Sequential nucleophilic substitution on halogenated triazines, pyrimidines, and purines: a novel approach to cyclic peptidomimetics.
A novel concept for the synthesis of macrocyclic peptidomimetics which incorporate heteroaromatic units is reported. The method involves sequential SNAr reactions of orthogonally protected amino groups of peptides and other linear oligomers on halogenated heterocycles such as 2,4,6-trichloro[1,3,5]triazine, 2,4,6-trichloropyrimidine, 4,6-dichloro-5-nitropyrimidine, and 2,6,8-trichloro-7-methylpurine. The scope of this novel solid-phase approach was systematically evaluated by means of the SPOT-synthesis methodology on planar cellulose membranes. Besides the question of the accessibility of different ring sizes and the compatibility with protecting groups of commonly used amino acids, the applicability of the technique toward different halogenated heteroaromatics and peptidomimetics was studied. It was found that the procedure is well suited to assemble a wide variety of cyclic peptidomimetics differing in both size (11- to 37-membered rings) and chemical nature of the assembled backbones.
Scharn
D
D
Institut für Medizinische Immunologie, Universitätsklinikum Charité, Humboldt Universität zu Berlin, Schumannstrasse 20-21, D-10098 Berlin, Germany.
Germeroth
L
L
Schneider-Mergener
J
J
Wenschuh
H
H
D000595:Amino Acid Sequence; D004151:Dipeptides / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry*; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry
D004151:Dipeptides; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011687:Purines; D011743:Pyrimidines; D014227:Triazines