Chemical synthesis, docking studies and biological effects of a pan peroxisome proliferator-activated receptor agonist and cyclooxygenase inhibitor

Autor(es):Mostrar menos -

Santin, Jose Roberto ^[1] ; Uchoa, Flavia D. T. ^[2] ; Lima, Maria do Carmo A. ^[2] ; Rabello, Marcelo M. ^[3] ; Machado, Isabel Daufenback ^[1] ; Hernandes, Marcelo Z. ^[3] ; Amato, Angelica A. ^[4] ; Milton, Flora Aparecida ^{[5, 4]} ; Webb, Paul ^[5] ; Rocha Neves, Francisco de Assis ^[4] ; Galdino, Suely L. ^[2] ; Pitta, Ivan Rocha ^[2] ; Farsky, Sandra H. P. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut, Dept Anal Clin & Toxicol, BR-05508900 Sao Paulo - Brazil

^[2] Univ Fed Pernambuco, LPSF, Recife, PE - Brazil

^[3] Univ Fed Pernambuco, LQTM, Dept Ciencias Farmaceut, Recife, PE - Brazil

^[4] Univ Brasilia, Fac Ciencias Saude, Dept Ciencias Farmaceut, Lab Farmacol Mol, BR-70910900 Brasilia, DF - Brazil

^[5] Methodist Hosp, Res Inst, Diabet Res Ctr, Houston, TX 77030 - USA

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmaceutical Sciences; v. 48, n. 4-5, p. 689-697, MAR 12 2013.
• Citações Web of Science: 13

Resumo

The compound (5Z)-5-{[}(5-bromo-1H-indol-3-yl)methylene]-3-(4-chlorobenzyl)-thiazolid ine-2,4-dione (LYSO-7) was synthesised in order to obtain a new type of anti-inflammatory drug, designed with hybrid features to inhibit cyclooxygenase (COX) and also to activate peroxisome proliferator-activated receptor (PPAR). Results obtained from docking (in silico) studies corroborated with experimental data, showing the potential affinity between the studied ligand and targets. The specificity of LYSO-7 for COX-enzymes was detected by the inhibition of COX-1 and COX-2 activities by 30% and 20%, respectively. In transactivation reporter gene assays LYSO-07 showed a pan partial agonist effect on the three PPAR subtypes (PPAR gamma, PPAR alpha and PPAR beta/delta). The agonist action on PPAR gamma was also observed by a pharmacological approach, as the reduction in the Escherichia coli lipopolysaccharide (LPS)-induced interleukin 1 beta (IL-1 beta) secretion and nitric oxide (NO) production by mouse neutrophils was blocked by GW9962, a specific PPAR gamma antagonist. Additionally, the in vivo effect was measured by reduced carrageenan-induced neutrophil influx into the subcutaneous tissue of mice. Taken together, these data show that LYSO-7 displays a potent in vivo anti-inflammatory effect during the innate acute response, which is dependent on its associated COX inhibitory activities and PPAR activation. (C) 2013 Elsevier B.V. All rights reserved. (AU)

• Processo FAPESP: 10/17175-0 - Efeito do agonista PPAR Lyso-07 sobre a instalação e cicatrização de úlceras gástricas induzidas em camundongos
• Beneficiário: José Roberto Santin
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 11/01848-8 - Avaliação da atividade gastroprotetora do agonista PPAR Lyso-07 e do ácido clorogênico
• Beneficiário: Sandra Helena Poliselli Farsky
• Modalidade de apoio: Auxílio à Pesquisa - Regular