DIOXIDOSQUALENES - CHARACTERIZATION AND ACTIVITY AS INHIBITORS OF 2,3-OXIDOSQUALENE LANOSTEROL CYCLASE

The preparation and characterization of dioxidosqualenes 4-10 is repor ted. Treatment of the appropriate epoxysqualene 1, 2, or 3 with NBS fo llowed by chromatographic purification afforded the corresponding epox ybromohydrins 11-14 as diastereomeric mixtures, with the exception of compound 11, which could be separated into the respective racemates 11 a and 11b. Further dehydrobromination with NaH in THF led to the respe ctive dioxidosqualenes 4-8 in good conversion yields. Dioxides 9 and 1 0 were isolated from the crude reaction mixture of the treatment of ep oxide 2 with dimethyldioxirane. Characterization of compounds 4-10 was carried out by combining IH and C-13 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 deriv atives 4-10 with periodic acid. Finally, data on the activity of dioxi dosqualenes as oxidosqualene-lanosterol cyclase (OSLC) inhibitors in r at liver microsomes are also presented. In this respect, 2,3:18,19-dio xidosqualene (7) was found to be the best inhibitor within the compoun ds assayed (IC50 = 0.11 muM), although dioxides 4, 5, and 9 also exhib ited a potent inhibitory activity (IC50 = 21.3, 13.0, and 9.3 muM, res pectively). The fact that these compounds could be potentially generat ed in an organism constitutes a remarkable difference relative to othe r OSLC inhibitors described to date.