Synthesis of novel (N-farnesyl)aniino acids and their incorporation into peptides

N-Alkylation, and particularly W-farnesylation, of bioactive peptides might be of wide interest: first, to increase peptide bioavailability by decreasing their elimination and by favouring their transport through biological membranes; second, to target peptides to cellular membranes; and third, to generate therapeutic double-substrate inhibitors of enzymes such as ras-farnesyltransferase. We report the synthesis of novel W-farnesyl amino acids [(N-Frn) amino acids]. We have synthesized (W-FrnJMetOCHj, (N-Frn)ValOBz and (W-Frn)PheOCH₃ by alkylation of the corresponding natural amino acid esters. In order to demonstrate the feasibility of the introduction of (TV-Frn) amino acids into peptides, we have synthesized representative dipeptide analogs: Cys-(N-Frn)ValOBz, Phe-(N-Frn)ValOBz, Lys-(Ar-Frn)ValOBz, Phe-(N-Frn)MetOCH₃, Glu-(N-Frn)MetOCH₃, Ser-(Ar-Frn)MetOCH₃, Trp-(AT-Frn)PheOCH₃ and Pro-(N-Frn)PheOCH₃. We also describe the synthesis of the model peptide Cys-Val-Phe-(N-Frn)MetOCH₃, which is derived from the tetrapeptide CysValPheMet inhibitor of human p21ra.y-farnesyl transferase.