以线粒体为作用靶点的羟基肉桂酸类生物抗氧化剂的设计、合成和生物活性研究

As natural polyphenolic antioxidants, Hydroxycinnamic acids (HCAs) are prophylactic against a varity of diseases, such as angiocardiopathy, cancer and neurodegenerative diseases. However, the poorer target specificity and lower bioavailability limitted its desired effects in the clinical trials. In the present research, HCAs as well as the lipophilic triphenylphosphonium (TPP) cation would be employed as antioxidant moiety and vehicle, respectively. Based on this strategy, we designed mitochondria-targeted hydroxycinnamic acids (MTHCAs). To futher research the inhibitory actions of MTHCAs against endogenous oxidative damages and the effects of mitochondrial microenvironments on prooxidative activities, hepatic L02 cell and C.elegans would be used. Furthermore, the stabilities of its connective covalent bond in isolated rat liver mitochondrion and hepatic L02 cell mitochondrion as well as the redox potential of MTHCAs would be evaluated, and thus the possible effects of the physicochemical properties on antioxidation and prooxidation wolud be explained. The implementation of this poposal would provide the foundation for the reaearch of targeted antioxidants based on natural polyphenolic molecules as guided structures, and offer candidate compounds for oxidative stress-related diseases.

天然多酚类抗氧化剂-羟基肉桂酸（HCAs）对癌症、心血管疾病及神经退行性疾病等多种疾病具有预防作用，但HCAs较弱的生物靶向性和较低的生物利用度影响了其临床试验的预期效果。本课题拟以HCAs为抗氧化活性组分，通过亲脂性三苯基膦阳离子（TPP）载体，设计、合成以线粒体为靶点的羟基肉桂酸类抗氧化剂MTHCAs，探索其分子结构、"嫁接"共价键与促氧化、抗氧化活性之间的关系。拟采用肝L02细胞和动物模型C.elegans，研究MTHCAs分子对内源性氧化应激损伤的抑制作用和线粒体微环境对促氧化活性的影响。并通过研究MTHCAs分子"嫁接"共价键在离体的大鼠肝脏线粒体和肝L02细胞线粒体内的稳定性以及MTHCAs分子的氧化还原电位，阐明分子的理化性质对抗氧化与促氧化活性的影响。本课题的开展将为以天然多酚类小分子为先导结构的靶标抗氧化剂研究奠定基础，进而为与氧化应激相关疾病的治疗提供候选化合物。

肿瘤细胞线粒体结构和功能的改变以及代谢变异的发生，使得他们比正常细胞更易于接受线粒体的影响。因此，开发一些能够直接作用于线粒体的抗肿瘤新药是研究的新热点。本项目以三苯基膦阳离子缀合的羟基肉桂酸、大黄素和萘醌衍生物为研究对象，研究了它们的抗肿瘤活性和与线粒体相干的活性机制，并发现了一些具有重要活性的先导分子。 主要研究结果包括：（1）以肉桂酸为药效基团，以三苯基膦阳离子为线粒体靶向载体，合成了三苯基膦阳离子缀合的羟基肉桂酸衍生物，并研究了化合物的抗氧化活性、线粒体稳定性和细胞毒活性。（2）发现了大黄素主要聚集在肝细胞线粒体，并通过作用于线粒体亲环蛋白D诱导细胞凋亡，从而揭示了线粒体是大黄素在细胞内的作用靶点之一。（3）1,4萘醌分子，具有平面的分子结构，研究证实它们可以作用于细胞线粒体DNA，进行诱导癌细胞死亡。因此，我们合成了1,4萘醌骨架的衍生物，研究了它们的抗肿瘤活性和线粒体相关机制。