Abstract 1905 Design And Synthesis of Potential Anticancer Therapeutics based on the 1,4-Naphthoquinone Scaffold

This structure-activity relationship (SAR) study investigates a 1,4-naphthoquinone scaffold to exploit the overexpression of the L-type amino acid transporter 1 (LAT1) in cancer cells as potential anticancer therapeutics. The long-term goal of this work is to address issues that can and often arise in cancer treatment due to cellular defense mechanisms, poor selectivity for cancer cells over healthy cells, and challenges with drug uptake. This ongoing project has two main objectives: (1) the design and synthesis of the 1,4-naphthoquinone derivatives, and (2) the biochemical characterization of the developed compounds in cancer cell lines. Studies involve commercially available scaffolds, and eight synthesized 1,4 naphthoquinone derivatives. The derivatives were synthesized via a nucleophilic substitution reaction with 2-bromo-1,4-naphthoquinone with yields ranging from 25%-75%, including a tyrosine-naphthoquinone assembly. The tyrosine backbone was selected because tyrosine is a substrate for LAT1. Previous reports in the literature point to the ability to increase uptake by linking a drug to LAT1 substrates. To the best of our knowledge, four of the eight synthesized molecules are novel and unknown in literature. Detailed SAR investigations probe the relationship between structure and cytotoxicity in the PC3 prostate cancer cell line, which is known to overexpress LAT1. Cell viability is measured at 48 hours using the MTS colorimetric assay, which utilizes a tetrazolium salt that can form a dye when reacted with NADPH dependent enzymes present in live cells. The SAR results suggest a correlation between the derivatives' lipophilicity and cytotoxicity; increased lipophilicity led to lower cell viability. Having confirmed that the compounds exhibit anticancer activity with at least one cell line of interest, future plans involve investigations with other LAT1-overexpressing cell lines such as A549, a human lung cancer, and affinity studies with LAT1. Funding for this project has come from Georgia Southern (GS) Biochemistry, Chemistry, & Physics, GS FRC Seed Grant (FY21), and NIH (Grant Award #1R15CA277652)