Studies directed at the chemistry and biology of bioactive compounds

针对生物活性化合物的化学和生物学的研究

• 批准号: RGPIN-2015-04726
• 负责人: Hanessian, Stephen
• 金额: $ 6.48万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=652998
• 关键词: Studies; directed; chemistry; biology; bioactive

Research activities in my group at UdeM will focus on four main areas at the interface of chemical synthesis and biology. In this context, our research program will continue to be biology-inspired and chemically driven.***Our choice of natural products for synthetic studies is primarily driven by the potential to improve and extend biological activity, to provide sufficient material for testing in the case of meager-yielding sources, and to expand our knowledge toward a better understanding of their mode of action at the molecular level. The very nature of the science of synthesis provides an excellent training ground for young collaborators, teaching them the rigors of research, perseverance and the resolve to reach the intended goal. My role is to teach them how to apply chemical knowledge to solve challenging problems in research.***Information gleaned from the co-crystal structures of synthetic molecules with macromolecules such as proteins (enzymes in particular), DNA, and RNA, have allowed us to develop excellent drug prototypes. Our privileged collaborations with other academics and with the pharma industry, where testing and X-ray work are done, will continue to provide further insights into these interactions which will allow us to improve biological activities, especially against resistant bacteria and protozoa. Constrained amino acids such as the 4,5 methanoprolines, first synthesized in our group, have gained wide prominence and are constituents of marketed antidiabetics. The consequence of flattening the proline ring holds great promise in the field of peptidomimetics, and this property will be studied to understand the nature of the amide bonds in peptides as well as their susceptibility to enzymatic cleavage by the enzyme prolidase vis-à-vis proline. Constrained polyprolines will be studied in relation to their tertiary structure.***Forming bonds to carbon atoms towards the practical synthesis of enantiomerically pure target molecules is the very backbone of organic chemistry. These methods must address reaction types that do not have universal solutions as yet, such as the formation of quaternary carbons centers, reagent and catalyst controlled asymmetric reactions, activation of otherwise inert C-H atoms, and the chemistry of highly functionalized azacyclic compounds of medicinal interest. The advent of flow chemistry will facilitate the development of such methods.***Our research has contributed to many facets of the drug discovery process through basic synthetic work delineating the relationship between structure, property, and function. In the process, excellent training was provided to young men and women who have gone on to chart their own paths in the pharma, biotech and other industries as well as in academia. We hope to continue this tradition of excellence of coworker training through the next granting period by addressing the areas highlighted in this summary.*****

我的小组在UdeM的研究活动将集中在化学合成和生物学界面的四个主要领域。在这种情况下，我们的研究计划将继续受到生物学和化学的启发。***我们选择用于合成研究的天然产物主要是出于提高和扩展生物活性的潜力，在低产量来源的情况下为测试提供足够的材料，并在分子水平上扩大我们对其作用方式的了解。合成科学的本质为年轻的合作者提供了一个极好的训练场地，教会他们研究的严谨性、毅力和达到预期目标的决心。我的职责是教他们如何运用化学知识来解决研究中的挑战性问题。***从合成分子与大分子（如蛋白质（特别是酶），DNA和RNA）的共晶结构中收集的信息使我们能够开发出优秀的药物原型。我们与其他学者和制药行业的合作将继续为这些相互作用提供进一步的见解，这将使我们能够提高生物活性，特别是针对耐药细菌和原生动物。约束氨基酸，如4,5甲烷脯氨酸，首先在我们的小组合成，已经获得了广泛的关注，并已上市的抗糖尿病药物的成分。脯氨酸环变平的结果在拟肽学领域具有很大的前景，这一性质将被研究以了解肽中酰胺键的性质以及它们对脯氨酸酶对-à-vis脯氨酸酶的酶切的敏感性。约束型聚脯氨酸将根据它们的三级结构进行研究。***与碳原子形成键以实际合成对映体纯目标分子是有机化学的核心。这些方法必须解决尚未有通用解决方案的反应类型，如季碳中心的形成，试剂和催化剂控制的不对称反应，否则惰性的碳氢原子的活化，以及具有药用价值的高功能化氮杂环化合物的化学反应。流动化学的出现将促进这类方法的发展。***我们的研究通过描述结构、性质和功能之间的关系的基本合成工作，为药物发现过程的许多方面做出了贡献。在此过程中，为青年男女提供了优秀的培训，这些青年男女后来在制药、生物技术和其他行业以及学术界开辟了自己的道路。我们希望通过解决本摘要中强调的领域，在下一个授权期继续这种优秀的同事培训传统。*****