Synthesis of novel (N‐farnesyl) amino acids and their incorporation into peptides

N-Alkylation, and particularly N-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 N-farnesyl amino acids [(N-Frn) amino acids]. We have synthesized (N-Frn)MetOCH3, (N-Frn)ValOBz and (N-Frn)PheOCH3, by alkylation of the corresponding natural amino acid esters. In order to demonstrate the feasibility of the introduction of (N-Frn) amino acids into peptides, we have synthesized representative dipeptide analogs: Cys-(N-Frn)ValOBz, Phe-(N-Frn)ValOBz, Lys-(N-Frn)ValOBz, Phe-(N-Frn)MetOCH3, Glu-(N-Frn)MetOCH3, Ser-(N-Frn)MetOCH3, Trp-(N-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 p21ras-farnesyl transferase.