Inhibition of xc(-) transporter-mediated cystine uptake by sulfasalazine analogs.

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Citation

Shukla K, Thomas AG, Ferraris DV, Hin N, Sattler R, Alt J, Rojas C, Slusher BS, Tsukamoto T

Inhibition of xc(-) transporter-mediated cystine uptake by sulfasalazine analogs.

Bioorg Med Chem Lett. 2011 Oct 15;21(20):6184-7. doi: 10.1016/j.bmcl.2011.07.081. Epub 2011 Aug 12.

PubMed ID
21889337 [ View in PubMed
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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.

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