Tolcapone’s potentially DEAD-ly influence: A stepwise synthesis and characterization of a Rok1p modulator

Cunningham, Walker

Tolcapone’s potentially DEAD-ly influence: A stepwise synthesis and characterization of a Rok1p modulator

Persistent URL

https://hdl.handle.net/10456/59272

Author(s)

Cunningham, Walker

Date Issued

April 11, 2025

Abstract

Colorectal cancer (CRC) is a major contributor to global cancer mortality, with increasing emphasis on identifying molecular targets for therapeutic intervention. DEAD-box proteins, a family of ATP-dependent RNA helicases characterized by the conserved Asp-Glu-Ala-Asp (D-E-A-D) motif, are integral to RNA metabolism, including ribosome biogenesis, splicing, and translation. Because DEAD-box helicases like DDX3 and DDX52 aid in cellular proliferation, their overexpression has been connected to the development of tumors. The yeast homolog of DDX52, Rok1p, provides a tractable model for researching the inhibition of RNA helicases. Tolcapone has been discovered as a possible Rok1p inhibitor by prior computational screening. To facilitate the subsequent assessment of Tolcapone's inhibitory action, this study offers a synthetic pathway toward the drug as an affordable substitute for commercial purchase. Key intermediates were successfully synthesized and described; however, the synthesis was not completed because of purification issues that arose in the concluding step. These findings lay the groundwork for further optimization and biological testing relevant to CRC research, as well as the creation of chemical factors targeted at DEAD-box helicases.

Major

Biochemistry

First Reader(s)

Betush, Matt