The care and treatment of patients exhibiting chronic wounds is a costly and painful ordeal for many across the world. Although there have been clinical treatments, including bandages, dressings, and debridement, there is only one FDA-approved pharmacological treatment for patients. The lack of pharmaceutical therapies represents an understudied and unmet medical need. An essential factor in wound healing and an important regulator of inflammation, NRF2 is a transcription factor that induces many cytoprotective and antioxidant genes. As seen in other inflammatory disorders, activating NRF2 could be a useful therapeutic strategy to treat chronic skin wounds. Non-covalent NRF2 activators can be developed by inhibiting the interaction of NRF2 with its negative regulator, KEAP1. We have developed a structure-activity relationship around a known, naphthalene-based non-covalent NRF2 activator, to create a NRF2 activator based on an isoquinoline scaffold. This work highlights some of the SAR of the peripheral aryl rings, in the hopes of increasing metabolic stability. The work also highlights introduction of positive charge to balance the overall charge of our lead compounds. Using a mouse model, we show that one of these isoquinolines can decrease the time to wound closure. Additionally, MALDI IMS presents a tool that we can use to detect macrocycles and small molecules, without the use of a chemical label. Here, we show a novel approach to analyze uptake of stabilized alpha-helical peptides in tumor explants using MALDI IMS. Another approach shown in this research is utilizing MALDI imaging to determine the penetration of the NRF2 activator treatment in the diabetic mouse model.
History
Advisor
Moore, Terry W.
Chair
Moore, Terry W.
Department
Medicinal Chemistry and Pharmacognosy
Degree Grantor
University of Illinois at Chicago
Degree Level
Doctoral
Degree name
PhD, Doctor of Philosophy
Committee Member
DiPietro, Luisa
DiMagno, Stephen
Sanchez, Laura
Riley, Andrew