Vinyl sulfide derivatives of truncated oxidosqualene as selective inhibitors of oxidosqualene and squalene-hopene cyclases
Vinyl sulfide derivatives of truncated oxidosqualene as selective inhibitors of oxidosqualene and squalene-hopene cyclases
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DOI：
10.1007/s11745-001-0767-8
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发表时间：
2001-06-01
期刊：
影响因子：
1.9
通讯作者：
Viola, F
中科院分区：
文献类型：
--
作者：
Ceruti, M;Balliano, G;Viola, F
开发了各种截断2,3-氧化角鲨烯的硫化乙烯和烯酮二硫缩醛衍生物。这些化合物在角鲨烯骨架的C-2、C-15和C-19位点具有活性，研究了它们作为猪肝和酿酒酵母氧化角鲨烯环化酶（OSC） （EC 5.4.99.7）和酸性酸环杆菌角鲨烯藿烯环化酶（SHC） （EC 5.4.99.-）的抑制剂。它们含有一个或两个位于α -骨架位置的硫原子，在底物的酶环化过程中被认为是阳离子的碳，并且应该与活性位点的酶亲核试剂强烈相互作用。大多数新化合物是OSC和SHC的抑制剂，具有不同程度的选择性。甲基硫代乙烯基衍生物的活性基团位于第19位，是该系列中对葡萄球菌OSC最有效和选择性的抑制剂，其浓度对50 nM活性的抑制作用为50%，而对动物酶的抑制作用为20倍。这些结果可能为抗真菌药物的设计提供新的思路。
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 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.