Valérie Bénéteau

Synthesis and biological evaluation of new 3-(6-hydroxyindol-2-yl)-5-(Phenyl) pyridine or pyrazine V-Shaped molecules as kinase inhibitors and cytotoxic agents

We here report the synthesis and biological evaluation of new 3-[(2-indolyl)]-5-phenyl-3,5-pyridine, 3-[(2-indolyl)]-5-phenyl-2,4-pyridine and 3-[(2-indolyl)]-5-phenyl-2,6-pyrazine derivatives designed as potential CDK inhibitors. Indoles and phenyls were used to generate several substitutions of the pyridine and pyrazine rings. The synthesis included Stille or Suzuki type reactions, which were carried out on the 3,5-dibromopyridine, 2,4-dichloropyridine and 2,6-dichloro-1-4-pyrazine moieties. Cell effects of the V-shaped family were in the micromolar range. Kinase assays were conducted and showed that compound 11 inhibited CDK5 with an inhibitory concentration of 160 nM with a moderate selectivity over GSK3 compared to the reference C which exhibited a slightly lower activity on CDK5 (1.5 μM). Compound 11 was also found to be the most potent compound in the series and was identified as a new lead for DYRK1A inhibitor discovery (IC(50) = 60 nM). Docking studies were carried out in order to investigate the inhibition of DYRK1A.

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.

Comparison of the efficiencies of two TR-FRET methods to detect in vitro natural and synthesized inhibitors of the Raf/MEK/ERK signaling pathway

Numerous types of cancer operate through the deregulation of the Raf/MEK/ERK pathway. It is therefore of importance to design and synthesize inhibitors of this pathway. Consequently, we have developed several tests to measure in vitro the effect of inhibitors on the activity of the complete cascade Raf-1/MEK/ERK and also on the activities of Raf-1, MEK, and ERK individually. We present here the results obtained with two time-resolved fluorescence resonance energy transfer (TR-FRET) methods by comparison with a classical radioactivity method and experimental data found in literature. The capability of a series of optimized assays to detect different types of inhibitors is evaluated and discussed. Keywords: Raf/MEK/ERK cascade, inhibitors of Raf-1, MEK, and ERK, PEBP/RKIP, phosphocellulose filter binding assay, time-resolved fluorescence resonance energy transfer