Synthesis and Biological Evaluation of Nonionic Prenyl, Geranyl, and Farnesyl Diphosphate Surrogates

Prenyl, geranyl, and farnesyl derivatives containing nonionic surrogates for the diphosphate moiety, including disulfones4–6and7–9,methylene disulfonamides10–12,and carbamyl sulfamides13–15,have been synthesized and evaluated biologically in an effort to find suitable nonlabile, neutral inhibitors for enzymatic reactions which use these isoprenoid diphosphates as substrates. Farnesyl derivatives6, 9, 12,and15were ineffective as squalene synthase inhibitorsin vitro.Compounds4–15were screened in human skin fibroblasts for their effects on fatty acid, cholesterol, and DNA synthesis. In general, compounds10–15showed more inhibition than4–9and had a greater effect on DNA synthesis than on lipid synthesis, with the exception of15.