22,23-Epoxy-2-aza-2,3-dihydrosqualene derivatives: potent new inhibitors of squalene 2,3-oxide-lanosterol cyclase.

Two new azasqualenoid derivatives, bearing a 22,23 epoxidic function, were synthesized, to obtain more efficient, competitive inhibitors of the enzyme squalene 2,3-oxide-lanosterol cyclase (EC 5.4.99.7). The activities of 22,23-epoxy-2-aza-2,3-dihydrosqualene 4 and of its N-oxide derivative 5 were studied using rat and pig liver microsomal preparations and compared with a pig liver partially purified squalene 2,3-oxide-lanosterol cyclase. The activities of compounds 4 and 5 were compared in the different enzymatic preparations with the activities of 2-aza-2,3-dihydrosqualene 2 and of 2-aza-2,3-dihydrosqualene N-oxide 3 previously studied only with rat liver microsomes. Using a solubilized, partially purified squalene 2,3-oxide cyclase, all the compounds exhibited a non-competitive type of inhibition. As the previously suggested mechanism of inhibition does not account for this kinetic behaviour, a new hypothesis is suggested.