Oxysterols from free radical chain oxidation of 7-dehydrocholesterol

Product and mechanistic studies

Libin Xu, Zeljka Korade, Ned A. Porter

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Free radical chain oxidation of highly oxidizable 7-dehydrocholesterol (7-DHC), initiated by 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), was carried out at 37 °C in benzene for 24 h. Fifteen oxysterols derived from 7-DHC were isolated and characterized with 1D and 2D NMR spectroscopy and mass spectrometry. A mechanism that involves abstraction of hydrogen atoms at C-9 and/or C-14 is proposed to account for the formation of all of the oxysterols and the reaction progress profile. In either the H-9 or H-14 mechanism, a pentadienyl radical intermediate is formed after abstraction of H-9 or H-14 by a peroxyl radical. This step is followed by the well-precedented transformations observed in peroxidation reactions of polyunsaturated fatty acids such as oxygen addition, peroxyl radical 5-exo cyclization, and SHi carbon radical attack on the peroxide bond. The mechanism for peroxidation of 7-DHC also accounts for the formation of numerous oxysterol natural products isolated from fungal species, marine sponges, and cactaceous species. In a cell viability test, the oxysterol mixture from 7-DHC peroxidation was found to be cytotoxic to Neuro2a neuroblastoma cells in the micromolar concentration range. We propose that the high reactivity of 7-DHC and the oxysterols generated from its peroxidation may play important roles in the pathogenesis of Smith-Lemli-Opitz syndrome, X-linked dominant chondrodysplasia punctata, and cerebrotendinous xanthomatosis, all of these being metabolic disorders characterized by an elevated level of 7-DHC.

Original languageEnglish (US)
Pages (from-to)2222-2232
Number of pages11
JournalJournal of the American Chemical Society
Volume132
Issue number7
DOIs
StatePublished - Mar 3 2010

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Polyunsaturated fatty acids
Cyclization
Peroxides
Free radicals
Nuclear magnetic resonance spectroscopy
Free Radicals
Mass spectrometry
Benzene
Cells
Atoms
Oxidation
Hydrogen
Carbon
Oxygen
Cerebrotendinous Xanthomatosis
Chondrodysplasia Punctata
Smith-Lemli-Opitz Syndrome
Porifera
Biological Products
Unsaturated Fatty Acids

ASJC Scopus subject areas

  • Catalysis
  • Biochemistry
  • Chemistry(all)
  • Colloid and Surface Chemistry

Cite this

Oxysterols from free radical chain oxidation of 7-dehydrocholesterol : Product and mechanistic studies. / Xu, Libin; Korade, Zeljka; Porter, Ned A.

In: Journal of the American Chemical Society, Vol. 132, No. 7, 03.03.2010, p. 2222-2232.

Research output: Contribution to journalArticle

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