Honors Theses
Date of Award
Spring 5-10-2023
Document Type
Undergraduate Thesis
Department
Biomolecular Sciences
First Advisor
Hoang Le
Second Advisor
Jing Li
Third Advisor
Eden Tanner
Relational Format
Dissertation/Thesis
Abstract
Metabolic pathways differ in cancer cells compared to noncancerous cells. Glutaminolysis is the primary producer of biosynthetic precursors in cancer cells, which allows for the cells to proliferate. In previous publications, the Le lab has established efficient synthetic routes to L-γ-methyleneglutamic acid amides which have shown to be as efficacious as tamoxifen and olaparib in inhibiting the growth of various breast cancer cell lines. These compounds have shown to inhibit the growth of MCF-7, SK-BR-3, and MDA-MB-231 breast cancer cell lines after 24 or 72 h of exposure. Furthermore, these compounds were selective in inhibiting the growth of cancer cells but the growth of nonmalignant MCF-10A breast cells. These compounds hold promising results as novel therapeutic agents for various breast cancer subtypes. The Le lab has extended this area of research, and herein, I report the synthesis and evaluation of the tert-butyl ester and ether ester prodrugs of these L-γ-methyleneglutamic acid amides, as well as the cyclic metabolite and its tert-butyl ester and ethyl ester prodrugs. Collaborations allowed the lab to, again, evaluate these compounds on the three breast cancer cell lines MCF-7, SKBR-3, and MDA-MB-231, as well as the nonmalignant MCF-10A breast cells. These prodrugs were shown to also suppress the growth of the breast cancer cells; however, they were less potent compared to the L-γ-methyleneglutamic acid amides. Further evaluation of pharmacokinetics on the lead L-γ-methyleneglutamic acid amides showed that it had good tissue-specific distribution. Particularly, the lead compound exhibited moderate brain exposure with a half-life of 0.74 h, as well as good kidney and liver distribution. With these promising results, the effects of the L-γ-methyleneglutamic acid amides were tested on glioblastoma cells, BNC3 and BNC6, as well as head and neck cancer cells, HN30 and HN31. These compounds were found to suppress the growth of these cells after 24 or 72 h of treatment in a concentration-dependent manner. Overall, the L-γ-methyleneglutamic acid amides hold promising potential as novel anticancer therapeutics.
Recommended Citation
Tran, Tristan D., "Synthesis of Tert-Butyl Ester and Ethyl Ester Prodrugs of L-Gamma-Methyleneglutamic Acid Amides for the Treatment of Cancer" (2023). Honors Theses. 2977.
https://egrove.olemiss.edu/hon_thesis/2977
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