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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=692380
• 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的启发和化学驱动。我们选择天然产物进行合成研究，主要是为了提高和扩展生物活性，在产量微薄的情况下提供足够的材料进行测试，并扩大我们的知识，以更好地了解它们在分子水平上的作用模式。合成科学的本质为年轻的合作者提供了一个很好的训练基地，教他们研究的严格性，毅力和达到预期目标的决心。我的角色是教他们如何应用化学知识来解决研究中具有挑战性的问题。从合成分子与蛋白质（特别是酶），DNA和RNA等大分子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特权合作，在那里进行测试和X射线工作，将继续为这些相互作用提供进一步的见解，这将使我们能够改善生物活性，特别是针对耐药细菌和原生动物。限制性氨基酸，如4，5-甲氧脯氨酸，首先在我们的小组中合成，已经获得了广泛的重视，是市售抗糖尿病药物的成分。脯氨酸环变平的结果在肽模拟物领域中具有很大的前景，并且将研究这种性质以了解肽中酰胺键的性质以及它们对脯氨酰二肽酶维斯维斯脯氨酸的酶裂解的敏感性。将研究受约束的聚脯氨酸与其三级结构的关系。与碳原子形成化学键，从而合成对映体纯的目标分子，是有机化学的主要研究方向。这些方法必须解决尚未具有通用解决方案的反应类型，例如季碳中心的形成，试剂和催化剂控制的不对称反应，否则惰性C-H原子的活化，以及具有药用价值的高度官能化氮杂环化合物的化学。流动化学的出现将促进这种方法的发展。我们的研究通过基本的合成工作描绘了结构，性质和功能之间的关系，为药物发现过程的许多方面做出了贡献。在这一过程中，向在制药、生物技术和其他行业以及学术界开辟自己道路的青年男女提供了出色的培训。我们希望通过解决本摘要中强调的领域，在下一个资助期内继续这种优秀的同事培训传统。****