Synthesis of a squalenoid oxaziridine and other new classes of squalene derivatives, as inhibitors of sterol biosynthesis

New classes of squalene derivatives, rationally designed as inhibitors of 2,3-oxidosqualene (SO) cyclase, a key enzyme in sterol biosynthesis, were synthesized. These were: N-methylimine 7, aminalic hydroperoxide 8, N-methyloxaziridine 9 and N-methylamide 10.9 was synthesized by a new method, in order to prevent acid decomposition of 7 and 9. The inhibitory activities of 7-10 were determined in vitro on SO cyclase associated with rat liver and yeast microsomes, and in vivo on sterol biosynthesis in 3T3 fibroblast cultures. 9 was the best inhibitor of SO cyclase associated with rat liver and yeast microsomes. In contrast, 7 and 10 strongly inhibited biosynthesis of C₂₇-sterols in 3T3 fibroblast cultures.