Synthesis of chromeno[3,4-b]indoles as Lamellarin D analogues : A novel DYRK1A inhibitor class
Synthesis of chromeno[3,4-b]indoles as Lamellarin D analogues : A novel DYRK1A inhibitor class
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DOI：
10.1016/j.ejmech.2012.01.040
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发表时间：
2012-03-01
影响因子：
6.7
通讯作者：
Routier, Sylvain
中科院分区：
文献类型：
--
作者：
Neagoie, Cleopatra;Vedrenne, Emeline;Routier, Sylvain
开发了取代的色烯并[3，4-B]吲哚的文库作为片螺素电子等排体。在涉及C-3碘化、Suzuki交叉偶联反应和一锅脱保护/内酯化步骤的四步途径序列之后，从吲哚实现合成。测试了20种最终化合物，以确定它们对拓扑异构酶I和激酶的活性，这是片螺素的两种主要生物活性。一种新合成的衍生物表现出与参比化合物如喜树碱和片孢菌素相当的强拓扑异构酶活性，仅具有弱的激酶抑制作用。另外两种先导化合物被确定为新的纳摩尔DYRK 1A抑制剂，其他几种药物在亚微摩尔范围内影响激酶。这些结果将使我们能够使用色烯并[3，4-B]吲哚作为药效团来开发用于DYRK 1A完全参与的神经或肿瘤疾病的有效治疗。(C)2012年Elsevier Masson SAS。All rights reserved.
A library of substituted chromeno[3,4-b]indoles was developed as Lamellarin isosters. Synthesis was achieved from indoles after a four-step pathway sequence involving C-3 iodination, a Suzuki cross-coupling reaction, and a one pot deprotection/lactonisation step. Twenty final compounds were tested in order to determine their activity against topoisomerase I and kinases, the two major biological activities of Lamellarins. One newly synthesized derivative exhibited a strong topoisomerase activity comparable to reference compounds such as campthotecin and Lamellarin with only a weak kinase inhibition. Two other lead compounds were identified as new nanomolar DYRK1A inhibitors and several other drugs affected the kinases in the sub-micromolar range. These results will enable us to use the chromeno[3,4-b]indole as a pharmacophore to develop potent treatments for neurological or oncological disorders in which DYRK1A is fully involved. (C) 2012 Elsevier Masson SAS. All rights reserved.