Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY/ABSTRACT Over the last several decades it has become apparent that carbon monoxide (CO) gas is an important small molecule that greatly impacts human health. Indeed, CO is created endogenously in small concentrations and has been shown to be an essential signaling molecule in the human neuronal system. Moreover, CO gas has been revealed to be a valuable therapeutic, specifically, it can ameliorate acute and chronic inflammation, can reduce rejection of organ transplants, and can treat cardiovascular diseases. However, the direct study or use of CO in biological systems is inherently complex because it is a gas, has limited solubility in water, and is toxic at high concentrations. As such, many of the mechanisms and pathways by which CO operates in the human body remain elusive. In response to these complications, CO Releasing Molecules (CORMs) have emerged as a class of materials that can release CO in response to an external stimulus. As transition metals readily ligate to and release CO under various conditions, these materials were the first class of CORMs developed and remain the most popular and frequently utilized to date. Unfortunately, CORMs based on transition metal carbonyl complexes are cytotoxic, form poorly defined products following release of CO, and cannot be directly polymerized to form macromolecular targeted therapeutics. Research in the Worrell laboratory is inspired by the shortcomings in current CORM technology, and we are actively engaged in creating stable, modular, and efficient organic CO releasing molecules. Our work has been concentrated on analogs of diphenylcyclopropenone (DPCP), a uniquely stable and bio-orthogonal molecule that features a highly strained 3 membered ring. Previous work in a small molecule setting has shown that DPCP is unrivaled in its ability to cleanly and efficiently produce CO gas. Proof-of-concept demonstrations have shown that analogs of DPCP can be effectively synthesized, can be directly polymerized, and can release CO gas by photolysis, however, for application as a CORM, this must be demonstrated in a biological system. Future work over the five-year course of this program will concentrate on the development of methods for the controlled polymerization of DPCP to create tailored macromolecular materials that are soluble, targeted, non-toxic, and biocompatible. We will further concentrate on improving the rate and efficacy of CO release by leveraging the unique photophysics of DPCPs while creating well-defined photoproducts. Ultimately, the most impactful extension of this work will be related to its development in studying and treating gastrointestinal inflammation as part of a long-term collaboration with the Colgan/Onyiah group at the University of Colorado Medical School. Although there are significant challenges associated with this program, its scientific impacts will be far-reaching. If successful, organic CORMs will supersede those based on transition metal complexes, stimulating the development of new targeted therapeutics based on the production of CO gas.
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