Saleh Tarek M, Connell Barry J, Kucukkaya Inan, Abd-El-Aziz Alaa S
Department of Biomedical Sciences, Atlantic Veterinary College, Charlottetown, PE C1A 4P3, Canada.
Department of Chemistry, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada.
Brain Sci. 2015 Apr 21;5(2):130-43. doi: 10.3390/brainsci5020130.
Previous work in our laboratory demonstrated the utility of synthetic combinations of two naturally occurring, biologically active compounds. In particular, we combined two known anti-oxidant compounds, lipoic acid and apocynin, covalently linked via an ester bond (named UPEI-100). In an animal model of ischemia-reperfusion injury (tMCAO), UPEI-100 was shown to produce equivalent neuroprotection compared to each parent compound, but at a 100-fold lower dose. However, it was determined that UPEI-100 was undetectable in any tissue samples almost immediately following intravenous injection. Therefore, the present investigation was done to determine if biological stability of UPEI-100 could be improved by replacing the ester bond with a more bio cleavage-resistant bond, an ether bond (named UPEI-104). We then compared the stability of UPEI-104 to the original parent compound UPEI-100 in human plasma as well as liver microsomes. Our results demonstrated that both UPEI-100 and UPEI-104 could be detected in human plasma for over 120 min; however, only UPEI-104 was detectable for an average of 7 min following incubation with human liver microsomes. This increased stability did not affect the biological activity of UPEI-104 as measured using our tMCAO model. Our results suggest that combining compounds using an ether bond can improve stability while maintaining biological activity.
我们实验室之前的研究证明了两种天然存在的生物活性化合物的合成组合的效用。具体而言，我们将两种已知的抗氧化化合物硫辛酸和白杨素通过酯键共价连接（命名为UPEI-100）。在缺血再灌注损伤动物模型（大脑中动脉闭塞）中，与每种母体化合物相比，UPEI-100显示出同等的神经保护作用，但剂量低100倍。然而，确定在静脉注射后几乎立即在任何组织样本中都检测不到UPEI-100。因此，进行本研究以确定用更具生物抗裂解性的键即醚键（命名为UPEI-104）取代酯键是否可以提高UPEI-100的生物稳定性。然后我们比较了UPEI-104与原始母体化合物UPEI-100在人血浆以及肝微粒体中的稳定性。我们的结果表明，UPEI-100和UPEI-104在人血浆中均可检测超过120分钟；然而，与人肝微粒体孵育后，只有UPEI-104平均可检测7分钟。这种增加的稳定性并不影响使用我们的大脑中动脉闭塞模型测得的UPEI-104的生物活性。我们的结果表明，使用醚键组合化合物可以提高稳定性，同时保持生物活性。
