2024 Undergraduate Research Showcase

Breaking the Chain: Synthesizing Quinoline-Based Small Molecule Inhibitors to Suppress Breast Cancer Metastasis

Document Type

Student Presentation

Presentation Date

4-19-2024

Faculty Sponsor

Dr. Don Warner

Abstract

One in eight females in the United States will develop breast cancer within their lifetime. With the occurrence of metastasis, survival rates drastically decline by as much as 70%. Prior research has confirmed that overexpression of an inflammatory cytokine (IC) promotes metastasis via the activation of the JAK/STAT signaling pathway, suggesting that the IC is a promising target for repression by a small molecule inhibitor (SMI). Initial computational screenings identified SMI-26, which contains a quinoline core, as a promising lead that is currently being optimized. A computational approach using UCFS Chimera and AutoDock Vina was used to design new analogs with a predicted increase in inhibitory activity and more favorable pharmacokinetic properties. As the new compounds retain the quinoline core, a Pfitzinger reaction between acetophenones and isatins was employed to generate this moiety. As such, a small library of substituted acetophenones was synthesized using Suzuki−Miyaura couplings between commercially available aryl halides and boronic acids. Reaction conditions were optimized by varying the catalyst (e.g., Pd(PPH3)4, Pd(dppf)Cl2, and cataCXium-A-Pd-G3), the solvent, and the added base. After subjecting the acetophenones to the Pfitzinger reaction, the resulting quinones are elaborated further via additional Suzuki-Miyaura reactions, peptide couplings, SNAr reactions, and other standard transformations to produce the new analogs. These and related efforts will be presented as part of our quest to generate an effective and safe drug for the prevention of breast cancer metastasis.

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