Dioxidosqualenes: Characterization and Activity as Inhibitors of 2,3-Oxidosqualene-Lanosterol Cyclase

Article abstract of DOI:10.1021/jo00067a036

The preparation and characterization of dioxidosqualenes 4-10 is reported.Treatment of the appropriate epoxysqualene 1,2, or 3 with NBS followed by chromatographic purification afforded the corresponding epoxybromohydrins 11-14 as diastereomeric mixtures, with the exception of compound 11, which could be separated into the respective racemates 11a and 11b.Further dehydrobromination with NaH in THF led to the respective dioxidosqualenes 4-8 in good conversion yields.Dioxides 9 and 10 were isolated from the crude reaction mixture of the treatment of epoxide 2 with dimethyldioxirane.Characterization of compounds 4-10 was carried out by combining 1H and 13C NMR spectral means with positive GC-MS-CI analysis.The GC-MS-CI analysis included the identification of the carbonyl compounds resulting from the cleavage of dioxido derivatives 4-10 with periodic acid.Finally, data on the activity of dioxidosqualenes as oxidosqualene-lanosterol cyclase (OSLC) inhibitors in rat liver microsomes are also presented.In this respect, 2,3:18,19-dioxidosqualene (7) was found to be the best inhibitor within the compounds assayed (IC₅₀=0.11 μM), although dioxides 4,5, and 9 also exhibited a potent inhibitory activity (IC₅₀=21.3, 13.0, and 9.3 μM, respectively).The fact that these compounds could be potentially generated in an organism constitutes a remarkable difference relative to other OSLC inhibitors described to date.