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.

New organotin(IV)-valproate complexes show specific inhibition of histone deacetylase in hepatic tumor cellsFigure optionsDownload as PowerPoint slide