Accueil > Publications > Recherche par années > Années 2010 > 2012

Neagoie, C., Vedrenne, E., Buron, F., Mérour, J.Y., Rosca, S., Bourg, S., Lozach, O., Meijer, L., Baldeyrou, B., Lansiaux, A. and Routier, S.

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

European Journal of Medicinal Chemistry 49 379-396

par Frapart - publié le , mis à jour le

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.