title: Synthesis, chemical characterization and biological activity of new histone acetylation/deacetylation specific inhibitors: a novel and potential approach to cancer therapy.
abstract: 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 24h 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.
authors.affiliation: Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Sezione di Scienze Biochimiche, Policlinico Universitario, Via del Vespro, 129-90127 Palermo, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Pellerito
authors.forename: Cristina
authors.initials: C
authors.lastname: Prinzivalli
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Foresti
authors.forename: Piera
authors.initials: P
authors.lastname: Sabatino
authors.forename: Michele
authors.initials: M
authors.lastname: Abbate
authors.forename: Girolamo
authors.initials: G
authors.lastname: Casella
authors.forename: Tiziana
authors.initials: T
authors.lastname: Fiore
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Scopelliti
authors.forename: Claudia
authors.initials: C
authors.lastname: Pellerito
authors.forename: Michela
authors.initials: M
authors.lastname: Giuliano
authors.forename: Giulia
authors.initials: G
authors.lastname: Grasso
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Pellerito
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival; D002478:Cells, Cultured; D056945:Hep G2 Cells; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009947:Organotin Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D009947:Organotin Compounds; D014635:Valproic Acid