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

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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.