In cancer cells, glutaminolysis is the primary source of biosynthetic precursors, and recent efforts to develop amino acid analogs to inhibit glutamine metabolism in cancer have been extensive. Our lab has discovered many L-γ-methyleneglutamic acid amides that were shown to be as efficacious as tamoxifen or olaparib at arresting cell growth among MCF-7 (ER+/PR+/HER2−), and SK-BR-3 (ER−/PR−/HER2+) breast cancer cells by 24 or 72 h of treatment. Several of these compounds exerted similar efficacy to olaparib at arresting cell growth among triple-negative MDA-MB-231 breast cancer cells by 72 h of treatment. None of the compounds inhibited cell growth in benign MCF-10A breast cells. Overall, N-phenyl amides and N-benzyl amides arrested the growth of all three (MCF-7, SK-BR-3, and MDA-MB-231) cell lines for 72 h and were devoid of cytotoxicity on MCF-10A control cells; N-benzyl amides with an electron withdrawing group at the para position inhibited the growth of triple-negative MDA-MB-231 cells commensurate to olaparib. These compounds hold promise as novel therapeutics for the treatment of multiple breast cancer subtypes. We also synthesized the ethyl ester and tert-butyl ester prodrugs of these compounds, as well as the cyclic metabolites, and tested them on the three cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231. While these compounds also suppressed the growth of these cancer cell lines, their potencies were not as high as their parent L-γ-methyleneglutamic acid amides. Therefore, we carried out pharmacokinetics studies on the lead L-γ-methyleneglutamic acid amide and determined the Cmax, Tmax, mean elimination half-life, mean clearance, and volume of distribution. In addition, we also tested these L-γ-methyleneglutamic acid amides on head and neck cancer (HN8, HN12, HN30, and HN31) and glioblastoma (BNC3 and BNC6) cell lines and observed that they effectively suppressed the growth of these cancer cell lines by 24 or 48 h of treatment. These results suggest broad applications of these L-γ-methyleneglutamic acid amides in anticancer therapy. We suspect glutamine transporters to be the biological target of these compounds; future experiments will aim to further characterize lead compounds to determine their mechanism(s) of action.

Development of L-γ-Methyleneglutamine-based compounds for cancers

ACS Fall 2021

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