Efficient syntheses, human and yeast farnesyl-protein transferase inhibitory activities of chaetomellic acids and analogues

Chaetomellic acids are a class of alkyl dicarboxylic acids that were isolat ed from Chaetomella acutiseta. They are potent and highly specific farnesyl -pyrophosphate (FPP) mimic inhibitors of Ras farnesyl-protein transferase. We have previously described the first biogenetic type aldol condensation-b ased total synthesis of chaetomellic acid A. Modification of the later step s of that synthesis resulted in the efficient syntheses of chaetomellic aci ds A and B in three steps with 75-80% overall yield. In this report, detail s of the original total syntheses of chaetomellic acids A, B and C, the new syntheses of acids A and B and structure-activity relationship of these co mpounds against various prenyl transferases including human and yeast FPTas e and bovine and yeast GGPTase I are described. Chaetomellic acids are diff erentially active against human and yeast FPTase. Chaetomellic acid A inhib ited human and yeast FPTase activity with IC50 values of 55 nM and 225 mu M , respectively. In contrast, chaetomellic acid C showed only a 10-fold diff erential in inhibitory activities against human versus yeast enzymes. In ke eping with molecular modeling-based predictions, the compounds with shorter alkyl side chains (C-8) were completely inactive against FPTase. (C) 2000 Elsevier Science Ltd. All rights reserved.