Síntese e avaliação farmacológica de derivados fenóxi-acetoacetatos em receptores ativadados por proliferadores peroxissomais e em receptores de hormônio tireoideano

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

Nuclear receptors (NRs) are of great importance for the worldwide drug market since they are involved in mechanisms which influence several diseases that affect humanity like, for instance, diabetes mellitus (DM2), obesity, dislypemia and atherosclerosis. Peroxisome Proliferator-Activated Receptors (PPAR) and Thyroid Hormone Receptors (TR) control important physiologic actions as the regulation of inflammatory processes, glucose and lipid homeostasis (PPAR), differentiation and cellular growth and metabolism (TR). Currently, the DM2 treatment is carried mainly by thiazolidinediones (TZD), a pharmacon category that reduces the insulin resistance. The therapy with thyroid hormone (TH) to reduce the serum cholesterol shows therapeutical imitations and undesirable cardiac effects. The compounds synthesized in this project: (4-phormyl-3,5- dimethylphenoxi)-acet ethyl acetate (KF01), (2-phormyl-3,5-dimethylphenoxi)-acet ethyl acetate (KF02) and (3,5-dimethylphenoxi)-acet ethyl acetate (KF03), were submitted to trials to evaluate its biological activity. In the cytotoxicity test, using Artemia salina larvae, all compounds evaluated presented activity and the compound KF03 showed itself 5.7 more active then the positive pattern (K2Cr2O7). This result indicates that KF01, KF02 and KF03 have antitumor activity. In the transfection and reporter gene trials in cell culture (U937 cells), the results showed that KF02 presented a pan-agonist action mediated by the three PPAR isoforms (a, b/d and g), besides a synergic effect in the presence of bezafibrate and rosiglitazone (PPAR synthetic ligants), KF03 presented a double agonism in the transcription mediated by PPARa and g, and acted synergically with the synthetic ligants of these receptors. In the thyroid hormone receptors (TRa and TRb), it was verified an agonist action of KF02 and a synergic effect of KF01, KF02 and KF03 in the presence of the thyroid hormone (T3). The B fragment derivatives (KF02 and KF03) showed themselves promising due to their biological activity mediated by PPAR and TR and these findings contribute to future studies in the development of pan and double PPAR agonists and also in the search for b-selective thyromimetic substances able to act in the metabolic syndrome control.

ASSUNTO(S)

tr organic synthesis ciencias da saude síndrome metabólica tiromiméticos ppar tr reporter gene síntese orgânica ppar synthetic ligants

ACESSO AO ARTIGO

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