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 100μM, 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 33.5μM, followed by the conjugates ACI-NHCH₂Ph (10, IC₅₀ 40.5μM), ACI-SPM-TRAA (7, IC₅₀ 41.5μM), DMCA-NH(CH₂CH₂O)₂-TRAA (15, IC₅₀ 65μM), 13 (IC₅₀ 81.5μM) and ACI-dopamine (11, IC₅₀ 87μM). The most potent inhibitors of lipid peroxidation at 100μM 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 (0.5-50μM) of the compounds. Conjugates 3 (IC₅₀ 2.6μM) and 4 (IC₅₀ 4.7μM) were more cytotoxic than the corresponding unconjugated retinoids ATRA (IC₅₀ 18.3μM) and ACI (IC₅₀ 14.6μM), whereas conjugate 15 (IC₅₀ 12.9μM) was less cytotoxic than either DCSP (IC₅₀ 11.3μM) or the tert-butyl ester of TRAA (IC₅₀ 2.9μM).
Department of Pharmaceutical Chemistry, Aristotle University of Thessaloniki, Greece. hadjipav@pharm.auth.gr
Dimitra
D
Hadjipavlou-Litina
George E
GE
Magoulas
Stavros E
SE
Bariamis
Denis
D
Drainas
Konstantinos
K
Avgoustakis
Dionissios
D
Papaioannou
D017255:Acitretin / Q000737:chemistry; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D007980:Levodopa / Q000737:chemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D051381:Rats; D013096:Spermine / Q000737:chemistry; D014212:Tretinoin / Q000737:chemistry
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D013096:Spermine; D007980:Levodopa; D014212:Tretinoin; D017255:Acitretin