Vinyl sulfide derivatives of truncated oxidosqualene as selective inhibitors of oxidosqualene and squalene-hopene cyclases.
Various vinyl sulfide and ketene dithioacetal derivatives of truncated 2,3-oxidosqualene were developed. These compounds, having the reactive functions at positions C-2, C-15 and C-19 of the squalene skeleton, were studied as inhibitors of pig liver and Saccharomyces cerevisiae oxidosqualene cyclases (OSC) (EC 5.4.99.7) and of Alicyclobacillus acidocaldarius squalene hopene cyclase (SHC) (EC 5.4.99.-). They contain one or two sulfur atoms in alpha-skeletal position to carbons considered to be cationic during enzymatic cyclization of the substrate and should strongly interact with enzyme nucleophiles of the active site. Most of the new compounds are inhibitors of the OSC and of SHC, with various degrees of selectivity. The methylthiovinyl derivative, having the reactive group at position 19, was the most potent and selective inhibitor of the series toward S. cerevisiae OSC, with a concentration inhibiting 500% of the activity of 50 nM, while toward the animal enzyme it was 20 times less potent. These results could offer new insight for the design of antifungal drugs.
Ceruti
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M
Dipartimento Farmacochimico, Tossicologico e Biologico, Università di Palermo, Italy.
Balliano
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Rocco
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Milla
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Arpicco
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Cattel
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Viola
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F
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013185:Squalene / Q000737:chemistry; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry* / Q000494:pharmacology*; D013552:Swine
C445138:(5,9,13)-17,18-epoxy-5,10,14,18-tetramethyl-1-methylthio-1,5,9,13-nonadecatetraene; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D013440:Sulfides; D013185:Squalene; D019751:Intramolecular Transferases; C066630:squalene-hopene cyclase; C021924:lanosterol synthase