L-Type amino acid transporter 1 (LAT1, SLC7A5) imports both natural amino acids and amino acid containing drugs (e.g. L-DOPA, gabapentin) into cancer cells and across the blood-brain barrier (BBB). Part of our group’s research includes designing new synthetic methods for the rapid assembly of amino acid prodrugs which recently has led us to pursue coupling drug molecules to 1,2,3-triazolyl β-amino acids conveniently synthesized using Click Chemistry. As proof of concept, we synthesized and tested an amino acid prodrug of the glycolysis inhibitor lonidamine, which has been investigated as an anti-cancer agent. We will present the synthesis and activity of this lonidamine prodrug in both LAT1 cell assays and cytotoxicity profile using MCF7 breast cancer cells. For comparison, we will also present the LAT1 SAR of triazole-amino acid analogs containing substituents of various size. Our results could influence the design of amino acid prodrugs or inhibitors targeting LAT1.

1,2,3-Triazolyl β-amino acids for LAT1-mediated drug delivery

ACS Fall 2020 Virtual Meeting

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