Selenium- and tellurium-containing redox modulators with distinct activity against macrophages: possible implications for the treatment of inflammatory diseases

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• 作者：Mandy Doering^a ; Britta Diesel^b ; Martin C.H. Gruhlke^c ; Uma M. Viswanathan^a ; Dominika M&aacute ; nikov&aacute ; ^d ; Miroslav Chovanec^d ; Torsten Burkholz^a ; Alan J. Slusarenko^c ; Alexandra K. Kiemer^b ; Claus Jacob^a ; ^{c.jacob@mx.uni-saarland.de}
• 关键词：Redox modulation ; Macrophages ; Chemogenetic analysis ; Nitric oxide ; Reactive oxygen species ; iNOS ; Lipopolysaccharide
• 刊名：Tetrahedron
• 出版年：2012
• 出版时间：23 December, 2012
• 年：2012
• 卷：68
• 期：51
• 页码：10577-10585
• 全文大小：476 K

文摘

Various selenium- and tellurium-containing molecules are able to modulate the intracellular redox state of cells, an effect which may be used for the (selective) targeting of cancer cells, which are naturally under oxidative stress (OS). As macrophages also generate an environment rich in Reactive Oxygen Species (ROS) and nitric oxide (NO), they may represent an additional, prime target for such redox-modulating agents. A range of selenium and tellurium-containing quinones have therefore been synthesized and subsequently tested in macrophage culture. The tellurium agents were generally cytotoxic at very low concentrations, and their mode of action seemed to involve the upregulation of intracellular ROS levels. This redox-modulating effect was confirmed by simple yeast-based chemogenetic analysis in conjunction with in?vitro redox assays and electrochemistry. Together, these studies point towards an intracellular build-up of superoxide radicals as the most likely cause of toxicity. In contrast, some of the selenium derivatives were less toxic and exerted a pronounced inhibitory effect on the formation of lipopolysaccharide-induced NO production. Whilst the Te-analogues therefore may enable the resolute, effective and fairly selective targeting of macrophages, the selenium agents could act less severely, but equally effectively by interfering with inflammatory signalling molecules.