Author ORCID Identifier
Date of Award
Doctor of Philosophy (PhD)
Suazette Reid Mooring
Carbon monoxide (CO) is an endogenous signaling molecule with known pharmacological activities in a range of animal model studies, including inflammation, cancer, and organ protection. With our long-standing interest in the development of organic CO prodrugs, we developed a new class of CO prodrugs immobilized on silica microparticles which are generally recognized as safe by the US FDA. Amidation-based conjugation with silica is shown to provide 0.2 mmol/g loading density, effective prodrug activation in buffer, and stable tethering to prevent detachment. One representative silica conjugate, SICO-101, is shown to exhibit anti-inflammation activity in LPS-challenged RAW264.7 cells and to deliver CO systemically in mice through oral administration and GI CO release.
For improved therapeutic delivery of CO, we developed an enrichment-triggered release approach for the activation of CO prodrug pair for CO delivery to lysosomes. This approach exploits the concentration-dependent nature of bimolecular reactions and increased concentrations of prodrug components after enrichment for targeted delivery. For this, we tether CO prodrug pair, each with a morpholine moiety for enrichment in lysosomes for their bio-orthogonal activation and subsequent release of CO in a kinetically-controlled fashion. In this regard, our LC-MS experiments showed morpholine-facilitated enrichment of CO prodrug pair in lysosomes led to 13-fold increase in CO release compared to the non-targeted controls. Furthermore, LysoTracker Red co-localization experiments confirmed the presence of the fluorescent product after CO release in lysosomes.
Overexpression of ubiquitin ligase MDM2 causes depletion of the p53 tumor-suppressor and thus leads to cancer progression. Previously, we have developed potent anthraquinone compounds having the ability to upregulate p53 via inhibition of MDM2 in both in-vitro and in-vivo models of acute lymphocytic leukemia. Earlier work was focused on mechanistic work, pharmacological validation of the compounds in animal models and mapping out structural space that allows for further modification and optimization. Herein, we describe our work in optimizing the substituents on the two phenol hydroxyl groups. It was found that the introduction of an alkylketone moiety led to a potent series of analogs with BW-AQ-350 being the most potent compound yet which exerts cytotoxicity by inducing MDM2 degradation and p53 upregulation.
Tripathi, Ravi, "Leveraging Chemical Tools for Improving Therapeutic Delivery of Carbon Monoxide and Potency of Anthraquinone-based MDM2 Inhibitors." Dissertation, Georgia State University, 2023.
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