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

Cleopatra Neagoie; Emeline Vedrenne; Frédéric Buron; Jean-Yves Mérour; Sorin Rosca; Stéphane Bourg; Olivier Lozach; Laurent Meijer; Brigitte Baldeyrou; Amelie Lansiaux; Sylvain Routier

doi:10.1016/j.ejmech.2012.01.040

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

Eur J Med Chem. 2012 Mar:49:379-96. doi: 10.1016/j.ejmech.2012.01.040. Epub 2012 Jan 25.

Authors

Cleopatra Neagoie¹, Emeline Vedrenne, Frédéric Buron, Jean-Yves Mérour, Sorin Rosca, Stéphane Bourg, Olivier Lozach, Laurent Meijer, Brigitte Baldeyrou, Amelie Lansiaux, Sylvain Routier

Affiliation

¹ Institut de Chimie Organique et Analytique, Université d'Orléans, Orléans, France.

PMID: 22305342
DOI: 10.1016/j.ejmech.2012.01.040

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Coumarins / chemical synthesis
Coumarins / chemistry*
Coumarins / pharmacology*
DNA Topoisomerases, Type I / metabolism
Dyrk Kinases
Heterocyclic Compounds, 4 or More Rings / chemical synthesis
Heterocyclic Compounds, 4 or More Rings / chemistry*
Heterocyclic Compounds, 4 or More Rings / pharmacology*
Humans
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / pharmacology*
Isoquinolines / chemical synthesis
Isoquinolines / chemistry*
Isoquinolines / pharmacology*
Models, Molecular
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship
Topoisomerase I Inhibitors / chemical synthesis
Topoisomerase I Inhibitors / chemistry
Topoisomerase I Inhibitors / pharmacology

Substances

Coumarins
Heterocyclic Compounds, 4 or More Rings
Indoles
Isoquinolines
Protein Kinase Inhibitors
Topoisomerase I Inhibitors
lamellarin D
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases
DNA Topoisomerases, Type I