Thursday, December 26, 2024
12/26/2024
PROJECT SUMMARY Carbon monoxide (CO) is of intense current interest as a potential therapeutic as pre-clinical studies have shown the beneficial health effects of this gaseous molecule, including its dose-dependent cell protective, anti- hypertensive, and anti-inflammatory effects. To date, studies directed at elucidating the biological effects of CO have been performed almost exclusively using variable concentrations of CO gas or metal carbonyl-based CO- releasing molecules (CORMs). These approaches have limitations in terms of control and tracking of the timing, location and amount of CO released in biological environments. The central hypothesis being tested in this project is that extended flavonol- and quinolone-type structural frameworks can be used as triggerable, trackable, and targetable visible light-induced CO-releasing molecules that can deliver CO in a highly controlled manner for applications in biological systems. Such molecules are also useful building blocks for the development of CO- releasing micelles and nanomaterials for anti-inflammatory and wound healing applications. Considering the current landscape of molecular CO donors, a major obstacle toward further applying such molecules to define the effects of CO in cellular environments involves limitations in their fluorescence trackability at biologically relevant concentrations. Additionally, CO donors that combine highly controlled CO release with other types of potentially beneficial biological reactivity are currently rare. Introduction of amino substituents and fluorescent appendages in extended flavonol and quinolone motifs is expected to enhance emission properties of the molecules for both pre- and post-CO release tracking. Incorporation of a superoxide-reactive structural component for reactivity prior to highly controlled CO release will be investigated as an approach toward enhancing the antioxidant properties of CO-delivery molecules. Overall, the specific aims of this study are to: 1) develop amino-functionalized visible light-triggered CO-releasing molecules based on an extended flavonol or quinolone framework that can be visualized at low micromolar to nanomolar concentrations via confocal microscopy; 2) develop visible light-triggered extended flavonol CO-releasing molecules that can be tracked via fluorescence both prior to and following CO release in cellular environments; and 3) develop visible light- triggered extended flavonols that enable studies of the antioxidant effects of combined O2- reactivity and CO release. Completion of this project will provide the research community with new innovative tools that enable more detailed investigations of the biological effects of CO delivery. Undergraduate and graduate researchers with interests in future careers in biomedical research or medicine will be involved in the project.
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