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 function s at positions C-2, C-15 and C-19 of the squalene skeleton, were studied as inhibitors of pig liver and Saccharomyces cerevisiae oxidosqualene cyclase s (OSC) (EC 5.4.99.7) and of Alicyclobacillus acidocaldarius squalene hopen e cyclase (SHC) (EC 5.4.99.-). They contain one or two sulfur atoms in alph a -skeletal position to carbons considered to be cationic during enzymatic cyclization of the substrate and should strongly interact with enzyme nucle ophiles of the active site. Most of the new compounds are inhibitors of the OSC and of SHC, with Various degrees of selectivity. The methylthiovinyl d erivative, having the reactive group at position 19, was the most potent an d selective inhibitor of the series toward S. cerevisiae OSC, with a concen tration inhibiting 50% of the activity of 50 nM, while toward the animal en zyme it was 20 times less potent. These results could offer new insight for the design of antifungal drugs.