Inhibition of x c - Transporter-mediated cystine uptake by sulfasalazine analogs

Krupa Shukla, Ajit G. Thomas, Dana V. Ferraris, Niyada Hin, Rita Sattler, Jesse Alt, Camilo Rojas, Barbara S. Slusher, Takashi Tsukamoto

Research output: Contribution to journalArticle

Abstract

A series of sulfasalazine analogs were synthesized and tested for their ability to block cystine-glutamate antiporter system xc- using l-[ 14Ccystine 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.

Original languageEnglish (US)
Pages (from-to)6184-6187
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number20
DOIs
StatePublished - Oct 15 2011

Keywords

  • Antiporter
  • Glutamate
  • Sulfasalazine
  • System x - cystine

ASJC Scopus subject areas

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

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