| Summary: | 碩士 === 國立陽明大學 === 藥理學研究所 === 87 === Recent studies demonstrated that endothelial dysfunction, monocyte infiltration and activation into macrophages, smooth muscle cell migration as well as proliferation are involved in atherogenesis. Oxidative modification of low density lipoprotein (LDL) plays a key role in its molecular pathogenesis. Oxidized LDL (OxLDL) appears in the circulation and tends to infiltrate into the aortic endothelium. It is further oxidized in the intima and finally taken by the macrophages.
Antioxidants, which are able to inhibit LDL oxidation, may reduce early atherogenesis and slow down the progression to advanced stages. The development of antioxidants to inhibit LDL oxidation has become a potential route for atherosclerotic diseases. In order to inhibit OxLDL formation, potential candidates have to reduce reactive oxygen species-mediated damages to polyunsaturated fatty acids in LDL.
In this study, a series of dopamine derivatives were synthesized. We have demonstrated the structure-activity relationship and also elucidated the potential of these dopamine derivatives to prevent LDL from oxidation with a-tocopherol, ascorbate and licorice extracts. Inhibition of Cu2+-induced human LDL oxidation was chosen as the in vitro assay system. Probucol was used as a positive control. Results showed that eight compounds, PA01, PA02, PA03, PA05, PA06, PA07 PA08 and PA09 exhibited strong antioxidant activities in a dose-dependent manner. The antioxidant activities to inhibit Cu2+-induced LDL oxidation were higher than probucol (IC50 = 3.9 mM). The IC50 values were 3.2, 3.7, 3.6, 2.9, 3.0, 3.3, 3.1 and 2.9 mM, respectively. PA05 and PA09 were the most potent compounds in the series of dopamine derivatives. PA05 and PA09 are isomers and their structures are silimar. The length of carbon chain between the phenyl group and the cis or trans form of the structure frame affect the antioxidant activities. The antioxidative activity increased significantly when combined PA05 (0.3 mg/mL) with low-dose ascorbate (0.1 mg/mL). The lag phase (Tlag, min) in Cu2+-induced LDL oxidation was prolonged by 1.4-fold (from 180 to 240 min). Combined supplementation with a-tocopherol, ascorbate, and licorice extracts is not superior to high dose a-tocopherol, ascorbate, and licorice extracts alone in inhibiting LDL oxidation.
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