Synthesis, chemical characterization and biological activity of new histone acetylation/deacetylation specific inhibitors: A novel and potential approach to cancer therapy

•New triorganotin(IV)valproate complexes are reported.•A crystallographic report of one of the complexes is included.•Bu3Sn(IV)valproate inhibits selectively histone deacetylase in HepG2 cells.•Specific inhibition could be a base for a new cancer therapy approach.

Three new triorganotin(IV) complexes of valproic acid (vp1, Me3Sn-valproate; vp2, Bu3Sn-valproate; vp3, Ph3Sn-valproate) have been synthesized and investigated by spectroscopic and biological methods. An anionic, monodentate valproate ligand was observed, ester-like coordinating the tin atom on a tetra-coordinated, monomeric environment. The structures, though, can distort towards a penta-coordination, as a consequence of a long range O · · · Sn interaction. Crystallographic and NMR findings confirm this situation both in solid state and solution. Biological finding evidenced a clear cytotoxic action of the complexes in hepatocellular carcinoma cell cultures: one of the complexes induced an 80% cell viability reduction after 24 h treatment in HepG2 cells. This effect was accompanied by the appearance of biochemical signs of apoptosis. In Chang liver cells, the same compound induced only modest effects, suggesting a potential use as anti-cancer drug. Preliminary evaluations on hyperacetylation state of histone H3 in tributyltin-valproate treated HepG2 cells showed an increase in Ac-H3 (histone H3 acetylated at lys-9 and lys-14), suggesting that the compound maintains the deacetylation inhibition activity of its ligand valproate.

Graphical abstractNew organotin(IV)-valproate complexes show specific inhibition of histone deacetylase in hepatic tumor cellsFigure optionsDownload full-size imageDownload as PowerPoint slide