Date of Award

2016

Document Type

Dissertation/Thesis

Submission Date

October 2026

Thesis/Dissertation Advisor [Chair]

Kirchman, Paul

Abstract

Cellular oxidative stress occurs when oxidant formation rate exceeds neutralization rate, shifting intracellular redox homeostasis and leading to cytotoxicity. Oxidants stimulate the Antioxidant Response Pathway (ARP) which activates Nrf2 transcription factor, increasing expression of antioxidant genes. Oxidative stress is implicated in many diseases and thus chemically targeting the ARP represents high therapeutic potential. Ironically, however, current drugs intended to simulate the ARP are electrophilic and function by inducing oxidative stress, thereby activating Nrf2. Therefore, non-oxidative alternatives for these drugs will increase therapeutic index, safety, and effectiveness especially in treating Rheumatoid Arthritis or Multiple Sclerosis. An initial chemical library screen of 403,862 compounds for non-electrophilic properties led to 28 hits and subsequent cell viability and ARP induction assays further decreased this number to five. Structure Activity Relationship (SAR) analysis revealed a single compound series that demonstrated preferential characteristics on all fronts tested in vitro. Further in vivo studies are needed to verify translational therapeutic properties.

Comments

Includes bibliography.

Extent

62 p.

Identifier

FA00003689

Download

Share

COinS