LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs

Evan Augustyn, Karissa Finke, Arik A. Zur, Logan Hansen, Nathan Heeren, Huan Chieh Chien, Lawrence Lin, Kathleen M. Giacomini, Claire Colas, Avner Schlessinger, Allen A Thomas

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The transporter protein Large-neutral Amino Acid Transporter 1 (LAT-1, SLC7A5) is responsible for transporting amino acids such as tyrosine and phenylalanine as well as thyroid hormones, and it has been exploited as a drug delivery mechanism. Recently its role in cancer has become increasingly appreciated, as it has been found to be up-regulated in many different tumor types, and its expression levels have been correlated with prognosis. Substitution at the meta position of aromatic amino acids has been reported to increase affinity for LAT-1; however, the SAR for this position has not previously been explored. Guided by newly refined computational models of the binding site, we hypothesized that groups capable of filling a hydrophobic pocket would increase binding to LAT-1, resulting in improved substrates relative to parent amino acid. Tyrosine and phenylalanine analogs substituted at the meta position with halogens, alkyl and aryl groups were synthesized and tested in cis-inhibition and trans-stimulation cell assays to determine activity. Contrary to our initial hypothesis we found that lipophilicity was correlated with diminished substrate activity and increased inhibition of the transporter. The synthesis and SAR of meta-substituted phenylalanine and tyrosine analogs is described.

Original languageEnglish (US)
Pages (from-to)2616-2621
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number11
DOIs
StatePublished - Jun 1 2016

Fingerprint

Large Neutral Amino Acid-Transporter 1
Phenylalanine
Tyrosine
Amino Acids
Aromatic Amino Acids
Halogens
Substrates
Drug delivery
Thyroid Hormones
Tumors
Assays
Neoplasms
Substitution reactions
Binding Sites
Pharmaceutical Preparations
Proteins

Keywords

  • Amino acid
  • Negishi coupling
  • SLC7A5
  • Transporter inhibitor
  • Transporter substrate

ASJC Scopus subject areas

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

Cite this

LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs. / Augustyn, Evan; Finke, Karissa; Zur, Arik A.; Hansen, Logan; Heeren, Nathan; Chien, Huan Chieh; Lin, Lawrence; Giacomini, Kathleen M.; Colas, Claire; Schlessinger, Avner; Thomas, Allen A.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 11, 01.06.2016, p. 2616-2621.

Research output: Contribution to journalArticle

Augustyn, E, Finke, K, Zur, AA, Hansen, L, Heeren, N, Chien, HC, Lin, L, Giacomini, KM, Colas, C, Schlessinger, A & Thomas, AA 2016, 'LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 11, pp. 2616-2621. https://doi.org/10.1016/j.bmcl.2016.04.023
Augustyn, Evan ; Finke, Karissa ; Zur, Arik A. ; Hansen, Logan ; Heeren, Nathan ; Chien, Huan Chieh ; Lin, Lawrence ; Giacomini, Kathleen M. ; Colas, Claire ; Schlessinger, Avner ; Thomas, Allen A. / LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs. In: Bioorganic and Medicinal Chemistry Letters. 2016 ; Vol. 26, No. 11. pp. 2616-2621.
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