Synthesis of chromeno[3,4-b]indoles as Lamellarin D analogues: a novel DYRK1A inhibitor class.
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.
Institut de Chimie Organique et Analytique, Université d'Orléans, Orléans, France.
Cleopatra
C
Neagoie
Emeline
E
Vedrenne
Frédéric
F
Buron
Jean-Yves
JY
Mérour
Sorin
S
Rosca
Stéphane
S
Bourg
Olivier
O
Lozach
Laurent
L
Meijer
Brigitte
B
Baldeyrou
Amelie
A
Lansiaux
Sylvain
S
Routier
D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000097603:Dyrk Kinases
D003374:Coumarins; D004264:DNA Topoisomerases, Type I; D006576:Heterocyclic Compounds, 4 or More Rings; D007211:Indoles; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D059004:Topoisomerase I Inhibitors; D000097603:Dyrk Kinases; C455554:lamellarin D