Mechanism And Structure-activity Relationship Of Resveratrol, Caffeic Acid Phenethyl Ester, Hydroxychalcones And Their Analogs As Potent Antioxidants And Prooxidants

Antioxidants have gained importance in recent years due to their ability to neutralize reactive oxygen species which are implicated in several major human diseases including cancer. In this thesis, we designed and synthesized some analogues with natural antioxidants such as resveratrol, caffeic acid phenethyl ester (CAPE) and chalcone as the lead compounds, and their antioxidant, prooxidant and anticancer activities were investigated. In additional, the detail mechanism and structure-activity relationship (SAR) were also discussed.(1) The detailed antioxidant and prooxidant mechanism and SAR of resveratrol and its analogues were studied by the oxidative product analysis of them with galvinoxyl radical or Cu(â…¡), and UV-visible spectra change in the presence of Cu(â…¡), which suggests the importance of o-dihydroxyl groups and 4-hydroxyl group. This study also reveals a good and interest correlation between antioxidant and prooxidant activity, as well as antiproliferative effect on HL-60 cells.(2) The anti-haemolysis capacity of CAPE analogues with different substituents and various lengths of the alkyl side chains against AAPH-mediated oxidative haemolysis of red blood cells was evaluated. It was found that the anti-haemolysis activity dependents significantly on the molecular structure (the number and position of hydroxyl groups), the lipophilicity and the chain length. Furthermore, their antiproliferative effect on HL-60 cells was also assessed. This study reveals an interest correlation between anti-haemolysis activity and antiproliferative effect.(3) The antioxidant effect of caffeates with the various lengths of the alkyl side chains against the AAPH-induced peroxidation of linoleic acid in SDS and CTAB micelles, lipid peroxidation of human erythrocyte ghosts and oxidative damage of pBR322 plasmid DNA was studied. In heterogeneous media (micelles and human erythrocyte ghosts), the antioxidant activity of caffeates dependents significantly on the lipophilicity and steric hindrance. However, in homogeneous medium (DNA), the antioxidant activity only dependents on the steric hindrance. These indicates chain length and microenvironment are very important to the antioxidant activity of caffeates.(4) We synthesized twelve hydroxychalcones with different number and position of hydroxyl groups, and investigated their antioxidant effect against peroxynitrite-induced damage of bovine serum albumin (BSA) protein. It was found that the compounds bearing o-diphenoxyl groups (10,11 and 12) were most active, followed by the compounds bearing 3-hydroxy group (2 and 5) and 3'-hydroxy group (8), while those bearing no such groups were weak or inactive.(5) The important role of hydroxychalcones as the pBR322 plasmid DNA-cleaving agents in the presence of Cu(II) was investigated. It was found that the compounds bearing o-diphenoxyl groups (10,11 and 12) exhibited higher activity in the DNA damages than the ones bearing no such groups, and 12 was the most active one among the examined hydroxychalcones. The interaction between 12 and Cu(II) and influence of ethylenediaminetetraacetic acid and pH on the interaction were also studied to help elucidate the detailed prooxidant mechanism using UV-visible spectroscopy. On the basis of these observations, it is proposed that it is the 12 phenolate anion, instead of the parent molecule, chelates with Cu(II) as a bidentate ligand, hence facilitating intramolecular electron transfer between 12 and Cu(II).