SÃntese, modelagem molecular e atividade hipoglicemiante de novas arilideno-tiazolidinadionas

AUTOR(ES)
DATA DE PUBLICAÇÃO

2006

RESUMO

The glitazones, also referred to as insulin sensitizers, are generically a class of thiazolidinediones (TZDs) that possess hypoglycemic activity and are orally administered in patients with type II diabetes mellitus. Two of these thiazolidinediones are rosiglitazone and pioglityazone. We synthesized 12 arylideno-thiazolidinediones (ATZDs) of 5-benzylideno-3-(4-methyl-benzyl)- thiazolidine-2.4-dione with potential hypoglycemic activity. We later investigated the metabolic and molecular effects of 3-(4-methyl-benzyl)-5-(4-chloro-benzylidene)-thiazolidine-2.4-dione (GQ2) in Swiss mice with hyperlipidic diet (HD) induced obesity. The new ATZDs were synthesized by the reaction that resulted from the nucleophilic addition of 3-(4- methyl-benzyl)- 5-(4-chloro-benzylidene)-thiazolidine-2.4-dione to substituted ethyl - (2-cyano-3-phenyl)- acrylates. According to molecular modeling studies, the combinations between the new ATZDs and the LBD domination of the PPARγ nuclear receptor present good stability (negative binding energy) when compared with the binding energy of rosiglitazone, an insulin sensitizer, used as a standard substance. GQ2 treatment of obese mice for a period of 14 days reduced the basal level of glucose, insulin and leptin, increased insulin sensitivity, reduced peri-epididymal fat, lowered fluid retention and concomitantly reduced weight gain. When the quantity of food intake during this same period was evaluated, no significant difference was observed between animals treated with GQ2 and those on DH during a period of 24 hours. The IR/IRSs/PI3K/Akt insulin-signaling pathway in the liver, muscle and adipose tissue reduced by DH, recovered completely after treatment with GQ2, together with a reduction in IR/IRSs/PI3K/Akt phosphorylation in the adipose and hepatic tissue. Treatment with GQ2 led to reduction in the iNOS enzyme in the muscle and adipose tissue, reduction of TNF-α in the adipose tissue and at the same time a reduction of IKK and JNK serine kinases in the three tissues under study. Therefore, the new PPARγ agonist, GQ2, reduces the insulin resistance and seems to increase the insulin sensibility of the liver, muscle and apipose tissue through alterations on expression and fosforilation of signal transmision related proteins (IR/IRSs/PI3K/Akt) on induced obesety and insulin resistance animals through hyperlipidic diet

ASSUNTO(S)

atividade hipoglicemiante ciencias biologicas modelagem molecular arilideno-tiazolidinadionas

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