Identification of novel low molecular weight CXCR4 antagonists by structural tuning of cyclic tetrapeptide scaffolds.
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 gamma-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 Arg(4) in 2 were also prepared. From these, several new leads possessing high to moderate CXCR4-antagonistic activity were characterized.
Tamamura
Hirokazu
H
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. tamamura@pharm.kyoto-u.ac.jp
Araki
Takanobu
T
Ueda
Satoshi
S
Wang
Zixuan
Z
Oishi
Shinya
S
Esaka
Ai
A
Trent
John O
JO
Nakashima
Hideki
H
Yamamoto
Naoki
N
Peiper
Stephen C
SC
Otaka
Akira
A
Fujii
Nobutaka
N
D000475:Alkenes / Q000737:chemistry; D000818:Animals; D001120:Arginine / Q000737:chemistry; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry
D000475:Alkenes; D009842:Oligopeptides; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4; D013440:Sulfides; D001120:Arginine