Synthesis of chromeno[3,4-b]indoles as Lamellarin D analogues : A novel DYRK1A inhibitor class

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.

Herein, the synthesis and biological evaluation of some new chromeno[3,4-b] derivatives are described.Figure optionsDownload as PowerPoint slideHighlights
► A library of chromeno[3,4-b]indoles was prepared.
► A Suzuki/deprotection/lactonisation sequence was used.
► Nanomolar DYRK1A inhibitors were found.
► A compound inhibit the topoisomerase I.
► Docking studies explained the results