Title

Inhibition of xc⁻ transporter-mediated cystine uptake by sulfasalazine analogs

Document Type

Article

Abstract

A series of sulfasalazine analogs were synthesized and tested for their ability to block cystine-glutamate antiporter system xc⁻ using L-[(14)C]cystine as a substrate. Replacement of sulfasalazine's diazo group with an alkyne group led to an equally potent inhibitor, 2-hydroxy-5-((4-(N-pyridin-2-ylsulfamoyl)phenyl)ethynyl)benzoic acid 6. Our SAR studies also revealed that the carboxylate group of sulfasalazine is essential for its inhibitory activity while the phenolic hydroxyl group is dispensable. Truncated analogs lacking an N-pyridin-2-ylsulfamoyl moiety were less potent than sulfasalazine, but may serve as more tractable templates because of their low molecular weight by applying a variety of fragment growing approaches. Given that sulfasalazine is rapidly metabolized through cleavage of the diazo bond, these analogs may possess a more desirable pharmacological profile as system xc- blockers, in particular, for in vivo studies.

Medical Subject Headings

Amino Acid Transport System X-AG (antagonists & inhibitors, metabolism); Antiporters (antagonists & inhibitors, metabolism); Cell Line; Cystine (metabolism); Humans; Structure-Activity Relationship; Sulfasalazine (analogs & derivatives, pharmacology)

Publication Date

10-15-2011

Publication Title

Bioorganic & medicinal chemistry letters

E-ISSN

1464-3405

Volume

21

Issue

20

First Page

6184

Last Page

7

PubMed ID

21889337

Digital Object Identifier (DOI)

10.1016/j.bmcl.2011.07.081

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