Department of Chemistry and Applied Biosciences, ETH Zürich, HCI H405, Vladimir-Prelog-Weg 4, 8093, Zürich, Switzerland.
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012, Bern, Switzerland.
ChemMedChem. 2022 Sep 5;17(17):e202200308. doi: 10.1002/cmdc.202200308. Epub 2022 Aug 10.
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 IC of 19 μM for inhibition of [ 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.
已研究了一系列底物氨基酸 l-色氨酸的衍生物，以抑制 L 型氨基酸转运体 LAT1（SLC7A5），这是抗癌药物发现中的一个新兴靶点。在四种同分异构的 4-、5-、6-或 7-苄氧基-l-色氨酸中，5-取代的衍生物活性最强，对 HT-29 人结肠癌细胞摄取 [H]-l-亮氨酸的抑制作用的 IC 为 19 μM。用生物等排体四唑取代 5-苄氧基-l-色氨酸中的羧基导致其活性完全丧失。同样，从 l-色氨酸本身衍生的相应四唑内酯既不是转运体的底物也不是抑制剂。在某些情况下，5 位的空间位阻增加虽然可以得到一定程度的耐受，但不会提高活性。同时，这些衍生物都没有被发现是 LAT1 介导的转运的底物。
