Studies directed at the chemistry and biology of bioactive compounds

我在UdeM的团队的研究活动将集中在化学合成和生物学的四个主要领域。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的驱动。 我们选择天然产品进行合成研究，主要是因为有可能改善和扩大生物活性，在产量较低的情况下提供足够的材料进行测试，并扩大我们的知识，以便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极好的训练场地，教会他们严谨的研究、毅力和实现预期目标的决心。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，将继续提供对这些相互作用的进一步见解，这将使我们能够改善生物活性，特别是对抗耐药细菌和原生动物。受限制的氨基酸，如4，5-甲基脯氨酸，由我们小组首次合成，已经获得了广泛的重视，是市场上抗糖尿病药物的成分。将脯氨酸环扁平的结果在肽仿生学领域具有很大的应用前景，人们将对这一性质进行研究，以了解多肽中酰胺键的性质以及它们对酶促脯氨酸酶切割的敏感性。我们将研究受约束的多聚脯氨酸与它们的三级结构的关系。 在实际合成对映体纯的目标分子的过程中，与碳原子形成键是有机化学的非常重要的支柱。这些方法必须解决目前还没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，其他惰性C-H原子的激活，以及具有药用价值的高度官能化的氮杂环化合物的化学。流动化学的出现将促进这些方法的发展。 我们的研究通过基础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，为青年男女提供了出色的培训，他们后来在制药、生物技术和其他行业以及学术界规划了自己的道路。我们希望通过处理本摘要中强调的领域，在下一个授权期内继续保持这一优秀的同事培训传统。

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.