Identification of novel low molecular weight CXCR4 antagonists by structural tuning of cyclic tetrapeptide scaffolds
Identification of novel low molecular weight CXCR4 antagonists by structural tuning of cyclic tetrapeptide scaffolds
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DOI：
10.1021/jm050009h
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发表时间：
2005-05-05
影响因子：
7.3
通讯作者：
Fujii, N
中科院分区：
文献类型：
--
作者：
Tamamura, H;Araki, T;Fujii, N
一个高效的CXCR4拮抗剂，化合物2，先前通过使用两个正交的环状五肽文库，包括基于构象的文库和基于序列的文库，基于一个14聚肽拮抗剂的药效团，1。本文合成了由γ -氨基酸取代二肽单元（Nal-Gly）而衍生的环四肽，以及由二硫烷和烯烃桥环化的假肽，以寻找不同于环五肽的新型支架结构。与化合物2相比，这些化合物含有较少数量的肽键。此外，还制备了几种对Arg(4) in 2侧链进行化学修饰的类似物。由此，几个具有高至中等cxcr4拮抗活性的新引线被鉴定出来。
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.