Reaction Mechanisms and Methodology for the Design and Synthesis of Bioactive Agents.

生物活性剂设计和合成的反应机制和方法。

• 批准号: RGPIN-2020-06507
• 负责人: Guindon, Yvan
• 金额: $ 2.62万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748681
• 关键词: Reaction; Mechanisms; Methodology; Design; Synthesis

The main objective of our research program is to develop novel methodologies and strategies to access challenging molecular scaffolds. Our research program will benefit Canadians through the advancement of our collective knowledge in chemistry and should also bring positive socio-economical impacts and health benefits. Some of our novel nucleoside analogues demonstrate remarkable activity against pancreatic cancer cell lines that do not respond to the clinical gold standard of treatment (Gemcitabine). Another family of molecules of this class protects the heart against cardiotoxic agents, such as anticancer drugs, and is remarkably active in heart failure models. These advancements were born out of our long-standing interest in free-radical based chemistry combined with our commitment to develop alternative methods to prepare nucleoside analogues. The highly reactive nature of radical intermediates was harnessed to produce stereogenic all-carbon quaternary centers that can be introduced at C3' or C2' of nucleoside scaffolds. Our key strategy for the synthesis of nucleoside analogues involves diastereoselective formation of acyclic thioaminals by introducing a nucleobase on dithioacetals, followed by kinetically controlled cyclizations. We plan to further improve the synthesis of our lead molecules and prepare photoaffinity probes to elucidate their mechanism of action in collaboration with research groups with expertise in cancer and cardioprotection. The free-radical approaches will also be applied to synthesize biologically relevant terpenes and analogues thereof, such as dictyoceratins A and C, a potential new avenue to antiproliferative agents. Finally, we are actively working on the discovery of E- and P- selectin antagonists that are key mediators in the immune system's inflammatory response. The objective of our synthetic design is to restrict the relevant pharmacophores of the endogenous polysaccharide, sialyl LewisX (sLeX), to mimic analogues that are locked in the bioactive conformation. This project stimulated us to elaborate efficient strategies to prepare bicyclic-like analogues of natural sugars that could find various biological applications.

我们研究项目的主要目标是开发新的方法和策略来获取具有挑战性的分子支架。我们的研究计划将通过提高我们在化学方面的集体知识使加拿大人受益，并应带来积极的社会经济影响和健康效益。我们的一些新型核苷类似物对临床金标准治疗（吉西他滨）无效的胰腺癌细胞系显示出显著的活性。这类分子的另一个家族保护心脏免受抗癌药物等心脏毒性物质的侵害，并且在心力衰竭模型中非常活跃。这些进步源于我们对自由基化学的长期兴趣，以及我们致力于开发制备核苷类似物的替代方法。利用自由基中间体的高活性，可以在核苷支架的C3′或C2′上引入立体全碳季中心。我们合成核苷类似物的关键策略包括通过在二硫缩醛上引入核碱基来非对映选择性地形成无环硫胺，然后进行动力学控制的环化。我们计划与具有癌症和心脏保护专业知识的研究小组合作，进一步改进我们的先导分子的合成并制备光亲和探针，以阐明其作用机制。自由基方法也将应用于合成生物学相关的萜烯及其类似物，如dictyoceratins A和C，这是一种潜在的抗增殖药物的新途径。最后，我们正积极致力于发现E-和P-选择素拮抗剂，它们是免疫系统炎症反应的关键介质。我们的合成设计目的是限制内源性多糖sialyl LewisX （sLeX）的相关药效团，以模拟锁定在生物活性构象中的类似物。这个项目激励我们制定有效的策略来制备天然糖的环状类似物，这些类似物可以找到各种生物应用。