title: Synthesis of side chain N,N'-diaminoalkylated derivatives of basic amino acids for application in solid-phase peptide synthesis.
abstract: Despite the enormous therapeutic potential, the clinical use of peptides has been limited by their poor bioavailability and low stability under physiological conditions. Hence, efforts have been undertaken to alter peptide structure in ways to improve their pharmacological properties. Inspired by the importance of basic amino acids in biological systems and the remarkable versatility displayed by lysine during the synthesis of complex peptide scaffolds, this chapter describes a simple procedure that enables rapid access to protected N,N'-diaminoalkylated basic amino acid building blocks suitable for standard solid-phase peptide synthesis. This procedure allows preparation of symmetrical, as well as unsymmetrical, dialkylated amino acid derivatives that can be further modified, enhancing their synthetic utility. The suitability of the synthesized branched basic amino acid building blocks for use in standard solid-phase peptide synthesis has been demonstrated by synthesis of an indolicidin analog in which the lysine residue was substituted with its synthetic polyamino derivate. The substitution provided indolicidin analog with increase net positive charge, more ordered secondary structure in biological membranes mimicking conditions, and enhanced antibacterial activity without altering hemolytic activity. Taking into consideration the increasing interest for peptides with unusual structural features due to their improved biological properties, the described synthesis of polyfunctional amino acid building blocks is of particular practical value.
authors.affiliation: Department of Chemistry, New York University, New York, NY, USA.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pitteloud
authors.forename: Nina
authors.initials: N
authors.lastname: Bionda
authors.forename: Predrag
authors.initials: P
authors.lastname: Cudic
mesh_terms: D000478:Alkylation; D024361:Amino Acids, Basic / Q000138:chemical synthesis*; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification; D010084:Oxidation-Reduction; D010455:Peptides / Q000138:chemical synthesis* / Q000302:isolation & purification; D060327:Solid-Phase Synthesis Techniques
chemical_list: D024361:Amino Acids, Basic; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D010455:Peptides