Solid phase synthesis of mitochondrial triphenylphosphonium-vitamin E metabolite using a lysine linker for reversal of oxidative stress.
Solid phase synthesis of mitochondrial triphenylphosphonium-vitamin E metabolite using a lysine linker for reversal of oxidative stress.
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DOI：
10.1371/journal.pone.0053272
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Abel ED
中科院分区：
文献类型：
--
作者：
Mossalam M;Soto J;Lim CS;Abel ED
由于线粒体在产生和代谢活性氧中的作用，抗氧化剂的线粒体靶向性一直是一个感兴趣的领域。抗氧化剂，尤其是维生素E （α-生育酚），已与亲脂性阳离子偶联以增加其线粒体靶向性。人工合成的维生素E类似物也被生产出来作为α-生育酚的替代品。在本文中，我们研究了维生素E代谢物2,5,7,8-四甲基-2-（2 ' -羧乙基）-6-羟色胺（α-CEHC）的线粒体靶向性，其结构与维生素E类似物相似。本文报道了一种固相合成的方法，通过赖氨酸连接剂将水溶性代谢物α-CEHC与三苯基膦阳离子结合。在牛主动脉内皮细胞中测试了最终产物（MitoCEHC）降低氧化应激的功效。此外，在2型糖尿病小鼠db/db中检测了MitoCEHC靶向线粒体的能力。结果表明，线粒体在体内积累，体外氧化应激减少。
Mitochondrial targeting of antioxidants has been an area of interest due to the mitochondria's role in producing and metabolizing reactive oxygen species. Antioxidants, especially vitamin E (α-tocopherol), have been conjugated to lipophilic cations to increase their mitochondrial targeting. Synthetic vitamin E analogues have also been produced as an alternative to α-tocopherol. In this paper, we investigated the mitochondrial targeting of a vitamin E metabolite, 2,5,7,8-tetramethyl-2-(2′-carboxyethyl)-6-hydroxychroman (α-CEHC), which is similar in structure to vitamin E analogues. We report a fast and efficient method to conjugate the water-soluble metabolite, α-CEHC, to triphenylphosphonium cation via a lysine linker using solid phase synthesis. The efficacy of the final product (MitoCEHC) to lower oxidative stress was tested in bovine aortic endothelial cells. In addition the ability of MitoCEHC to target the mitochondria was examined in type 2 diabetes db/db mice. The results showed mitochondrial accumulation in vivo and oxidative stress decrease in vitro.
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