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

doi:10.1016/j.bmcl.2019.06.033

Bioorganic & Medicinal Chemistry Letters

Volume 29, Issue 16, 15 August 2019, Pages 2254-2258

https://doi.org/10.1016/j.bmcl.2019.06.033 Get rights and content

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.

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Declaration of Competing Interest

The authors confirm no conflict of interest.

Acknowledgements

This work was supported by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke Grant R15 NS099981 (to A.A.T), the National Institutes of Health's National Institute of General Medical Sciences Grant R01 GM117163 (to H.C.C. and K.M.G.) and R01 GM108911 (to A.S. and C.C.). We appreciate OpenEye Scientific Software Inc. for granting us access to its high-performance molecular modeling applications through its academic license program.

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^d: Pharmacoinformatics Research Group, Department of Pharmaceutical Chemistry, University of Vienna, Althanstraße 14 (UZA II), 1090 Vienna, Austria.

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

Abstract

Graphical abstract

Section snippets

Declaration of Competing Interest

Acknowledgements

J Biol Chem

Eur J Pharm Sci

Lung Cancer

Bioorg Med Chem Lett

Bioorg Med Chem Lett

Tetrahedron

Coord Chem Rev

Biochim Biophys Acta

Bioorg Med Chem Lett

Tetrahedron Lett

Bioorg Med Chem

J Biol Chem

Mol Aspects Med

Adv Heterocycl Chem

Eur J Pharm Sci

J Controlled Release

Mol Pharmacol

Proc Natl Acad Sci USA