Oxidative stress protection by newly synthesized nitrogen compounds with pharmacological potential.
In this study we used new nitrogen compounds obtained by organic synthesis whose structure predicted an antioxidant potential and then an eventual development as molecules of pharmacological interest in diseases involving oxidative stress. The compounds, identified as FMA4, FMA5, FMA7 and FMA8 differ in the presence of hydroxyl groups located in the C-3 and/or C-4 position of a phenolic unit, which is possibly responsible for their free radicals' buffering capacity. Data from the DPPH discoloration method confirm the high antiradical efficiency of the compounds. The results obtained with cellular models (L929 and PC12) show that they are not toxic and really protect from membrane lipid peroxidation induced by the ascorbate-iron oxidant pair. The level of protection correlates with the drug's lipophilic profile and is sometimes superior to trolox and equivalent to that observed for alpha-tocopherol. The compounds FMA4 and FMA7 present also a high protection from cell death evaluated in the presence of a staurosporine apoptotic stimulus. That protection results in a significant reduction of caspase-3 activity induced by staurosporine which by its turn seems to result from a protection observed in the membrane receptor pathway (caspase-8) together with a protection observed in the mitochondrial pathway (caspase-9). Taken together the results obtained with the new compounds, with linear chains, open up perspectives for their use as therapeutical agents, namely as antioxidants and protectors of apoptotic pathways. On the other hand the slight pro-oxidant profile obtained with the cyclic structures suggests a different therapeutic potential that is under current investigation.
Silva
João P
JP
Department of Biology, Center of Biology, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal.
Areias
Filipe M
FM
Proença
Fernanda M
FM
Coutinho
Olga P
OP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D009584:Nitrogen / Q000737:chemistry*; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells; D020011:Protective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
D016166:Free Radical Scavengers; D008563:Membrane Lipids; D020011:Protective Agents; D009584:Nitrogen