Veri seti Açık Erişim
Pehlivanlar Ezgi; Şimşek Rahime
ŞİMŞEK, Rahime
Inflammation is a response to injury and infection in the organism. It can be categorized as acute and chronic inflammation. Chronic inflammation is the underlying cause of many diseases such as Alzheimer's, diabetes, rheumatoid arthritis, atherosclerosis and cardiovascular diseases. Recent studies have proven the anti-inflammatory properties of 1,4-dihydropyridines (1,4-DHPs) and its derivatives, which have many biological properties including calcium channel blockers. In this study, 15 compounds with the general structure of hexahydroquinoline-3-carboxylate, which are condensed derivatives of 1,4-DHPs, were synthesized. These compounds, expected to show inhibitory activity on inflammatory mediators, were obtained by the reaction of 4-(difluoromethoxy)benzaldehyde, substituted/non-substituted 1,3-cyclohexanedione derivatives and appropriate alkyl acetoacetate compounds in the presence of ammonium acetate as nitrogen source according to Hantszch synthesis method. The structures of the synthesized compounds were elucidated by IR, 1H-NMR, 13C-NMR and HRMS methods. The cytotoxic properties of the compounds were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method in 3T3 cell line. Among the 15 compounds, the three compounds with the lowest cytotoxic properties were selected for further experiments. Inflammation was induced by lipooxygenase (LPS) and the effects of the selected compounds on the levels of reactive oxygen species (ROS), cytokines, complement C3 and C9 regulatory proteins were investigated. It was found that three selected compounds decreased the transforming growth factor beta 1 (TGF-b1) levels. Among these compounds, compound 3e provided the most significant decrease in this cytokine. Moreover, compound 3e increased both C3 and C9 levels. Molecular modeling studies also showed that compound 3e has a better affinity for TGF-b1. When the binding modes of these compounds in the active site of TGF-b1were analyzed, it was found that compound 3e had hydrophobic interactions with amino acids Leu142, Tyr84, and Ile13; halogen bond interactions with Asp92 and hydrogen bond interactions with amino acids Ser89, Gly88, and Gly14 in the active binding site. Further in vitro and in vivo studies are needed to show the possible mechanism of action of compound 3e.
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