- Synthesis of chromeno[3,4-b]indoles as Lamellarin D analogues: A novel DYRK1A inhibitor class
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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.
- Neagoie, Cleopatra,Vedrenne, Emeline,Buron, Frédéric,Mérour, Jean-Yves,Rosca, Sorin,Bourg, Stéphane,Lozach, Olivier,Meijer, Laurent,Baldeyrou, Brigitte,Lansiaux, Amelie,Routier, Sylvain
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p. 379 - 396
(2012/04/10)
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