芳酰胺类衍生物的合成及蛋白酪氨酸磷酸酶1B和含SH2结构域蛋白酪氨酸磷酸酶2抑制活性研究

Synthesis of Aromatic Amide Derivatives and Their Biological Evaluation against Protein Tyrosine Phosphatase 1B and Scr Homology-2 Domain Containing Protein Tyrosine Phosphatase-2

为拓展含串联二芳酰胺结构的蛋白酪氨酸磷酸酶1B(PTP1B)抑制剂的化学空间,将其中的联苯二胺结构单元简化为芳基酰胺结构单元,设计并合成了18个芳酰胺类化合物.活性测试结果表明,部分芳酰胺衍生物对PTP1B和含SH2结构域蛋白酪氨酸磷酸酶2(SHP2)显示了一定强度的抑制活性.其中化合物3c[IC_(50)=(5.13±0.21)μmol/L]对PTP1B显示了中等强度的抑制活性,并且对其他亚型[T细胞蛋白酪氨酸磷酸酶(TCPTP)、含SH2结构域蛋白酪氨酸磷酸酶1(SHP1)和SHP2]显示了一定的选择性.有意思的是,化合物12对SHP2显示了中等强度的抑制活性[IC50=(7.47±1.26)μmol/L],对PTP1B、TCPTP以及SHP1显示了2倍的选择性,为发现新型选择性SHP2抑制剂提供了新的骨架类型.

To explore the chemical space of protein tyrosine phosphatase 1B （PTP1B） inhibitors by changing bis-aromatic amide moiety into aromatic amide moiety, a series of aromatic amide derivatives were designed, synthesized and their biological activities were evaluated against PTP1B and Scr homology-2 domain containing protein tyrosine phosphatase-2 （SHP2）. Among them, compound 3c displayed moderate inhibitory activity with IC50 of （5.13±0.21） μmol/L against PTP1B and showed two times selectivity for other related PTPs. Interestingly, compound 12[IC50=（7.47±1.26） μmol/L] showed moderate inhibitory activity against SHP2 and 2-fold selectivity against PTP1B, T-cell protein tyrosine phosphatase （TCPTP） or Src homology-2 domain containing protein tyrosine phosphatase-1 （SHP1） respectively, and offered a novel scaffold to develop new SHP2 inhibitors.