Synthesis, activity and molecular modeling of a new series of chromones as low molecular weight protein tyrosine phosphatase inhibitors
Synthesis, activity and molecular modeling of a new series of chromones as low molecular weight protein tyrosine phosphatase inhibitors
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DOI：
10.1016/j.bmc.2009.02.060
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发表时间：
2009-04-01
影响因子：
3.5
通讯作者：
Costantino, Luca
中科院分区：
文献类型：
--
作者：
Forghieri, Marco;Laggner, Christian;Costantino, Luca
蛋白酪氨酸磷酸酶（PTP）是真核生物信号转导的重要组成部分。一些报道表明LMW-PTP家族具有致癌相关性。此外，LMW-PTP已被认为是胰岛素介导的有丝分裂和代谢信号的负调节因子。因此，抑制LMW-PTP可以被认为是设计治疗II型糖尿病的新药物和新的抗肿瘤药物的一个有吸引力的方法。迄今为止，已经确定的LMW-PTP抑制剂非常少（和弱）。在已有报道的一些类黄酮对磷酸酶活性较弱的基础上，我们发现了一类新的高活性LMW-PTP抑制剂；这些化合物也抑制PTP-1B，并在细胞检测中具有活性。对接实验和SAR突出了这些化合物与酶的可能结合模式，为未来优化它们对密切相关的酶PTP-1B的抑制活性和选择性提供了背景。(c) 2009 Elsevier Ltd.版权所有。
Protein tyrosine phosphatases (PTP) are crucial elements in eukaryotic signal transduction. Several reports suggested that the LMW-PTP family has oncogenic relevance. Moreover, LMW-PTP has been recognized as a negative regulator of insulin-mediated mitotic and metabolic signaling. Thus, inhibition of the LMW-PTP can be considered an attractive approach for the design of new therapeutic agents for the treatment of type II diabetes and for new antitumoral drugs. To date very few (and weak) inhibitors of LMW-PTP have been identified. On the basis of the reported weak activity of some flavonoids on phosphatases, we discovered a lead that originated a new class of highly active LMW-PTP inhibitors; these compounds inhibit also PTP-1B and are active in cellular assays. Docking experiments and SAR highlighted the possible binding mode of these compounds to the enzyme, putting the background for the future optimization of their inhibitory activity and selectivity towards the closely related enzyme PTP-1B. (c) 2009 Elsevier Ltd. All rights reserved.