Direct access to side chain N,N′-diaminoalkylated derivatives of basic amino acids suitable for solid-phase peptide synthesis

• Published in: Amino acids 2013-02, Vol.44 (2), p.321-333
• Main Authors: Pitteloud, Jean-Philippe, Bionda, Nina, Cudic, Predrag
• Format: Article
• Language: English
• Subjects: Alkylation; Amino acids; Amino Acids, Basic - chemical synthesis; Amino Acids, Basic - chemistry; Analogue; Analytical Chemistry; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacteria - drug effects; Biochemical Engineering; Biochemistry; Biomedical and Life Sciences; Branched; Derivatives; Erythrocytes - drug effects; Hemolytic Agents - chemical synthesis; Hemolytic Agents - chemistry; Hemolytic Agents - pharmacology; Humans; Life Sciences; Molecular Structure; Neurobiology; Original Article; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Proteomics; Solid-Phase Synthesis Techniques; Synthesis
• ISSN: 0939-4451; 1438-2199
• DOI: 10.1007/s00726-012-1336-5

A simple and efficient one-pot procedure that enables rapid access to orthogonally protected N , N′ -diaminoalkylated basic amino acid building blocks fully compatible with standard Boc and Fmoc solid-phase peptide synthesis is reported. Described synthetic approach includes double reductive alkylation of N α -protected diamino acids with N -protected amino aldehydes in the presence of sodium cyanoborohydride. This approach allows preparation of symmetrical, as well as unsymmetrical, basic amino acid derivatives with branched side-chains 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 analogue in which the lysine residue was substituted with the synthetic derivative N α -(9 H -fluorenyl-9-methoxycarbonyl)- N β , N β ′ -bis[2-( tert -butoxycarbonylamino)ethyl]- l -2,3-diaminopropionic acid. This substitution resulted in an analogue with more ordered secondary structure in 2,2,2-trifluoroethanol and enhanced antibacterial activity without altering hemolytic activity. Graphical abstract