Histone deacetylases inhibition and tumor cells cytotoxicity by CNS-active VPA constitutional isomers and derivatives

The tumor cells toxicity of the antiepileptic drug valproic acid (VPA) has been associated with the inhibition of histone deacetylases (HDACs). We have assessed, in comparison to VIA, the HDACs inhibition and tumor cells cytotoxicities of CNS-active VPA`s constitutional isomers, valnoctic acid (VCA), propylisopropylacetic acid (PIA), diisopropylacetic acid (DIA), VPA's cyclopropyl analogue 2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMCA) and VPA's metabolites, 2-ene-VPA and 4-ene-VPA, all possessing, as does VIA, eight carbon atoms in their structures. The aim was to define structural components of the VPA molecule that are involved in HDACs inhibition and tumor cells cytotoxicity. HDACs inhibition by the above-mentioned compounds was estimated using an acetylated lysine substrate and HeLa nuclear extract as a HDACs source. SW620 cells were used for assessing HDACs inhibition in vivo. The cytotoxicity of these compounds was assessed in SW620 and 1106mel cells. HDAC inhibition potency was the highest for VIA and 4-ene-VPA (IC50 = 1.5 mM each). 2-Ene-VPA inhibited HDACs with IC50 = 2.8 mM. IC50 values of the other tested compounds for HDACs inhibition were higher than 5 mM, 4-ene-VPA and VIA induced histone hyperacetylation in SW620 cells. 4-Ene-VPA and VIA at 2 mM each were also most potent in reducing cell viability, to 59 2.0% and 67.3 +/- 5.4%, respectively, compared to control. VCA, PIA, DIA, TMCA, 2-ene-VPA and valpromide (VPD) did not reduce viability to less than 80%. All tested compounds did not significantly affect the cell cycle of SW620 cells. In conclusion, in comparison to the VIA derivatives and constitutional isomers tested in this study, VIA had the optimal chemical structure in terms of HDACs inhibition and tumor cells cytotoxicity. (c) 2005 Elsevier Inc. All rights reserved.