Symmetrical bis-tertiary amines as novel CXCR4 inhibitors.
Symmetrical bis-tertiary amines as novel CXCR4 inhibitors.
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DOI：
10.1016/j.ejmech.2016.04.040
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发表时间：
2016-08-08
影响因子：
6.7
通讯作者：
Shim H
中科院分区：
文献类型：
--
作者：
Bai R;Liang Z;Yoon Y;Liu S;Gaines T;Oum Y;Shi Q;Mooring SR;Shim H
CXCR4抑制剂是治疗癌症转移和炎症的有前途的药物。设计、合成并评估了一系列针对CXCR4的新型叔胺衍生物。对中心苯环连接基和侧链进行修饰和优化，以研究构效关系。在结合亲和力测定和基质胶侵袭功能阻断测定中，七种化合物显示出比参考药物 AMD3100 更有效的活性。这些化合物在结合亲和力测定中表现出1至100 nM的有效浓度，与100 nM的AMD3100相比，抑制入侵65.3%至100%。在小鼠模型中，化合物 IIn 对角叉菜胶诱导的爪子炎症显示出 50% 的抑制效果，与肽拮抗剂 TN14003 (48%) 一样有效。这些数据表明对称双叔胺是独特的高效CXCR4抑制剂。
CXCR4 inhibitors are promising agents for the treatment of cancer metastasis and inflammation. A series of novel tertiary amine derivatives targeting CXCR4 were designed, synthesized, and evaluated. The central benzene ring linker and side chains were modified and optimized to study the structure-activity relationship. Seven compounds displayed much more potent activity than the reference drug, AMD3100, in both the binding affinity assay and the blocking of Matrigel invasion functional assay. These compounds exhibited effective concentration ranging from 1 to 100 nM in the binding affinity assay and inhibited invasion from 65.3% to 100% compared to AMD3100 at 100 nM. Compound IIn showed a 50% suppressive effect against carrageenan-induced paw inflammation in a mouse model, which was as effective as the peptidic antagonist, TN14003 (48%). These data demonstrate that symmetrical bis-tertiary amines are unique CXCR4 inhibitors with high potency.