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-oxidohexanorsqualene (21), and (18Z)- (31), (18E)-29-methylidene-2,3-oxidosqualene (34), have been obtained in a fully stereospecific manner, as inhibitors of rat and yeast oxidosqualene cyclase. A new method for the synthesis of C22 squalene aldehyde 2,3-epoxide is reported, as well as that of other 19-modified 2,3-oxidosqualene analogues. We found that the activity is the opposite in the two series: the (E)-hexanormethylidene 21 and the (Z)-methylidene 31 are potent and irreversible inhibitors of oxidosqualene cyclase, while (Z)-hexanormethylidene 8 and (E)-methylidene 34 are almost completely inactive. Reduction of the 18,19-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 reduces inhibition of the enzyme. (E)-Hexanormethylidene 21 results the first irreversible inhibitor of the series toward the yeast enzyme.
Ceruti
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Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Italy.
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D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology*; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D013185:Squalene / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine
D004791:Enzyme Inhibitors; C076537:29-methylidene-2,3-oxidosqualene; D013185:Squalene; D019751:Intramolecular Transferases; C021924:lanosterol synthase