Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 49, Issue -, Pages 379-396Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2012.01.040
Keywords
Lamellarin; Indoles; Kinase; DYRK1A; Topoisomerase inhibition
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Funding
- Ligue Nationale contre le Cancer (Comites du Nord, du Centre et du Grand Quest)
- Canceropole Grand Quest (strand Valorisation des produits de la met)
- Hubert Curien Brancusi program
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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. (C) 2012 Elsevier Masson SAS. All rights reserved.
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