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Vinyl sulfide derivatives of truncated oxidosqualene as selective inhibitors of oxidosqualene and squalene‐hopene cyclases
Author(s) -
Ceruti Maurizio,
Balliano Gianni,
Rocco Flavio,
Milla Paola,
Arpicco Silvia,
Cattel Luigi,
Viola Franca
Publication year - 2001
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/s11745-001-0767-8
Subject(s) - chemistry , stereochemistry , squalene , saccharomyces cerevisiae , cyclase , enzyme , active site , nucleophile , biochemistry , yeast , catalysis
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 α‐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 50% 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.