Synthesis and biological evaluation of nonionic prenyl, geranyl, and farnesyl diphosphate surrogates

Abstract

Prenyl, geranyl, and farnesyl derivatives containing nonionic surrogates for the diphosphate moiety, including disulfones 4-6 and 7-9, methylene disulfonamides 10-12, and carbamyl sulfamides 13-15, 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 derivatives 6, 9, 12, and 15 were ineffective as squalene synthase inhibitors in vitro. Compounds 4-15 were screened in human skin fibroblasts for their effects on fatty acid, cholesterol, and DNA synthesis. In general, compounds 10-15 showed more inhibition than 4-9 and had a greater effect on DNA synthesis than on lipid synthesis, with the exception of 15.