Synthesis and biological evaluation of new penta- and heptacyclic indolo- and quinolinocarbazole ring systems obtained via Pd(0) catalysed reductive N-heteroannulation.
A short route, involving a tetramolecular condensation reaction and a Pd/C catalyst-H(2)-mediated reductive N-heteroannulation as the key-steps, has been found for the synthesis of some new penta- and heptacyclic indolo- (12), quinolino- (13) and indoloquinolinocarbazole (11) derivatives. HF-DFT (B3LYP) energy profiles and NMR calculations were carried out to help in the understanding of the experimental results. N-Alkylated indoloquinolinocarbazoles (16b, 17a, 17b and 18) were prepared and screened essentially toward some cancer-(G-quadruplex, DNA, topoisomerase I) and CNS-related (kinases) targets. Biological results evidenced 13 as a potent CDK-5 and GSK-3β kinases inhibitor, while di- or triaminopropyl-substituted indoloquinolinocarbazoles 17b or 18 targeted rather DNA-duplex or telomeric G-quadruplex structures, respectively.
Laronze-Cochard
Marie
M
Université de Reims-Champagne-Ardenne, Institut de Chimie Moléculaire de Reims, CNRS UMR 6229, Groupe BSMA, UFR de Pharmacie, 51 rue Cognacq-Jay, F-51096 Reims, Cedex, France.
Cochard
Fabien
F
Daras
Etienne
E
Lansiaux
Amélie
A
Brassart
Bertrand
B
Vanquelef
Enguerran
E
Prost
Elise
E
Nuzillard
Jean-Marc
JM
Baldeyrou
Brigitte
B
Goosens
Jean-François
JF
Lozach
Olivier
O
Meijer
Laurent
L
Riou
Jean-François
JF
Henon
Eric
E
Sapi
Janos
J
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D045744:Cell Line, Tumor; D054856:G-Quadruplexes; D006801:Humans; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry; D010165:Palladium / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry*
D000970:Antineoplastic Agents; D002227:Carbazoles; D009942:Organometallic Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D010165:Palladium