Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
Bioorg Med Chem Lett. 2011 Oct 15;21(20):6184-7. doi: 10.1016/j.bmcl.2011.07.081. Epub 2011 Aug 12.
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.
合成了一系列柳氮磺胺吡啶类似物，并使用 L-[(14)C]胱氨酸作为底物测试它们阻断胱氨酸-谷氨酸反向转运蛋白系统 xc⁻的能力。用炔基取代柳氮磺胺吡啶的重氮基团得到了同样有效的抑制剂 2-羟基-5-((4-(吡啶-2-基磺酰基)苯基)乙炔基)苯甲酸 6。我们的 SAR 研究还表明，柳氮磺胺吡啶的羧基对于其抑制活性是必不可少的，而酚羟基则是可有可无的。缺乏 N-吡啶-2-基磺酰胺部分的截断类似物的活性比柳氮磺胺吡啶低，但由于其分子量较小，通过应用各种片段生长方法，可能成为更易于处理的模板。鉴于柳氮磺胺吡啶通过重氮键的裂解迅速代谢，这些类似物作为系统 xc-抑制剂可能具有更理想的药理学特性，特别是用于体内研究。
