Solid-phase synthesis of a farnesylated CaaX peptide library: Inhibitors of the Ras CaaX endoprotease

A solid-phase method. based on Kaiser's p-benzophenone oxime resin, was dev eloped for the synthesis of a series of N-acetyl-S-(E,E-farnesylated) Ca(1) a(2)X tetrapeptides as potential inhibitors of recombinant Ras and a-factor converting enzyme (RCE). N-Acetyl-S-(E, E-farnesyl)-L-cysteine was coupled to resin-bound a(1)a(2) dipeptide using HOBt/DCC activation in conjunction with N-BOC chemistry. The protected farnesylated tripeptide was cleaved fr om the resin with simultaneous addition of the X residue by treating the re sin-bound farnesylated Ca(1)a(2) tripeptide with L-amino acid benzyl ester tosylates under mildly acidic conditions. The benzyl ester was saponified, and the resulting carboxylate precipitated by ether to afford a library of tetrapeptides as a mixture of diastereomers at the cysteine center. The pep tides were evaluated as inhibitors of recombinant yeast RCE endoprotease (y RCE) to obtain information about the affinity of the enzyme for the a(1)a(2 )X portion of the Ca(1)a(2)X moiety.