiparasitic agents.
authors.affiliation: Laboratorio de Biocatálisis, Departamento de Química Orgánica y UMYMFOR, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Piso 3, C1428EGA Buenos Aires, Argentina.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: García Liñares
authors.affiliation: Laboratorio de Biocatálisis, Departamento de Química Orgánica y UMYMFOR, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Piso 3, C1428EGA Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Antonela Zígolo
authors.affiliation: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular 'Dr. Héctor N. Torres', CONICET, Vuelta de Obligado 2490, C1428ADN Buenos Aires, Argentina.
authors.forename: Leandro
authors.initials: L
authors.lastname: Simonetti
authors.affiliation: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular 'Dr. Héctor N. Torres', CONICET, Vuelta de Obligado 2490, C1428ADN Buenos Aires, Argentina.
authors.forename: Silvia A
authors.initials: SA
authors.lastname: Longhi
authors.affiliation: Laboratorio de Biocatálisis, Departamento de Química Orgánica y UMYMFOR, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Piso 3, C1428EGA Buenos Aires, Argentina. Electronic address: alib@qo.fcen.uba.ar.
authors.forename: Alicia
authors.initials: A
authors.lastname: Baldessari
mesh_terms: D000107:Acetylation; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D055162:Biocatalysis; D004353:Drug Evaluation, Preclinical; D004951:Esterification; D005656:Fungal Proteins / Q000378:metabolism*; D008049:Lipase / Q000378:metabolism*; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism; D013379:Substrate Specificity; D013696:Temperature; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000981:Antiprotozoal Agents; D001647:Bile Acids and Salts; D005656:Fungal Proteins; D012997:Solvents; D008049:Lipase; C431349:lipase B, Candida antarctica
keywords: Bile acids; Chagas disease; Lipase-catalyzed; Molecular modeling