设计并评估了一系列含硫四环化合物抑制蛋白激酶 DYRK1A 的能力，该靶标已知具有多种潜在的治疗应用，包括癌症、唐氏综合症或阿尔茨海默病。我们的药物化学策略依赖于使用环收缩/等排替换和已知 DYRK1A 抑制剂的约束类比来设计新化合物，从而增强其 DYRK1A 抑制活性。虽然观察到靶向 DYRK1A 蛋白对 5-羟基化合物 4i-k (IC50 = 35-116 nM) 和 5-甲氧基衍生物 4e (IC50 = 52 nM) 具有良好的抑制作用，但对其已知的 DYRK1B 具有相当好的选择性- 观察到目标为 4k。此外，最活跃的化合物 4k 具有 ATP 竞争性作用机制，被证明也是 CLK1/CLK4 的有效抑制剂（IC50 = 20 和 26 nM），并且在较小程度上也是 haspin 的有效抑制剂（IC50 = 76 nM) 激酶。在 DYRK1A、CLK1/CLK4 和 haspin ATP 结合位点内进行了计算机对接研究，以了解我们的四环衍生物 4 与这些靶标的相互作用。最有效的化合物 4k 对 U87/U373 胶质母细胞瘤细胞系的抗增殖活性显示出中等效果（IC50 值在 33 至 46 μM 之间）。还研究了设计的化合物 4a-m 的微粒体稳定性，显示出很大的差异，具体取决于苯并[b]噻吩环 5-取代。该期刊版权所有 © 英国皇家化学学会。

A series of sulfur-containing tetracycles was designed and evaluated for their ability to inhibit protein kinase DYRK1A, a target known to have several potential therapeutic applications including cancers, Down syndrome or Alzheimer's disease. Our medicinal chemistry strategy relied on the design of new compounds using ring contraction/isosteric replacement and constrained analogy of known DYRK1A inhibitors, thus resulting in their DYRK1A inhibitory activity enhancement. Whereas a good inhibitory effect of targeted DYRK1A protein was observed for 5-hydroxy compounds 4i-k (IC50 = 35-116 nM) and the 5-methoxy derivative 4e (IC50 = 52 nM), a fairly good selectivity towards its known DYRK1B off-target was observed for 4k. In addition, the most active compound 4k, having an ATP-competitive mechanism of action, proved to be also a potent inhibitor of CLK1/CLK4 (IC50 = 20 and 26 nM) and, to a lesser extent, of haspin (IC50 = 76 nM) kinases. In silico docking studies within the DYRK1A, CLK1/CLK4 and haspin ATP binding sites were carried out to understand the interactions of our tetracyclic derivatives 4 with these targets. Antiproliferative activities on U87/U373 glioblastoma cell lines of the most potent compound 4k showed a moderate effect (IC50 values between 33 and 46 μM). Microsomal stabilities of the designed compounds 4a-m were also investigated, showing great disparities, depending on benzo[b]thiophene ring 5-substitution.This journal is © The Royal Society of Chemistry.