Institut de Chimie Organique et Analytique, Université d'Orléans, Orléans, France.
Eur J Med Chem. 2012 Mar;49:379-96. doi: 10.1016/j.ejmech.2012.01.040. Epub 2012 Jan 25.
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.
开发了一系列取代的色烯并[3,4-b]吲哚作为 Lamellarin 的类似物。该合成路线从吲哚开始，经过四步反应，包括 C-3 碘化、Suzuki 偶联反应和一锅脱保护/内酯化步骤。最后测试了 20 种终产物，以确定它们对拓扑异构酶 I 和激酶的活性，这是 Lamellarins 的两种主要生物学活性。一个新合成的衍生物表现出与参考化合物如 Camptothecin 和 Lamellarin 相当的强拓扑异构酶活性，只有弱的激酶抑制作用。另外两种先导化合物被鉴定为新的纳摩尔 DYRK1A 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，开发针对 DYRK1A 完全参与的神经或肿瘤疾病的有效治疗方法。
