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

概述：我的研究项目由我的NSERC发现基金资助，重点研究含磷分子的设计和合成，这可以成为(I)药物化学和（II）催化不对称合成的宝贵工具。将新的合成方法的研究与药物化学的研究结合起来有明显的好处。在我的两个研究目标的大保护伞下，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，磷在生物活性化合物中的掺入仍然是一个未充分探索的研究领域。

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 -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.