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

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).