Exploring the molecular diversity of phenolic acids and polyphenols to advance the knowledge for the development of new biologically-active molecules

提出的研究计划包括通过有机合成和药物化学方法的适应，通过合成新的类似物来探索多酚和酚酸的多样性，同时包括分子建模。根据近年来取得的成果，申请人对酚酸和多酚分子多样性的利用将使新分子的开发成为可能。相关结构-活性关系的确定将有助于开发新的生物活性分子。无论是通过抑制其产物的生物合成还是通过直接抑制，新型酚酸或多酚基类似物对脂肪加氧酶和环加氧酶（炎症级联反应的关键酶）的影响将被研究。酚酸和多酚是广泛分布的天然化合物，将被用作构建特异性和高效分子的基石。由于炎症与癌症之间的联系，抗癌活性测试将与申请人的合作者网络合作进行。同样，计划与申请人的合作者一起在动物疾病模型（如炎性关节炎）中进行选定化合物的体内试验。阐明新开发的类似物的结构-活性关系将为开发选择性和高效的生物活性分子提供知识，同时限制不良反应。在未来五年内，4名研究生和6名本科生将接受有机化学和药物化学艺术以及其他研究相关技能的高质量培训。除了提供密集的高素质人才培训外，该项目还将扩大合成生物相关的酚酸和多酚类似物的方法的数量，这些方法对分子多样性有很大的需求。致力于开发新的酚酸或基于多酚的类似物的药物化学社区和一般人群将从拟议的研究计划的结果中受益。

The proposed research program involves exploring the diversity of polyphenols and phenolic acids by the synthesis of new analogs through the adaptation of organic synthesis and medicinal chemistry methodologies while including molecular modeling. Based on the results obtained in recent years, the use by the applicant of the molecular diversity of phenolic acids and polyphenols will allow the development of new molecules. The determination of associated structure-activity relationships will help advance knowledge for the development of new biologically active molecules. Whether by inhibiting the biosynthesis of their products or through their direct inhibition, the effects of novel phenolic acids or polyphenols-based analogs on lipoxygenases and cyclooxygenases, key enzymes involved in the inflammatory cascade, will be investigated. Phenolic acids and polyphenols, which are widely distributed natural compounds, will be used as building blocks to construct specific and efficient molecules. Due to the link between inflammation and cancer, anticancer activity tests will be carried out in collaboration with the applicant's network of collaborators. Similarly, in vivo tests with the applicant's collaborators of select compounds in animal models of disease such as inflammatory arthritis are projected. Elucidating the structure-activity relationships of the newly developed analogs will expand knowledge for the development of selective and efficient bioactive molecules while limiting adverse effects. Over the next five years, 4 graduate and 6 undergraduate students will receive high quality training in the art of organic and medicinal chemistry, and other research-related skills. In addition to imparting intensive highly qualified personnel training, this program will expand the number of approaches available for the synthesis of biologically-relevant analogs of phenolic acids and polyphenols where molecular diversity is in great demand. The medicinal chemistry community working on the development of new phenolic acids or polyphenols-based analogs and the general population will benefit from the outcomes of the proposed research program.