Structure-Based Design and Synthesis of Harmine Derivatives with Different Selectivity Profiles in Kinase versus Monoamine Oxidase Inhibition
Structure-Based Design and Synthesis of Harmine Derivatives with Different Selectivity Profiles in Kinase versus Monoamine Oxidase Inhibition
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DOI：
10.1002/cmdc.201600539
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发表时间：
2017-06-21
期刊：
影响因子：
3.4
通讯作者：
Kotschy, Andras
中科院分区：
文献类型：
--
作者：
Balint, Balazs;Weber, Csaba;Kotschy, Andras
双特异性酪氨酸磷酸化调节激酶1A （DYRK1A）是一种新兴的生物学靶点，在神经系统疾病（特别是唐氏综合征）、代谢和肿瘤等多种治疗领域具有重要意义。Harmine是一种在激酶中选择性抑制DYRK1A的天然产物，可以作为一种工具化合物，更好地了解DYRK1A抑制产生的生物过程。另一方面，毒芹碱也是单胺氧化酶a （MAO-A）的有效抑制剂。采用基于结构的设计，我们合成了一组对这两种酶具有可调选择性的有害生物碱类似物。7号位置的修饰通常会降低对DYRK1A的亲和力，而9号位置的取代对MAO-A的抑制作用相似，但对DYRK1A的抑制作用保持不变。由此收集的化合物可以帮助了解DYRK1A的生物学作用，也可以评估MAO-A抑制对生物效应的干扰。
Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is an emerging biological target with implications in diverse therapeutic areas such as neurological disorders (Down syndrome, in particular), metabolism, and oncology. Harmine, a natural product that selectively inhibits DYRK1A amongst kinases, could serve as a tool compound to better understand the biological processes that arise from DYRK1A inhibition. On the other hand, harmine is also a potent inhibitor of monoamine oxidase A (MAO-A). Using structure-based design, we synthesized a collection of harmine analogues with tunable selectivity toward these two enzymes. Modifications at the 7-position typically decreased affinity for DYRK1A, whereas substitution at the 9-position had a similar effect on MAO-A inhibition but DYRK1A inhibition was maintained. The resulting collection of compounds can help to understand the biological role of DYRK1A and also to assess the interference in the biological effect originating in MAO-A inhibition.