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Abstract
A series of derivatives of the substrate amino acid l‐tryptophan have been investigated for inhibition of the L‐type amino acid transporter LAT1 (SLC7A5), which is an emerging target in anticancer drug discovery. Of the four isomeric 4‐, 5‐, 6‐, or 7‐benzyloxy‐l‐tryptophans, the 5‐substituted derivative was the most potent, with an IC50 of 19 μM for inhibition of [3H]‐l‐leucine uptake into HT‐29 human colon carcinoma cells. The replacement of the carboxy group in 5‐benzyloxy‐l‐tryptophan by a bioisosteric tetrazole moiety led to a complete loss in potency. Likewise, the corresponding tetrazolide derived from l‐tryptophan itself was found to be neither a substrate nor an inhibitor of the transporter. Increasing the steric bulk at the 5‐position, while reasonably well tolerated in some cases, did not result in an improvement in potency. At the same time, none of these derivatives was found to be a substrate for LAT1‐mediated transport.
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