Microwave-assisted construction of triazole-linked amino acid-glucoside conjugates as novel PTP1B inhibitors
Microwave-assisted construction of triazole-linked amino acid-glucoside conjugates as novel PTP1B inhibitors
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DOI：
10.1039/c0nj00835d
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发表时间：
2011-01-01
影响因子：
3.3
通讯作者：
Xie, Juan
中科院分区：
文献类型：
--
作者：
He, Xiao-Peng;Li, Cui;Xie, Juan
蛋白酪氨酸磷酸酶1B（PTP 1B）抑制剂用于治疗2型糖尿病、肥胖和乳腺癌的研究越来越受到关注。在这里，我们报告了一系列的单和双苯丙氨酸和酪氨酸葡萄糖苷衍生物作为新的PTP 1B抑制剂的鉴定。通过微波辅助Cu（I）催化的叠氮-炔环加成反应，在葡萄糖基支架的6-、2，3-、2，6-、3，4-和4，6-位上有效地构建了所设计的带有一个或两个苯丙氨酸或酪氨酸衍生物的化合物，产率中等至优异。连续的生物测定鉴定这些化合物作为新的PTP 1B抑制剂，与4，6-二取代的酪氨酸葡萄糖苷是最有效的。动力学研究表明，单和双三唑连接的糖基酸作为典型的竞争性抑制剂，而双三唑酯，也表现出抑制活性的PTP 1B显示混合型抑制模式。此外，对接模拟合理地提出了这些化合物与酶靶的多种结合模式。
There has been increasing interest in the development of protein tyrosine phosphatase 1B (PTP1B) inhibitors for the treatment of type 2 diabetes, obesity and breast cancer. We report here the identification of a series of mono-and bis-phenylalaninyl and tyrosinyl glucoside derivatives as novel PTP1B inhibitors. The designed compounds bearing one or two phenylalanine or tyrosine derivatives on the 6-, 2,3-, 2,6-, 3,4- and 4,6-positions of the glucosyl scaffolds were efficiently constructed via the microwave-assisted Cu(I)-catalyzed azide-alkyne cycloaddition in moderate-to-excellent yields. Successive biological assays identified these compounds as novel PTP1B inhibitors, with the 4,6-disubstituted tyrosinyl glucoside being the most potent. A kinetic study established that both mono-and bis-triazole-linked glycosyl acids act as typical competitive inhibitors whereas the bis-triazolyl ester that also exhibited inhibitory activity on PTP1B displayed a mixed-type inhibition pattern. Furthermore, docking simulation plausibly proposed the diverse binding modes of these compounds with the enzymatic target.