Feng Zikai, Smith Jason A, Gueven Nuri, Quirino Joselito P
Australian Centre for Research on Separation Sciences (ACROSS), School of Natural Sciences-Chemistry, College of Science and Engineering, University of Tasmania, Hobart TAS 7000, Australia.
School of Natural Sciences-Chemistry, College of Science and Engineering, University of Tasmania, Hobart TAS 7000, Australia.
Pharmaceuticals (Basel). 2020 Feb 12;13(2):29. doi: 10.3390/ph13020029.
Short-chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which is largely dependent on their reversible redox characteristics of the active quinone core. We recently synthesized a SCQ library of > 148 naphthoquinone derivatives and identified 16 compounds with enhanced cytoprotection compared to the clinically used benzoquinone idebenone. One of the major drawbacks of idebenone is its high metabolic conversion in the liver, which significantly restricts is therapeutic activity. Therefore, this study assessed the metabolic stability of the 16 identified naphthoquinone derivatives - using hepatocarcinoma cells in combination with an optimized reverse-phase liquid chromatography (RP-LC) method. Most of the derivatives showed significantly better stability than idebenone over 6 h ( < 0.001). By extending the side-chain of SCQs, increased stability for some compounds was observed. Metabolic conversion from the derivative to and reduced idebenone metabolism in the presence of were also observed. These results highlight the therapeutic potential of naphthoquinone-based SCQs and provide essential insights for future drug design, prodrug therapy, and polytherapy, respectively.
短链醌（SCQs）已被确定为对抗线粒体功能障碍的潜在候选药物，这在很大程度上取决于其活性醌核心的可逆氧化还原特性。我们最近合成了一个包含超过148种萘醌衍生物的SCQ文库，并鉴定出16种与临床使用的苯醌艾地苯醌相比具有增强细胞保护作用的化合物。艾地苯醌的一个主要缺点是其在肝脏中的高代谢转化率，这显著限制了其治疗活性。因此，本研究使用肝癌细胞结合优化的反相液相色谱（RP-LC）方法评估了16种已鉴定的萘醌衍生物的代谢稳定性。大多数衍生物在6小时内显示出比艾地苯醌明显更好的稳定性（<0.001）。通过延长SCQs的侧链，观察到一些化合物的稳定性增加。还观察到衍生物向[具体衍生物]的代谢转化以及在[具体物质]存在下艾地苯醌代谢的减少。这些结果分别突出了基于萘醌的SCQs的治疗潜力，并为未来的药物设计、前药治疗和联合治疗提供了重要见解。
