Conjugated methyl sulfide and phenyl sulfide derivatives of oxidosqualene as inhibitors of oxidosqualene and squalene-hopene cyclases.
Various (1E,3E)- and (1Z,3E)-conjugated methylthio derivatives of oxidosqualene (OS) and conjugated and non-conjugated phenylthio derivatives of OS were obtained. These compounds, designed as inhibitors of pig liver and Saccharomyces cerevisiae 2,3-oxidosqualene-lanosterol cyclases (OSC) (EC 5.4.99.7) and of Alicyclobacillus acidocaldarius squalene-hopene cyclase (SHC) (EC 5.4.99.-), contain the reactive function adjacent to carbons involved in the formation of the third and the fourth cycle during OS cyclization. All the new compounds are inhibitors of OSC and SHC, with various degrees of selectivity. The conjugated methylthio derivatives behaved as potent inhibitors of S. cerevisiae OSC, whereas most of the phenylthio derivatives were especially active toward SHC.
Rocco
Flavio
F
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, 10125 Torino, Italy.
Bosso
Simonetta Oliaro
SO
Viola
Franca
F
Milla
Paola
P
Roma
Giorgio
G
Grossi
Giancarlo
G
Ceruti
Maurizio
M
D000818:Animals; D001406:Bacillaceae / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013185:Squalene / Q000031:analogs & derivatives* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry; D013552:Swine; D013997:Time Factors
C002821:2,3-oxidosqualene; D004791:Enzyme Inhibitors; D013440:Sulfides; D013185:Squalene; D019751:Intramolecular Transferases; C066630:squalene-hopene cyclase; C021924:lanosterol synthase