L-Type amino acid transporter 1 activity of 1,2,3-triazolyl analogs of L-histidine and L-tryptophan

Colton Hall, Hannah Wolfe, Alyssa Wells, Huan Chieh Chien, Claire Colas, A. Schlessinger, Kathleen M. Giacomini, Allen A. Thomas

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2254-2258
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number16
DOIs
StatePublished - Aug 15 2019

Fingerprint

Amino Acid Transport Systems
Triazoles
Histidine
Tryptophan
Amino Acids
Prodrugs
Large Neutral Amino Acid-Transporter 1
Click Chemistry
Cycloaddition
Cycloaddition Reaction
Brain Diseases
Structure-Activity Relationship
Brain Neoplasms
Brain
Ac-Nal(1)-Cpa(2)-Pal(3,6)-Arg(5)-Ala(10)-lHRH
Pharmaceutical Preparations

Keywords

  • Amino acid
  • Blood-brain barrier
  • Cancer
  • Click chemistry
  • Membrane transporter
  • Solute carrier family
  • Triazole

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

L-Type amino acid transporter 1 activity of 1,2,3-triazolyl analogs of L-histidine and L-tryptophan. / Hall, Colton; Wolfe, Hannah; Wells, Alyssa; Chien, Huan Chieh; Colas, Claire; Schlessinger, A.; Giacomini, Kathleen M.; Thomas, Allen A.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 16, 15.08.2019, p. 2254-2258.

Research output: Contribution to journalArticle

Hall, Colton ; Wolfe, Hannah ; Wells, Alyssa ; Chien, Huan Chieh ; Colas, Claire ; Schlessinger, A. ; Giacomini, Kathleen M. ; Thomas, Allen A. / L-Type amino acid transporter 1 activity of 1,2,3-triazolyl analogs of L-histidine and L-tryptophan. In: Bioorganic and Medicinal Chemistry Letters. 2019 ; Vol. 29, No. 16. pp. 2254-2258.
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AU - Giacomini, Kathleen M.

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