Silva João P, Areias Filipe M, Proença Fernanda M, Coutinho Olga P
Department of Biology, Center of Biology, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal.
Life Sci. 2006 Feb 9;78(11):1256-67. doi: 10.1016/j.lfs.2005.06.033. Epub 2005 Oct 25.
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.
在本研究中，我们使用了通过有机合成获得的新型氮化合物，其结构预示着具有抗氧化潜力，并最终可能发展成为对涉及氧化应激的疾病具有药理意义的分子。这些化合物被鉴定为FMA4、FMA5、FMA7和FMA8，它们在酚单元的C-3和/或C-4位置上存在羟基，这可能是其自由基缓冲能力的原因。DPPH褪色法的数据证实了这些化合物具有高抗自由基效率。细胞模型（L929和PC12）实验结果表明，它们无毒，并且确实能保护细胞免受抗坏血酸-铁氧化对诱导的膜脂质过氧化。保护水平与药物的亲脂性特征相关，有时优于生育三烯酚，与α-生育酚相当。在存在星形孢菌素凋亡刺激的情况下评估，化合物FMA4和FMA7对细胞死亡也具有高度保护作用。这种保护导致星形孢菌素诱导的caspase-3活性显著降低，而这似乎又源于在膜受体途径（caspase-8）中观察到的保护以及在线粒体途径（caspase-9）中观察到的保护。综合这些新型直链化合物的实验结果，为它们作为治疗剂，即作为抗氧化剂和凋亡途径保护剂的应用开辟了前景。另一方面，环状结构呈现出的轻微促氧化特征表明其具有不同的治疗潜力，目前正在对此进行研究。
