Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 29, Issue 16, Pages 2254-2258Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2019.06.033
Keywords
Membrane transporter; Solute carrier family; Triazole; Click chemistry; Amino acid; Cancer; Blood-brain barrier
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Funding
- National Institutes of Health's National Institute of Neurological Disorders and Stroke [R15 NS099981]
- National Institutes of Health's National Institute of General Medical Sciences [R01 GM117163]
- [R01 GM108911]
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A series of 1,2,3-triazole analogs of the amino acids L-histidine and t-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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