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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Design, synthesis and biological evaluation of indole-2-carboxylic acid derivatives as IDO1/TDO dual inhibitors
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Design, synthesis and biological evaluation of indole-2-carboxylic acid derivatives as IDO1/TDO dual inhibitors

机译：吲哚-2-羧酸衍生物作为IDO1 / TDO双抑制剂的设计，合成和生物学评价

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摘要

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are involved in the key steps of tryptophan metabolism and are potential new targets for tumor immunotherapy. In this work, a variety of indole-2-carboxylic acid derivatives were synthesized, and their inhibitory activities against both enzymes along with structure-activity relationships were investigated. As a result, a number of 6-acetamido-indole-2-carboxylic acid derivatives were found to be potent dual inhibitors with IC50 values at low micromolar levels. Among them, compound 90-1 was the most potent inhibitor with an IC50 value of 1.17 mu M for IDO1, and 1.55 mu M for TDO, respectively. In addition, a para-benzoquinone derivative 9p-O, resulted from the oxidation of compound 9p, was also identified and it showed strong inhibition against the two enzymes with IC50 values at the double digit nanomolar level. Using molecular docking and molecular dynamic simulations, we predicted the binding modes of this class of compounds within IDO1 and TDO binding pocket. The results provide insights for further structural optimization of this series of IDO1/TDO dual inhibitors. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：吲哚胺2,3-二氧化根酶1（IDO1）和色氨酸2,3-二氧化根酶（TDO）参与色氨酸代谢的关键步骤，是肿瘤免疫疗法的潜在新靶标。在这项工作中，合成了各种吲哚-2-羧酸衍生物，研究了它们对两种酶以及结构活性关系的抑制作用。结果，发现许多6-乙酰氨基吲哚-2-羧酸衍生物是具有低微摩尔水平的IC 50值的有效的双抑制剂。其中，化合物90-1是最有效的抑制剂，IC50值为IC50值为1.17 mu m，分别为1.55μm的TDO。此外，还鉴定了由化合物9p的氧化产生的对苯并醌衍生物9p-o，并且它表现出对两位数纳米摩尔水平的IC 50值对两种酶的强烈抑制。使用分子对接和分子动态模拟，我们预测了IDO1和TDO结合口袋内这类化合物的结合模式。结果为该系列IDO1 / TDO双抑制剂的进一步结构优化提供了见解。 （c）2019年Elsevier Masson SAS。版权所有。

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