Solid Phase Syntheses of Oligoureas

• Published in: Journal of the American Chemical Society Vol. 119; no. 7; pp. 1556 - 1564
• Main Authors: Burgess, Kevin, Ibarzo, Javier, Linthicum, D. Scott, Russell, David H, Shin, Hunwoo, Shitangkoon, Aroonsiri, Totani, Reiko, Zhang, Alex J
• Format: Journal Article
• Language: English
• Published: American Chemical Society 19-02-1997
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja9631256

Isocyanates 7 were formed from monoprotected diamines 3 or 6, which in turn can be easily prepared from commercially available N-BOC- or N-FMOC-protected amino acid derivatives. Isocyanates 7, formed in situ, could be coupled directly to a solid support functionalized with amine groups or to amino acids anchored on resins using CH2Cl2 as solvent and an 11 h coupling time at 25 °C. Such couplings afforded peptidomimetics with an N-phthaloyl group at the N-terminus. The optimal conditions identified for removal of the N-phthaloyl group were to use 60% hydrazine in DMF for 1−3 h. Several sequences of amino acids coupled to ureas (“peptidic ureas”) and of sequential urea units (“oligoureas”) were prepared via solid phase syntheses and isolated by HPLC. Partition coefficients were measured for two of these peptidomimetics, and their water solubilities were found to be similar to the corresponding peptides. A small library of 160 analogues of the YGGFL-amide sequence was prepared via Houghten's tea bag methodology. This library was tested for binding to the anti-β-endorphin monoclonal antibody. Overall, this paper describes methodology for solid phase syntheses of oligourea derivatives with side chains corresponding to some of the protein amino acids. The chemistry involved is ideal for high-throughput syntheses and screening operations. The products can be expected to have an interesting range of pharmacological properties and enhanced proteolytic stabilities relative to the corresponding peptides.