Potential therapeutic antioxidants that combine the radical scavenging ability of myricetin and the lipophilic chain of vitamin E to effectively inhibit microsomal lipid peroxidation

C J Bennett, S T Caldwell, D B McPhail, P C Morrice, G G Duthie, R C Hartley

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82 Citations (Scopus)

Abstract

The flavonol myricetin, reacts with oxygen-centred galvinoxyl radicals 28 times faster than d-alpha-tocopherol (vitamin E), the main lipid-soluble antioxidant in biological membranes. Moreover, each myricetin molecule reduces twice as many such radicals as vitamin E. However, myricetin fails to protect vitamin E-deficient microsomes from lipid peroxidation as assessed by the formation of thiobarbituric acid reactive substances (TBARS). Novel and potentially therapeutic antioxidants have been prepared that combine the radical-scavenging ability of a myricetin-like head group with a lipophilic chain similar to that of vitamin E. C-6-C-12 alkyl chains are attached to the A-ring of either a 3,3',4',5'-tetrahydroxyflavone or a 3,2',4',5'-tetrahydroxyflavone head group to give lipophilic flavonoids (Clog P = 4 to 10) that markedly inhibit iron-ADP catalysed oxidation of microsomal preparations. Orientation of the head group as well as total lipophilicity are important determinants of antioxidant efficacy. MM2 models indicate that our best straight chain 7-alkylflavonoids embed to the same depth in the membrane as vitamin E. The flavonoid head groups are prepared by aldol condensation followed by Algar-Flynn-Oyamada (AFO) oxidation or by Baker-Venkataraman re-arrangement. The alkyl tails are introduced by Suzuki or Negishi palladium-catalysed cross-coupling or by cross-metathesis catalysed by first generation Grubbs catalyst, which tolerate phenolic hydroxyl and ketone groups. (C) 2004 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)2079-2098
Number of pages20
JournalBioorganic & Medicinal Chemistry
Volume12
Issue number9
DOIs
Publication statusPublished - 1 May 2004

Keywords

  • cross-coupling reactions
  • alkylboronic acids
  • organic-synthesis
  • facile synthesis
  • building blocks
  • flavonoids
  • aryl
  • halides
  • metathesis
  • oxidation

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