Synthesis and biological evaluation of novel oxophenylarcyriaflavins as potential anticancer agents.
We report the synthesis and biological evaluation of new oxophenylarcyriaflavins designed as potential anticancer agents. An efficient synthesis involving palladium-catalyzed Suzuki and Stille reactions is presented, without any indolic protective group. The central ring closure of the scaffold was performed through an electrophilic reaction on the position C-2 of the indole ring. The use of indole and 5-benzyloxyindole, along with substituted phenyl rings, generated three different scaffolds, which were successively exploited to modulate the structure. The cytotoxicity of the newly designed compounds on four cancer cell lines and activities against three kinases (CDK1, CDK5 and GSK3) were evaluated. Several compounds showed a marked cytotoxicity with IC(50) values in the sub-micromolar range, and induced important cell cycle perturbations, with a G2/M arrest. Some compounds revealed DNA binding properties and were found to inhibit topoisomerase-mediated DNA relaxation of supercoiled DNA, but these properties are not mandatory for a cytotoxic action. A novel lead compound () has been identified and warrants further investigations.
Bourderioux
Aurélie
A
Institut de Chimie Organique et Analytique, Université d'Orléans, CNRS UMR 6005, Rue de Chartres, BP 6759, 45067, Orléans Cedex 2, France.
Bénéteau
Valérie
V
Mérour
Jean-Yves
JY
Baldeyrou
Brigitte
B
Ballot
Caroline
C
Lansiaux
Amélie
A
Bailly
Christian
C
Le Guével
Rémy
R
Guillouzo
Christiane
C
Routier
Sylvain
S
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002384:Catalysis; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005415:Flavins / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010165:Palladium / Q000737:chemistry
D000970:Antineoplastic Agents; D005415:Flavins; D010165:Palladium