LAT1 activity of carboxylic acid bioisosteres: Evaluation of hydroxamic acids as substrates

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Large neutral amino acid transporter 1 (LAT1) is a solute carrier protein located primarily in the blood–brain barrier (BBB) that offers the potential to deliver drugs to the brain. It is also up-regulated in cancer cells, as part of a tumor's increased metabolic demands. Previously, amino acid prodrugs have been shown to be transported by LAT1. Carboxylic acid bioisosteres may afford prodrugs with an altered physicochemical and pharmacokinetic profile than those derived from natural amino acids, allowing for higher brain or tumor levels of drug and/or lower toxicity. The effect of replacing phenylalanine's carboxylic acid with a tetrazole, acylsulfonamide and hydroxamic acid (HA) bioisostere was examined. Compounds were tested for their ability to be LAT1 substrates using both cis-inhibition and trans-stimulation cell assays. As HA-Phe demonstrated weak substrate activity, its structure–activity relationship (SAR) was further explored by synthesis and testing of HA derivatives of other LAT1 amino acid substrates (i.e., Tyr, Leu, Ile, and Met). The potential for a false positive in the trans-stimulation assay caused by parent amino acid was evaluated by conducting compound stability experiments for both HA-Leu and the corresponding methyl ester derivative. We concluded that HA's are transported by LAT1. In addition, our results lend support to a recent account that amino acid esters are LAT1 substrates, and that hydrogen bonding may be as important as charge for interaction with the transporter binding site.

Original languageEnglish (US)
Pages (from-to)5000-5006
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number20
DOIs
StatePublished - Jan 1 2016

Fingerprint

Large Neutral Amino Acid-Transporter 1
Hydroxamic Acids
Carboxylic Acids
Amino Acids
Substrates
Prodrugs
Tumors
Assays
Brain
Esters
Derivatives
Pharmacokinetics
Hydrogen Bonding
Phenylalanine
Brain Neoplasms
Pharmaceutical Preparations
Toxicity
Neoplasms
Carrier Proteins
Hydrogen bonds

Keywords

  • Acyl sulfonamide
  • Amino acid
  • SLC7A5
  • Tetrazole
  • Transporter inhibitor
  • Transporter substrate

ASJC Scopus subject areas

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

Cite this

LAT1 activity of carboxylic acid bioisosteres : Evaluation of hydroxamic acids as substrates. / Zur, Arik A.; Chien, Huan Chieh; Augustyn, Evan; Flint, Andrew; Heeren, Nathan; Finke, Karissa; Hernandez, Christopher; Hansen, Logan; Miller, Sydney; Lin, Lawrence; Giacomini, Kathleen M.; Colas, Claire; Schlessinger, Avner; Thomas, Allen A.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 20, 01.01.2016, p. 5000-5006.

Research output: Contribution to journalArticle

Zur, AA, Chien, HC, Augustyn, E, Flint, A, Heeren, N, Finke, K, Hernandez, C, Hansen, L, Miller, S, Lin, L, Giacomini, KM, Colas, C, Schlessinger, A & Thomas, AA 2016, 'LAT1 activity of carboxylic acid bioisosteres: Evaluation of hydroxamic acids as substrates', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 20, pp. 5000-5006. https://doi.org/10.1016/j.bmcl.2016.09.001
Zur, Arik A. ; Chien, Huan Chieh ; Augustyn, Evan ; Flint, Andrew ; Heeren, Nathan ; Finke, Karissa ; Hernandez, Christopher ; Hansen, Logan ; Miller, Sydney ; Lin, Lawrence ; Giacomini, Kathleen M. ; Colas, Claire ; Schlessinger, Avner ; Thomas, Allen A. / LAT1 activity of carboxylic acid bioisosteres : Evaluation of hydroxamic acids as substrates. In: Bioorganic and Medicinal Chemistry Letters. 2016 ; Vol. 26, No. 20. pp. 5000-5006.
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