Tamamura Hirokazu, Araki Takanobu, Ueda Satoshi, Wang Zixuan, Oishi Shinya, Esaka Ai, Trent John O, Nakashima Hideki, Yamamoto Naoki, Peiper Stephen C, Otaka Akira, Fujii Nobutaka
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
J Med Chem. 2005 May 5;48(9):3280-9. doi: 10.1021/jm050009h.
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.
一种高效的CXCR4拮抗剂化合物2，先前是通过使用两个正交的环五肽文库发现的，这两个文库基于一种14肽拮抗剂1的药效团，分别是基于构象的文库和基于序列的文库。在此，合成了通过用γ-氨基酸取代二肽单元（Nal-Gly）衍生的环四肽以及通过二硫键和烯烃桥环化的假肽，以寻找与环五肽不同的新型支架结构。与化合物2相比，这些化合物含有的肽键数量减少。此外，还制备了几种对化合物2中Arg(4)侧链进行化学修饰的类似物。从中鉴定出了几种具有高至中等CXCR4拮抗活性的新先导化合物。
