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García Liñares, G.; Antonela Zígolo, M.; Simonetti, L.; Longhi, S.A.; Baldessari, A. "Enzymatic synthesis of bile acid derivatives and biological evaluation against Trypanosoma cruzi" (2015) Bioorganic and Medicinal Chemistry. 23(15):4804-4814
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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. © 2015 Elsevier Ltd. All rights reserved.

Registro:

Documento: Artículo
Título:Enzymatic synthesis of bile acid derivatives and biological evaluation against Trypanosoma cruzi
Autor:García Liñares, G.; Antonela Zígolo, M.; Simonetti, L.; Longhi, S.A.; Baldessari, A.
Filiación: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, Buenos Aires, C1428EGA, Argentina
Instituto de Investigaciones en Ingenieria Genetica y Biologia Molecular Dr. Hector N. Torres, CONICET, Vuelta de Obligado 2490, Buenos Aires, C1428ADN, Argentina
Palabras clave:Bile acids; Chagas disease; Lipase-catalyzed; Molecular modeling; acetic acid derivative; bile acid; chenodeoxycholic acid; chenodeoxycholic acid 3,7 diacetate; deoxycholic acid; ethyl chenodeoxycholate 3 acetate; lithocholic acid; nucleophile; unclassified drug; antiprotozoal agent; bile acid; fungal protein; lipase B, Candida antarctica; solvent; triacylglycerol lipase; alcoholysis; Article; controlled study; enzyme active site; enzyme mechanism; enzyme substrate; enzyme synthesis; esterification; growth inhibition; hydrophilicity; hydrophobicity; IC50; molecular model; nonhuman; nucleophilicity; protein acetylation; reaction analysis; solvent effect; structure activity relation; structure analysis; temperature measurement; Trypanosoma cruzi; acetylation; binding site; biocatalysis; biosynthesis; chemistry; drug effects; enzyme specificity; growth, development and aging; metabolism; molecular docking; preclinical study; protein tertiary structure; stereoisomerism; temperature; Trypanosoma cruzi; Protozoa; Trypanosoma cruzi; Acetylation; Antiprotozoal Agents; Bile Acids and Salts; Binding Sites; Biocatalysis; Drug Evaluation, Preclinical; Esterification; Fungal Proteins; Lipase; Molecular Docking Simulation; Protein Structure, Tertiary; Solvents; Stereoisomerism; Substrate Specificity; Temperature; Trypanosoma cruzi
Año:2015
Volumen:23
Número:15
Página de inicio:4804
Página de fin:4814
DOI: http://dx.doi.org/10.1016/j.bmc.2015.05.035
Título revista:Bioorganic and Medicinal Chemistry
Título revista abreviado:Bioorg. Med. Chem.
ISSN:09680896
CODEN:BMECE
CAS:chenodeoxycholic acid, 474-25-9; deoxycholic acid, 83-44-3; lithocholic acid, 434-13-9; triacylglycerol lipase, 9001-62-1; Antiprotozoal Agents; Bile Acids and Salts; Fungal Proteins; Lipase; lipase B, Candida antarctica; Solvents
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09680896_v23_n15_p4804_GarciaLinares

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Citas:

---------- APA ----------
García Liñares, G., Antonela Zígolo, M., Simonetti, L., Longhi, S.A. & Baldessari, A. (2015) . Enzymatic synthesis of bile acid derivatives and biological evaluation against Trypanosoma cruzi. Bioorganic and Medicinal Chemistry, 23(15), 4804-4814.
http://dx.doi.org/10.1016/j.bmc.2015.05.035
---------- CHICAGO ----------
García Liñares, G., Antonela Zígolo, M., Simonetti, L., Longhi, S.A., Baldessari, A. "Enzymatic synthesis of bile acid derivatives and biological evaluation against Trypanosoma cruzi" . Bioorganic and Medicinal Chemistry 23, no. 15 (2015) : 4804-4814.
http://dx.doi.org/10.1016/j.bmc.2015.05.035
---------- MLA ----------
García Liñares, G., Antonela Zígolo, M., Simonetti, L., Longhi, S.A., Baldessari, A. "Enzymatic synthesis of bile acid derivatives and biological evaluation against Trypanosoma cruzi" . Bioorganic and Medicinal Chemistry, vol. 23, no. 15, 2015, pp. 4804-4814.
http://dx.doi.org/10.1016/j.bmc.2015.05.035
---------- VANCOUVER ----------
García Liñares, G., Antonela Zígolo, M., Simonetti, L., Longhi, S.A., Baldessari, A. Enzymatic synthesis of bile acid derivatives and biological evaluation against Trypanosoma cruzi. Bioorg. Med. Chem. 2015;23(15):4804-4814.
http://dx.doi.org/10.1016/j.bmc.2015.05.035