Solid phase synthesis of mitochondrial triphenylphosphonium-vitamin E metabolite using a lysine linker for reversal of oxidative stress.
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.
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA. mohanad.mossalam@utah.edu
Mohanad
M
Mossalam
Jamie
J
Soto
Carol S
CS
Lim
E Dale
ED
Abel
D000818:Animals; D002417:Cattle; D002839:Chromans / Q000138:chemical synthesis* / Q000737:chemistry; D008239:Lysine / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000378:metabolism*; D018384:Oxidative Stress; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D060327:Solid-Phase Synthesis Techniques / Q000379:methods*; D014810:Vitamin E / Q000138:chemical synthesis* / Q000737:chemistry
D002839:Chromans; D009943:Organophosphorus Compounds; D011422:Propionates; D017382:Reactive Oxygen Species; D014810:Vitamin E; C084852:2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman; D008239:Lysine