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
发布时间：2018-11-11 10:42
【摘要】：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.
[Abstract]:In order to expand the chemical space of protein tyrosine phosphatase 1B (PTP1B) inhibitor containing diarylamides in series, the biphenyl diamine structure unit was simplified to aryl amide structure unit, and 18 aromatic amides were designed and synthesized. The results of activity test showed that some aromatic amide derivatives showed strong inhibitory activity against PTP1B and SH2 domain protein tyrosine phosphatase 2 (SHP2). Among them, compound 3c [IC_ (50) = (5.13 卤0.21) 渭 mol/L] showed moderate inhibitory activity to PTP1B, and showed moderate inhibitory activity to other subtypes [T cell protein tyrosine phosphatase (TCPTP),]. Tyrosine phosphatase 1 (SHP1) and SHP2 containing SH2 domain proteins showed certain selectivity. Interestingly, compound 12 showed moderate inhibitory activity to SHP2 [(7.47 卤1.26) 渭 mol/L], double selectivity to PTP1B,TCPTP and SHP1, which provided a new skeleton type for the discovery of novel selective SHP2 inhibitors.
【作者单位】： 江南大学药学院;中国科学院上海药物研究所国家新药筛选中心新药研究国家重点实验室;
【基金】：国家自然科学基金(No.21472069) 中国科学院上海药物研究所新药研究国家重点实验室(No.SIMM1302KF-05)资助项目~~
【分类号】：O625.525
，
本文编号：2324598
[Abstract]:In order to expand the chemical space of protein tyrosine phosphatase 1B (PTP1B) inhibitor containing diarylamides in series, the biphenyl diamine structure unit was simplified to aryl amide structure unit, and 18 aromatic amides were designed and synthesized. The results of activity test showed that some aromatic amide derivatives showed strong inhibitory activity against PTP1B and SH2 domain protein tyrosine phosphatase 2 (SHP2). Among them, compound 3c [IC_ (50) = (5.13 卤0.21) 渭 mol/L] showed moderate inhibitory activity to PTP1B, and showed moderate inhibitory activity to other subtypes [T cell protein tyrosine phosphatase (TCPTP),]. Tyrosine phosphatase 1 (SHP1) and SHP2 containing SH2 domain proteins showed certain selectivity. Interestingly, compound 12 showed moderate inhibitory activity to SHP2 [(7.47 卤1.26) 渭 mol/L], double selectivity to PTP1B,TCPTP and SHP1, which provided a new skeleton type for the discovery of novel selective SHP2 inhibitors.
【作者单位】： 江南大学药学院;中国科学院上海药物研究所国家新药筛选中心新药研究国家重点实验室;
【基金】：国家自然科学基金(No.21472069) 中国科学院上海药物研究所新药研究国家重点实验室(No.SIMM1302KF-05)资助项目~~
【分类号】：O625.525
，
本文编号：2324598
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