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

概述：我的研究计划，由我的NSERC发现补助金资助，重点是含磷分子的设计和合成，这可以是有价值的工具（I）药物化学和（II）催化不对称合成。将新合成方法学的研究与药物化学的研究相结合有明显的好处。在我的两个研究目标的大伞下，几个项目将展示我们在药物化学（I）和不对称催化（II）方面的努力之间的“异花授粉”。值得注意的是，尽管基于磷的配体在催化中的价值是毋庸置疑的，但很少有人类治疗剂含有磷，因此，在生物活性化合物中掺入磷仍然是一个基本上未开发的研究领域。目标一：我们将设计和合成对锌金属蛋白酶（Ia）ZMPSTE 24和（Ib）MPP具有高亲和力的含磷化合物。我们目前正在研究ZMPSTE 24的抑制剂，ZMPSTE 24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有价值的治疗靶点。此外，我们正在研究激酶PINK 1和金属蛋白酶MPP之间的相互作用，这是PINK 1正常加工所必需的;这些研究将为与线粒体损伤相关的生化机制提供有价值的见解。目标二：我们开始挖掘我们自己的含磷化合物的药物化学库，在配体设计中寻找新的“命中”。我们发现我们的一些α-氨基膦化合物螯合通常用于催化的金属。4元PN-金属杂环的催化应用是有限的，我们相信我们的化学可以在这一领域作出重要贡献。此外，我们正在开发高效和原子经济的方法来制备磷原子上具有手性的化合物（P-手性）。我们将准备结构不同的P-手性配体和有机催化剂的库。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，包括我们自己的项目Ia和Ib的抑制剂。 HQP培训：我的HQP的主要培训是合成/催化和药物化学。然而，我也为他们提供机会，以获得大量的知识和技能，在其他科学领域，在药物发现的多学科奋进。我们的药物化学研究受益于合成方法的发展，这些方法适合于结构多样的手性分子库的模块化，高通量合成。这种类型的学习经验已被证明是非常有价值的，我过去的HQP在他们的独立职业生涯在制药行业或学术界。

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.