biostudies-literatureUnknown17(17)Graff JSwiss National Science FoundationA 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 [³ H]-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.ChemMedCheme202200308https://www.ebi.ac.uk/biostudies/studies/S-EPMC9545129biostudies-literatureThe Evaluation of l-Tryptophan Derivatives as Inhibitors of the l-Type Amino Acid Transporter LAT1 (SLC7A5).PMC9545129Keller CSinger SHartmann MGraff JAltmann KHSadurni ARubin MCanivete Cuissa IAMuller JGertsch JfalseThe Evaluation of l-Tryptophan Derivatives as Inhibitors of the l-Type Amino Acid Transporter LAT1 (SLC7A5).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 [³ H]-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.2022-01-01T00:00:00Z2022 Sep2024-10-19T08:49:48.805Z2024-10-19T08:49:48.805ZS-EPMC95451293589528610.1002/cmdc.202200308