While there have been significant advances in treatments for pre-metastatic breast cancer, the five-year survival rate post-metastasis remains an abysmal 27%. Systemic therapy continues to be the recommended course of treatment for patients diagnosed with metastatic breast cancer, but treatments that prevent distant metastases have yet to be discovered. Inflammatory cytokines (IC) are small proteins involved in cell signaling that regulate inflammation and other important cellular processes. Certain ICs bind to their main receptors to activate cell signaling pathways that are capable of promoting the invasive potential of cancer cells during the preliminary stages of the metastatic cascade. This has led to an interest in the development of small molecule inhibitors (SMIs) that bind to and inhibit the IC responsible. Previously, an enzyme-linked immunosorbent assay (ELISA) demonstrated that IC-SMI-10 inhibited the expression of pSTAT3 to a significant extent, indicative of competitive inhibition of the IC binding to its main receptor. Structurally, IC-SMI-10 contains a furan core appended with two benzodioxole groups at positions 4 and 5, a nitro group at position 3, and a phenyl hydrazone moiety at position 2. The aim of this research is to optimize inhibitory activity by systematically investigating the role of each component. Thus far, the furan core has been converted to a thiophene, an N-H pyrrole, and an N-Me pyrrole to assess the importance of the heterocycle. Also, to begin to investigate the aryl groups, Suzuki coupling reactions have been used to incorporate other 3,4-alkoxy or phenolic groups. Substitution of the aryl group with even slightly more hindered groups seems to decrease inhibition, while the heterocycle does not appear to have a substantial impact. Lastly, substitution of the phenyl hydrazone moiety with a carboxylic acid, a,b-unsaturated acids, amides, amines, and other groups has sought to explore the importance of substitution at this site. Preliminary ELISA experiments confirm molecular docking experiments that suggested the nitro group was not an important contributor to inhibition, while the length of the side chain at position 2 is significantly important, as shorter, non-conjugated chains exhibit little to no binding to the IC. These and other results will be reported.

Synthesis of substituted heterocycles to inhibit a pro-metastatic cytokine

2019 Spring National Meeting

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