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ID: ALA1944600
Journal: Eur J Med Chem
Title: Synthesis of chromeno[3,4-b]indoles as Lamellarin D analogues: a novel DYRK1A inhibitor class.
Authors: Neagoie C, Vedrenne E, Buron F, Mérour JY, Rosca S, Bourg S, Lozach O, Meijer L, Baldeyrou B, Lansiaux A, Routier S.
Abstract: 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.
CiteXplore: 22305342