The Design and Synthesis of Novel Chaetomellic Acid A Analogues

Chaetomellic acid A is an alkyl dicarboxylic acid isolated from the fermentation of Chaetomella acutiseta. Chaetomellic acid A has been shown to be a potent, highly specific inhibitor of RAS farnesyl protein transferase (FPTase). The association between RAS proteins and cancer has made chaetomellic acd A a potential chemotherapeutic agent. Two novel chaetomellic acid A analogues have been prepared that incorporate aromoatic rings in the alkyl tail. It is anticipated that these compounds will bind more tightly to the FPTase active site than the natural product due to intermolecular interactions between the aromatic rings in the tail and the aromatic amino acid residues that have been shown to line the enzyme pocket