Development of a tripeptide mimetic strategy for the inhibition of proteinfarnesyltransferase

This paper describes the development of a novel terphenyl-based tripeptide mimetic of the CAAX carboxy terminal sequence of Ras. We employ a concise s ynthesis to form a series of differently functionalized terphenyl inhibitor s of protein farnesyltransferase (PFTase), exemplified by 5, 6 and 7. The k ey reaction in the synthesis of the terphenyl methyl ester 13, and therefor e 6 and 7, was the Pd-catalyzed chemoselective Suzuki cross-coupling of 3-b romo-4-chloronitrobenzene 16 with an appropriate boronic acid derivative ut ilizing a commercially available, electron rich phosphine Ligand. We furthe r show that one member of this series is a potent inhibitor of PFTase. (C) 2000 Elsevier Science Ltd. All rights reserved.