摘要：

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(CH 2CH 2O) 2-FICA ( 14) was the most powerful LOX inhibitor with IC 50 33.5 μM, followed by the conjugates ACI-NHCH 2Ph ( 10, IC 50 40.5 μM), ACI-SPM-TRAA ( 7, IC 50 41.5 μM), DMCA-NH(CH 2CH 2O) 2-TRAA ( 15, IC 50 65 μM), 13 (IC 50 81.5 μM) and ACI-dopamine ( 11, IC 50 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 (IC 50 2.6 μM) and 4 (IC 50 4.7 μM) were more cytotoxic than the corresponding unconjugated retinoids ATRA (IC 50 18.3 μM) and ACI (IC 50 14.6 μM), whereas conjugate 15 (IC 50 12.9 μM) was less cytotoxic than either DCSP (IC 50 11.3 μM) or the tert-butyl ester of TRAA (IC 50 2.9 μM).

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