29-METHYLIDENE-2,3-OXIDOSQUALENE DERIVATIVES AS STEREOSPECIFIC MECHANISM-BASED INHIBITORS OF LIVER AND YEAST OXIDOSQUALENE CYCLASE

Two pairs of isomers (18Z)-(8), (18E)-29-methylidene-2,3-oxidohexanors qualene (21), and (18Z)-(31), (18E)-29-methylidene-2,3-oxidosqualene ( 34), have been obtained in a fully stereospecific manner, as inhibitor s of rat and yeast oxidosqualene cyclase. A new method for the synthes is of C-22 squalene aldehyde 2,3-epoxide is reported, as well as that of other 19-modified 2,3-oxidosqualene analogues. We found that the ac tivity is the opposite in the two series: the (E)-hexanormethylidene 2 1 and the (Z)-methylidene 31 are potent and irreversible inhibitors of oxidosqualene cyclase, while (Z)-hexanormethylidene 8 and (E)-methyli dene 34 are almost completely inactive. Reduction of the l8,19-double bond, such as in 39, eliminates the activity, while removal of both of the 19-linked groups such as in heptanor derivative 40 greatly reduce s inhibition of the enzyme. (E)-Hexanormethylidene 21 results the firs t irreversible inhibitor of the series toward the yeast enzyme.