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Identification of Novel Low Molecular Weight CXCR4 Antagonists by Structural Tuning of Cyclic Tetrapeptide Scaffolds

2005; American Chemical Society; Volume: 48; Issue: 9 Linguagem: Inglês

10.1021/jm050009h

1520-4804

Hirokazu Tamamura, Takanobu Araki, Satoshi Ueda, Zixuan Wang, Shinya Oishi, Ai Esaka, John O. Trent, Hideki Nakashima, Naoki Yamamoto, Stephen C. Peiper, Akira Otaka, Nobutaka Fujii,

Chemical Synthesis and Analysis

A highly potent CXCR4 antagonist, compound 2, was previously found by using two orthogonal cyclic pentapeptide libraries involving conformation-based and sequence-based libraries based on the pharmacophore of a 14-mer peptidic antagonist, 1. Herein, cyclic tetrapeptides derived from replacements of the dipeptide unit (Nal-Gly) with a γ-amino acid and pseudopeptides cyclized by disulfide and olefin bridges were synthesized to find novel scaffold structures different from that of cyclic pentapeptides. These compounds contain a reduced number of peptide bonds compared to compound 2. Furthermore, several analogues with chemical modification of the side chain of Arg4 in 2 were also prepared. From these, several new leads possessing high to moderate CXCR4-antagonistic activity were characterized.