SYNTHESIS AND BIOLOGICAL EVALUATION OF NONIONIC PRENYL, GERANYL, AND FARNESYL DIPHOSPHATE SURROGATES

Prenyl, geranyl, and farnesyl derivatives containing nonionic surrogat es for the diphosphate moiety, including disulfones 4-6 and 7-9, methy lene disulfonamides 10-12, and carbamyl sulfamides 13-15, have been sy nthesized and evaluated biologically in an effort to find suitable non labile, neutral inhibitors for enzymatic reactions which use these iso prenoid diphosphates as substrates. Farnesyl derivatives 6, 9, 12, and 15 were ineffective as squalene synthase inhibitors in vitro. Compoun ds 4-15 were screened in human skin fibroblasts for their effects on f atty acid, cholesterol, and DNA synthesis. In general, compounds 10-15 showed more inhibition than 4-9 and had a greater effect on DNA synth esis than on lipid synthesis, with the exception of 15. (C) 1996 Acade mic Press, Inc.