Synthetic Retinoids for the Modulation of Genomic and Nongenomic Processes in Neurodegenerative Diseases

Butler, Abbey M.; Chisholm, David R.; Tomlinson, Charles W.E.; Khatib, Thabat; Clark, Jason; Wan, Shunzhou; Coveney, Peter V.; Greig, Iain R.; McCaffery, Peter; Pohl, Ehmke; Whiting, Andrew

Abstract

Retinoids, such as all-trans retinoic acid (ATRA), are the active metabolite forms of endogenous Vitamin A and function as key signaling molecules involved in the regulation of a variety of cellular processes. Due to their highly diverse biological roles, retinoids have been implicated in a wide range of diseases such as neurological disorders and some cancers. However, their therapeutic potential is limited due to their chemical and metabolic instability and adverse side effects. Synthetic retinoid analogues with increased stability and specificity have therefore attracted significant attention. In this study, we developed a scalable synthetic platform to generate a library of novel synthetic retinoids. Twenty-three new compounds were synthesized, and their receptor binding was assessed by an in vitro fluorescence competition binding assay, complemented by molecular docking and molecular dynamics (MD) simulations. We show that while computational studies are extremely useful for predicting binding modes and hence can guide synthetic efforts, the binding assays demonstrated that these novel retinoids exhibit strong binding albeit with limited selectivity for the different retinoic acid receptors (RARs). Therefore, their biological activity was measured by assessing their genomic and nongenomic activities in neuroblastoma cells with the goal of correlating binding properties and pathway activation to neuro-regenerative potential measured by neurite outgrowth. Importantly, four of the novel retinoids are shown to bind tightly to RARs and exhibit dual action in the relevant cellular models, with an ability to induce both genomic and nongenomic responses as well as significant neurite outgrowth. The compound with the highest biological activity possesses significant potential to be used as therapeutics for treating a wide range of neurological disorders like Alzheimer’s disease and motor neuron disease.

Citation

Butler, A. M., Chisholm, D. R., Tomlinson, C. W., Khatib, T., Clark, J., Wan, S., Coveney, P. V., Greig, I. R., McCaffery, P., Pohl, E., & Whiting, A. (online). Synthetic Retinoids for the Modulation of Genomic and Nongenomic Processes in Neurodegenerative Diseases. ACS Omega, https://doi.org/10.1021/acsomega.5c00934

• Journal Article Type: Article
• Acceptance Date: May 14, 2025
• Online Publication Date: May 28, 2025
• Deposit Date: Jun 6, 2025
• Publicly Available Date: Jun 6, 2025
• Journal: ACS Omega
• Electronic ISSN: 2470-1343
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1021/acsomega.5c00934
• Public URL: https://durham-repository.worktribe.com/output/4090811