L-Type amino acid transporter 1 activity of 1, 2, 3-triazolyl analogs of l-histidine and l-tryptophan. Issue 16 (15th August 2019)

• Record Type: Journal Article
• Authors: Hall, Colton; Wolfe, Hannah; Wells, Alyssa; Chien, Huan-Chieh; Colas, Claire; Schlessinger, Avner; Giacomini, Kathleen M.; Thomas, Allen A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 16(2019)
• Page Start: 2254
• Page End: 2258
• Publication Date: 2019-08-15
• Subjects: Membrane transporter -- Solute carrier family -- Triazole -- Click chemistry -- Amino acid -- Cancer -- Blood-brain barrier; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.06.033
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A series of 1, 2, 3-triazole analogs of the amino acids l -histidine and l -tryptophan were modeled, synthesized and tested for l -type amino acid transporter 1 (LAT1; SLC7A5) activity to guide the design of amino acid-drug conjugates (prodrugs). These triazoles were conveniently prepared by the highly convergent Huisgen 1, 3-dipolar cycloaddition (Click Chemistry). Despite comparable predicted binding modes, triazoles generally demonstrated reduced cell uptake and LAT1 binding potency relative to their natural amino acid counterparts. The structure-activity relationship (SAR) data for these triazoles has important ramifications for treating cancer and brain disorders using amino acid prodrugs or LAT1 inhibitors.