Engineering Phosphorus-Containing Molecules as Leads for Medicinal Chemistry and as Tools for Asymmetric Synthesis

工程化含磷分子作为药物化学的先导化合物和不对称合成的工具

• 批准号: RGPIN-2020-04049
• 负责人: Tsantrizos, Youla
• 金额: $ 4.66万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=739643
• 关键词: Engineering; Phosphorus; Containing; Molecules; Leads

Overview: My research program, funded by my NSERC Discovery grant, focuses on the design and synthesis of Phosphorus-Containing Molecules, which can be valuable tools in (I) Medicinal Chemistry and (II) Catalytic Asymmetric Synthesis. There are obvious benefits in combining studies in novel synthetic methodologies with investigations in medicinal chemistry. Under the large umbrella of my two research objectives, several projects will demonstrate the "cross-pollination" between our efforts in medicinal chemistry (I) and those in asymmetric catalysis (II). It is noteworthy that although the value of phosphorus-based ligands in catalysis is unquestionable, few human therapeutics contain phosphorus and consequently, the incorporation of phosphorus in biologically active compounds is still a substantially underexplored area of research. Objective I: We will design and synthesize phosphorus-containing compounds that have high affinity for the zinc metalloprotease enzymes (Ia) ZMPSTE24 and (Ib) MPP. We are currently investigating inhibitors of ZMPSTE24, an enzyme that catalyzes the maturation of the nuclear envelope filament lamin A, and presumed to be a valuable therapeutic target for the treatment of pancreatic adenocarcinoma. Additionally, we are investigating the interactions between the kinase PINK1 and the metalloprotease MPP, which is required for normal processing of PINK1; these studies will provide valuable insight into the biochemical mechanism associated with mitochondrial damage. Objective II: We began to mine our own medicinal chemistry libraries of phosphorus-containing compounds  for novel "hits" in ligand design. We discovered that some of our a-aminophosphine compounds chelate metals that are typically used in catalysis. Catalytic applications of 4-member PN-metallacycles are limited and we believe that our chemistry can make important contributions in this area. Additionally, we are developing efficient and atom economical methodologies for the preparation of compound with chirality on the phosphorus atom (P-chiral). We will prepare libraries of structurally diverse P-chiral ligands and organocatalysts. These molecules will be used to explore the asymmetric synthesis of key building blocks found in biologically active compounds, including our own inhibitors for projects Ia and Ib. HQP Training: The primary training of my HQPs is in Synthesis/Catalysis and Medicinal Chemistry. However, I also provide them with the opportunity to acquire substantial knowledge and skills in other areas of science, within the multidisciplinary endeavor of drug discovery. Our studies in medicinal chemistry benefit from the development of synthetic methodologies that are amenable to modular, high throughput synthesis of structurally diverse libraries of chiral molecules. This type of learning experience has proven to be of great value to my past HQPs in their independent careers at pharmaceutical industries or in academia.

概述：我的研究项目由 NSERC 发现资助资助，重点是含磷分子的设计和合成，这在 (I) 药物化学和 (II) 催化不对称合成中是有价值的工具，两者结合起来有明显的好处。在我的两个研究目标的大范围内，研究新的合成方法和研究药物化学，几个项目将展示我们在药物化学方面的努力之间的“异花授粉”（I）。值得注意的是，尽管磷基配体在催化中的价值是毋庸置疑的，但很少有人类治疗药物含有磷，因此，在生物活性化合物中掺入磷仍然是一个尚未充分探索的领域。​研究目标 I：我们将设计并合成对锌金属蛋白酶 (Ia) ZMPSTE24 和 (Ib) 有高亲和力的含磷化合物MPP。我们目前正在研究 ZMPSTE24 的抑制剂，ZMPSTE24 是一种催化核膜丝核纤层蛋白 A 成熟的酶，被认为是治疗胰腺癌的一个有价值的治疗靶标。此外，我们正在研究激酶 PINK1 之间的相互作用。以及 PINK1 正常加工所需的金属蛋白酶 MPP；这些研究将为了解与线粒体损伤相关的生化机制提供有价值的见解。我们开始挖掘我们自己的含磷化合物药物化学库，以寻找配体设计中的新“亮点”。我们发现，我们的一些 α-氨基膦化合物可以螯合通常用于 4 元 PN-金属环催化应用的金属。有限，我们相信我们的化学可以在这一领域做出重要贡献此外，我们正在开发高效且原子经济的方法来制备具有手性的化合物。我们将制备结构多样的 P-手性配体和有机催化剂库，这些分子将用于探索生物活性化合物中发现的关键构件的不对称合成，包括我们自己的 Ia 和项目抑制剂。 Ib. HQP 培训：我的 HQP 的主要培训是合成/催化和药物化学，但​​是，我也为他们提供获得其他领域的大量知识和技能的机会。我们在药物发现的多学科努力中受益于合成方法的发展，这些方法适合模块化、高通量合成结构多样的手性分子库。对我过去在制药行业或学术界的独立职业生涯的 HQP 有很大价值。