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Bioorg Med Chem Lett. 2016 Jun 1;26(11):2616-2621. doi: 10.1016/j.bmcl.2016.04.023. Epub 2016 Apr 11.

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

Author information

1
Department of Chemistry, University of Nebraska Kearney, Kearney, NE, 68849.
2
Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, CA 94158.
3
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
4
Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
#
Contributed equally

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.

KEYWORDS:

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

PMID:
27106710
PMCID:
PMC4875506
DOI:
10.1016/j.bmcl.2016.04.023
[Indexed for MEDLINE]
Free PMC Article

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