title: Inhibition of xc⁻ transporter-mediated cystine uptake by sulfasalazine analogs.
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.
authors: Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
authors: Krupa
authors: K
authors: Shukla
authors: Ajit G
authors: AG
authors: Thomas
authors: Dana V
authors: DV
authors: Ferraris
authors: Niyada
authors: N
authors: Hin
authors: Rita
authors: R
authors: Sattler
authors: Jesse
authors: J
authors: Alt
authors: Camilo
authors: C
authors: Rojas
authors: Barbara S
authors: BS
authors: Slusher
authors: Takashi
authors: T
authors: Tsukamoto
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017920:Antiporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D003553:Cystine / Q000378:metabolism*; D006801:Humans; D013329:Structure-Activity Relationship; D012460:Sulfasalazine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D027322:Amino Acid Transport System X-AG; D017920:Antiporters; D012460:Sulfasalazine; D003553:Cystine