Discipline: Chemistry & Chemical Sciences
Subcategory: STEM Research
Jacqueline Smith - Bowie State University
Co-Author(s): Brenda Tankeu, Bowie State University Bowie MD; Ike Nwadike, Bowie State University Bowie MD; Kayla Tucker, Bowie State University Bowie MD; Bayanna Melchishua, Bowie State University Bowie MD
There are many biological processes of which the scientific community is still working to fully understand. Due to their stability, reversibility and selectivity, small molecules can be used to understand how specific proteins play a role in cellular pathways. The cell has many adaptive mechanisms used for the cellular repair during endoplasmic reticulum (ER) stress. If proteostasis is not re-established, unfolded proteins are tagged for clearance through the ubiquitin-proteasome system (UPS). Aberrant cells have been shown to exploit these prosurvival mechanisms as a way to circumvent cell death. However proteasome disruption leads to cell death. Valosin-containing protein (VCP) is a key component of the UPS which can be targeted to investigate its role in proteostasis. Small molecule heterocycles such as imidazoles have the potential to allosterically bind to VCP to disrupt the UPS in rogue cells. We have synthesized a small library of novel imidazole compounds to be used as allosteric VCP binders. Using a microwave-assisted multi-component reaction, a variety of imidazole compounds have been rapidly synthesized. We have explored many factors which may affect MCRs and/or microwave reactions including reaction time, temperature, reagent stoichiometry, as well as the substituent position, steric and electronic effects. Thus far we have found that temperature plays a significant role on this reaction as elevated temperatures result in higher yields. Ultimately these compounds will be used to identify the structural features which are key for allosteric binding to VCP through biochemical and cell proliferation assays. Understanding how these small molecules affect proteins involved in cellular stress and repair can help scientists understand and control cell death.
Funder Acknowledgement(s): NSF Award # 1800165
Faculty Advisor: None Listed,
NSF Affiliation: HBCU-UP