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

Sara Eyal, Boris Yagen, Jakob Shimshoni, Meir Bialer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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 VPA, 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 VPA, 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 VPA 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 VPA induced histone hyperacetylation in SW620 cells. 4-Ene-VPA and VPA 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 VPA derivatives and constitutional isomers tested in this study, VPA had the optimal chemical structure in terms of HDACs inhibition and tumor cells cytotoxicity.

Original languageAmerican English
Pages (from-to)1501-1508
Number of pages8
JournalBiochemical Pharmacology
Issue number10
StatePublished - 15 May 2005


  • Anticancer drugs
  • Antiepileptic drugs
  • Histone deacetylase
  • Valproic acid
  • Valproic acid constitutional isomers


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