title: Synthesis, chemical characterization, computational studies and biological activity of new DNA methyltransferases (DNMTs) specific inhibitor. Epigenetic regulation as a new and potential approach to cancer therapy.
abstract: This work deals with the synthesis, the chemical characterization of dibutyltin(IV) complex of caffeic acid (Bu2Sn(IV)HCAF, caf1) and its cytotoxic action on tumor cells. The coordination environment at the tin center was investigated by FTIR, (119)Sn{(1)H} cross polarization magic angle spinning, electrospray ionization mass spectroscopy in the solid state and UV-vis, fluorescence and (1)H, (13)C and (119)Sn NMR spectroscopy in solution phases. Density functional theory study confirmed the proposed structures in solution phase and indicated the most probably stable conformation. The effects on viability of breast cancer MDA-MB231, colorectal cancer HCT116, hepatocellular carcinoma HepG2 and Chang liver cells, an immortalized non-tumor hepatic cell line, have been investigated. The effect of a variation in structure of caf1 was found to lead to a change in the respective antiproliferative properties: caf1 induces loss of viability in HCT116, MDA-MB-231, and HepG2; the complex shows only moderate effects in non-tumor Chang liver cells. caf1 exerts lower cytotoxic activity than Bu2SnCl2, suggesting that the binding with H3CAF modulates the marked cytotoxic activity exerted by Bu2SnCl2; caf1 displays a considerably more pronounced antitumoural effect towards cell lines than caffeic acid. It is known that caffeic acid can modulate DNA (cytosine-5)-methyltransferases 1 (DNMT1) mediated DNA methylation. In this paper we demonstrate that caf1 treatment was able to induce a time-dependent reduction of global DNA methylated status. This effect was also confirmed by a concomitant reduction DNMT1 expression level. The effect induced by caf1 was more evident not only with respect to untreated cells but also compared to H3CAF treated cells.
authors.affiliation: Dipartimento di Fisica e Chimica (DiFC), Università degli Studi di Palermo, Viale delle Scienze, Ed. 17-90128 Palermo, Italy; Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici (C.I.R.C.M.S.B.), Piazza Umberto I, 1-70121 Bari, Italy. Electronic address: claudia.pellerito@unipa.it.
authors.forename: C
authors.initials: C
authors.lastname: Pellerito
authors.affiliation: Dipartimento di Fisica e Chimica (DiFC), Università degli Studi di Palermo, Viale delle Scienze, Ed. 17-90128 Palermo, Italy.
authors.forename: O
authors.initials: O
authors.lastname: Morana
authors.affiliation: Dipartimento di Fisica e Chimica (DiFC), Università degli Studi di Palermo, Viale delle Scienze, Ed. 17-90128 Palermo, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ferrante
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Laboratorio di Biochimica, Policlinico Universitario, Via del Vespro, 129-90127 Palermo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Calvaruso
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Laboratorio di Biochimica, Policlinico Universitario, Via del Vespro, 129-90127 Palermo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Notaro
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Laboratorio di Biochimica, Policlinico Universitario, Via del Vespro, 129-90127 Palermo, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Sabella
authors.affiliation: Dipartimento di Fisica e Chimica (DiFC), Università degli Studi di Palermo, Viale delle Scienze, Ed. 17-90128 Palermo, Italy; Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici (C.I.R.C.M.S.B.), Piazza Umberto I, 1-70121 Bari, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Fiore
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002109:Caffeic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D019175:DNA Methylation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D008956:Models, Chemical; D009947:Organotin Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000970:Antineoplastic Agents; D002109:Caffeic Acids; D004791:Enzyme Inhibitors; D009947:Organotin Compounds; C000610398:dibutyl(caffeic acid)tin(IV); D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C040048:caffeic acid
keywords: Caffeic acid; Cancer; DNA methylation; DNMT1; Organotin(IV)