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：由我的NSERC Discovery Grant资助的我的研究计划着重于含磷的分子的设计和合成，这些分子可以是（i）药物化学和（ii）催化不对称合成中的有价值的工具。将新型合成方法与药物化学研究的研究结合在一起有明显的好处。在我的两个研究目标的大型保护下，几个项目将证明我们在医学化学方面的努力（i）与非对称催化的努力之间的“交叉授粉”（II）。值得注意的是，尽管基于磷的配体在催化中的价值是毫无疑问的，但很少有人类治疗含有磷，因此，在生物活性化合物中掺入磷仍然是一个基本上没有倍增的研究领域。目标I：我们将设计和合成含磷的化合物，这些化合物对锌金属蛋白酶（IA）ZMPSTE24和（IB）MPP具有高亲和力。我们目前正在研究ZMPSTE24的抑制剂，ZMPSTE24是一种催化核包膜丝层层层层的成熟的酶，并提出是治疗胰腺腺癌的有价值的治疗靶标。此外，我们正在研究激酶Pink1和金属蛋白酶MPP之间的相互作用，这是粉红色1的正常处理所必需的。这些研究将为与线粒体损伤相关的生化机制提供宝贵的见解。目标II：我们开始挖掘出含磷的化合物的医学化学文库，用于新颖的配体设计中的“命中”。我们发现我们的一些A-氨基膦化合物化合物通常用于催化中。 4成员的PN-Enetallacycles的催化应用是有限的，我们认为我们的化学反应可以在这一领域做出重要贡献。此外，我们正在开发有效和原子的经济方法，用于在磷原子（p-hiral）上制备具有手性的化合物。我们将准备结构多样的P-手续配体和有机催化剂的文库。这些分子将用于探索在生物活性化合物中发现的关键构件的不对称合成，包括我们自己的项目IA和IB抑制剂。 HQP培训：我的HQP的主要培训是合成/催化和药物化学。但是，我还为他们提供了在药物发现的多学科努力中，在其他科学领域获得大量知识和技能的机会。我们在医学化学方面的研究受益于合成方法的发展，这些方法与手性分子的结构多样性库的模块化，高吞吐量合成。事实证明，这种学习经验对我过去在制药行业或学术界的独立职业中的HQP具有巨大的价值。