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

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.
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https://hal.archives-ouvertes.fr/hal-00726237
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Submitted on : Wednesday, August 29, 2012 - 2:18:04 PM
Last modification on : Friday, July 12, 2019 - 1:01:57 AM

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Cleopatra Neagoie, Emeline Vedrenne, Frédéric Buron, Jean-Yves Mérour, Sorin Rosca, et al.. Synthesis of chromeno[3,4-b]indoles as Lamellarin D analogues: a novel DYRK1A inhibitor class.. European Journal of Medicinal Chemistry, Elsevier, 2012, 49, pp.379-96. ⟨10.1016/j.ejmech.2012.01.040⟩. ⟨hal-00726237⟩

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