title: Identification of novel low molecular weight CXCR4 antagonists by structural tuning of cyclic tetrapeptide scaffolds.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. tamamura@pharm.kyoto-u.ac.jp
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
authors.forename: Takanobu
authors.initials: T
authors.lastname: Araki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueda
authors.forename: Zixuan
authors.initials: Z
authors.lastname: Wang
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Ai
authors.initials: A
authors.lastname: Esaka
authors.forename: John O
authors.initials: JO
authors.lastname: Trent
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakashima
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Peiper
authors.forename: Akira
authors.initials: A
authors.lastname: Otaka
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: 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
chemical_list: D000475:Alkenes; D009842:Oligopeptides; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4; D013440:Sulfides; D001120:Arginine