In cancer cells, glutaminolysis is the primary source of biosynthetic precursors, fueling the TCA cycle with glutamine-derived α-ketoglutarate. The enhanced production of α-ketoglutarate is critical to cancer cells as it provides carbons for the citric acid cycle to produce glutathione, fatty acids, and nucleotides, and contributes nitrogens to produce hexosamines, nucleotides, and many nonessential amino acids. Efforts to inhibit glutamine metabolism in cancer using amino acid analogs have been extensive. L-γ-Methyleneglutamine was shown to be of considerable biochemical importance, playing a major role in nitrogen transport in Arachis and Amorpha plants. This presentation is intended to report for the first time an efficient synthetic route to L-γ-methyleneglutamine and its amide derivatives. Many of these compounds were shown to be as efficacious as tamoxifen or olaparib at arresting cell growth among MCF-7 (ER/PR/HER2+), and SK-BR-3 (HER2+) breast cancer cells at 24 or 72 h of treatment. Several of these compounds were as efficacious as olaparib at arresting cell growth among triple-negative MDA-MB-231 breast cancer cells at 72 h of treatment. Cytotoxicity assays on these three breast cancer cell lines and on the non-cancerous breast cell line MCF10A suggested that the mechanism of action for growth inhibition by these compounds involve cancer-cell selective cytotoxicity. This presentation is also intended to give an introduction to the current research in the Le lab at the University of Mississippi School of Pharmacy.

Efficient synthetic route to L-γ-methyleneglutamine and its amide derivatives, and their anticancer activity

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.