Low-Molecular-Weight CXCR4 Ligands with Variable Spacers
Low-Molecular-Weight CXCR4 Ligands with Variable Spacers
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DOI：
10.1002/cmdc.201200390
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发表时间：
2013-01-01
期刊：
影响因子：
3.4
通讯作者：
Tamamura, Hirokazu
中科院分区：
文献类型：
--
作者：
Narumi, Tetsuo;Aikawa, Haruo;Tamamura, Hirokazu
设计并合成了基于已知先导化合物的低分子量CXCR 4配体，所述先导化合物包括14-mer肽T140、环状五肽FC 131、肽模拟物和含吡啶二甲基胺的化合物。三种类型的芳香族间隔基，1，4-亚苯基二甲胺，萘-2，6-二基二甲胺和[1，1 '-联苯基]-4，4'-二基二甲胺，用于构建四个药效团基团。作为药效团基团，2-吡啶基甲基和1-萘基甲基存在于所有化合物中，并且还使用了几个芳香族基团和来自1-丙基胍和1，1，3，3-四甲基-2-丙基胍的阳离子基团。几种化合物显示出显著的CXCR 4结合亲和力，并且双（吡啶-2-基甲基）胺部分的锌（II）络合导致CXCR 4结合亲和力显著增加。
Low-molecular-weight CXCR4 ligands based on known lead compounds including the 14-mer peptide T140, the cyclic pentapeptide FC131, peptide mimetics, and dipicolylamine-containing compounds were designed and synthesized. Three types of aromatic spacers, 1,4-phenylenedimethanamine, naphthalene-2,6-diyldimethanamine, and [1,1'-biphenyl]-4,4'-diyldimethanamine, were used to build four pharmacophore groups. As pharmacophore groups, 2-pyridylmethyl and 1-naphthylmethyl are present in all of the compounds, and several aromatic groups and a cationic group from 1-propylguanidine and 1,1,3,3-tetramethyl-2-propylguanidine were also used. Several compounds showed significant CXCR4 binding affinity, and zinc(II) complexation of bis(pyridin-2-ylmethyl)amine moieties resulted in a remarkable increase in CXCR4 binding affinity.