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)Me OCH3, 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.
Byk
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UMR 133 CNRS/Rhône-Poulenc Rorer, Vitry-Alfortville Research Centre, Vitry-sur-Seine, France.
Scherman
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D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D010455:Peptides / Q000737:chemistry*; D017368:Protein Prenylation
D000596:Amino Acids; D010455:Peptides