Does conjugation of antioxidants improve their antioxidative/anti-inflammatory potential?

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• 作者：Dimitra Hadjipavlou-Litina ; George E. Magoulas ; Stavros E. Bariamis ; Denis Drainas ; Konstantinos Avgoustakis ; Dionissios Papaioannou
• 关键词：Retinoids ; Psoralens ; Spermine ; Caffeic acid analogs ; l-DOPA ; Dopamine ; Conjugates ; Antioxidant activities ; Anti-inflammatory activities ; Lipoxygenase inhibitors ; Lipid peroxidation ; Cytotoxicity
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2010
• 出版时间：1 December 2010
• 年：2010
• 卷：18
• 期：23
• 页码：8204-8217
• 全文大小：510 K

文摘

A series of symmetric and asymmetric spermine (SPM) conjugates with all-trans-retinoic acid (ATRA), acitretin (ACI), (E)-3-(trioxsalen-4′-yl)acrylic acid (TRAA) and l-DOPA, amides of ACI, l-DOPA and TRAA with 1-aminobutane, benzylamine, dopamine and 1,12-diaminobutane as well as hybrid conjugates of O,O′-dimethylcaffeic acid (DMCA) with TRAA or N-fumaroyl-indole-3-carboxanilide (FICA) and 2-(2-aminoethoxy)ethanol were synthesized and their antioxidant properties were studied. The reducing activity (RA) % of the compounds were evaluated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging assay and found to be in the range 0–92(20 min) % /96(60 min) % at 100 μM, the most powerful being the conjugates l-DOPA-SPM-l-DOPA (8, RA = 89 % /96 % ) and l-DOPA-dopamine (13, RA = 92 % /92 % ). Conjugate DMCA-NH(CH₂CH₂O)₂-FICA (14) was the most powerful LOX inhibitor with IC₅₀ 33.5 μM, followed by the conjugates ACI-NHCH₂Ph (10, IC₅₀ 40.5 μM), ACI-SPM-TRAA (7, IC₅₀ 41.5 μM), DMCA-NH(CH₂CH₂O)₂-TRAA (15, IC₅₀ 65 μM), 13 (IC₅₀ 81.5 μM) and ACI-dopamine (11, IC₅₀ 87 μM). The most potent inhibitors of lipid peroxidation at 100 μM were the conjugates 15 (98 % ) and ACI-SPM-ACI (4, 97 % ) whereas all other compounds showed activities comparable or lower than trolox. The most interesting compounds, namely ATRA-SPM-ATRA (3), 4, 10, 11 and 15, as well as unconjugated compounds such as ATRA and dopamine, were studied for their anti-inflammatory activity in vivo on rat paw oedema induced by Carrageenan and found to exhibit, for doses of 0.01 mmol/mL of conjugates per Kg of rat body weight, weaker anti-inflammatory activities (3.6–40 % ) than indomethacin (47 % ) with conjugate 3 being the most potent (40 % ) in this series of compounds. The cytocompatibility of selected compounds was evaluated by the viability of RAMEC cells in the presence of different concentrations (0.5–50 μM) of the compounds. Conjugates 3 (IC₅₀ 2.6 μM) and 4 (IC₅₀ 4.7 μM) were more cytotoxic than the corresponding unconjugated retinoids ATRA (IC₅₀ 18.3 μM) and ACI (IC₅₀ 14.6 μM), whereas conjugate 15 (IC₅₀ 12.9 μM) was less cytotoxic than either DCSP (IC₅₀ 11.3 μM) or the tert-butyl ester of TRAA (IC₅₀ 2.9 μM).