SYNTHESIS OF A SQUALENOID OXAZIRIDINE AND OTHER NEW CLASSES OF SQUALENE DERIVATIVES, AS INHIBITORS OF STEROL BIOSYNTHESIS

Article abstract of DOI:10.1016/0223-5234(88)90096-7

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-methylamine 10. 9 was synthesized by a new method, in order to prevent acid decomposition of 7 and 9.The inhibitory activities of 7-9 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.Keywords: squalene derivatives / polyenic oxaziridines / 2,3-oxidosqualene cyclase inhibitors / rat liver yeast microsomes / 3T3 fibroblasts