A unique and rapid approach toward the efficient development of novel protein tyrosine phosphatase (PTP) inhibitors based on 'clicked' pseudo-glycopeptides.
A unique and rapid approach toward the efficient development of novel protein tyrosine phosphatase (PTP) inhibitors based on 'clicked' pseudo-glycopeptides.
复制标题
DOI：
10.1016/j.bmcl.2010.12.126
复制
发表时间：
2011-02
影响因子：
2.7
通讯作者：
Jin-Wei Yang;Xiao‐Peng He;Cui Li;Li-xin Gao;Li Sheng;Juan Xie;Xiao-Xin Shi;Yun Tang;Jia Li-Jia-L
中科院分区：
文献类型：
--
作者：
Jin-Wei Yang;Xiao‐Peng He;Cui Li;Li-xin Gao;Li Sheng;Juan Xie;Xiao-Xin Shi;Yun Tang;Jia Li-Jia-L
蛋白酪氨酸磷酸酶(PTP)抑制剂的开发引起了人们的极大兴趣，因为许多PTP成员与包括自身免疫性疾病、糖尿病和癌症在内的人类重大疾病密切相关。我们在这里报告了一种独特而快速的方法来开发基于三唑基假性糖肽的新型PTP抑制剂实体。利用微波催化铜(I)催化叠氮-炔基-1，3-偶极环加成反应(CuAAc或‘点击反应’)，仅用∼30min就高产率地合成了一系列三唑连接的丝氨酸基、苏氨酸基、苯丙氨基和酪氨酸基1-O-葡萄糖或半乳糖苷。连续的生物实验证明这些糖肽三唑类化合物是良好的PTP1B和CDC25B抑制剂，对TCPTP、LAR、SHP-1和SHP-2具有选择性。引入的氨基酸(Ser、Thr、Phe和Tyr)的结构多样性和单糖支架上的同位异构体(GLC或Gal)都影响了相应的抑制活性和选择性。此外，苯基化糖支架在增强抑制剂与靶向PTP的结合亲和力方面起着至关重要的作用。最后进行了对接模拟，提出了该化合物系列与PTP1B和CDC25B的合理结合方式。我们的方法从天然丰富的原料(糖和氨基酸)和通过简便、区域选择性和快速的合成方法(微波辅助点击反应)实现，可能为‘点击’制备结构多样的PTP抑制剂提供新的见解。
There has been considerable interest in the development of protein tyrosine phosphatase (PTP) inhibitors since many of the PTP members are tightly associated with major human diseases including autoimmune disorders, diabetes and cancer. We report here a unique and rapid approach toward the development of novel PTP inhibitor entities based on triazolyl pseudo-glycopeptides. By employing microwave-accelerated Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC or ‘click reaction’), a series of triazole-linked serinyl, threoninyl, phenylalaninyl and tyrosinyl 1-O-gluco- or galactosides have been efficiently synthesized in high yields within only ∼30min. Successive biological assay identified these glycopeptidotriazoles as favorable PTP1B and CDC25B inhibitors with selectivity over TCPTP, LAR, SHP-1 and SHP-2. Both the structural diversity of the amino acid (Ser, Thr, Phe and Tyr) introduced and the epimeric identity (Glc or Gal) on monosaccharide scaffold were determined to impact the corresponding inhibitory activity and selectivity. In addition, the benzylated sugar scaffold was demonstrated to act as a crucial role for enhancing the binding affinity of the inhibitors with the targeted PTP. Docking simulation was eventually conducted to propose plausible binding modes of this compound series with PTP1B and CDC25B. Our approach readily realized from naturally abundant raw materials (sugar and amino acid) and via facile, regioselective and expeditious synthetic method (microwave-assisted click reaction) might provide new insights toward the ‘click’ fabrication of structurally diverse PTP inhibitors.