title: Exploring the DNA binding/cleavage, cellular accumulation and topoisomerase inhibition of 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone Mannich bases and their platinum(II) complexes.
abstract: Several chlorido and amino Pt(2+) complexes of 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone Mannich bases HL exhibiting moderate to high cytotoxicity against cancer cell lines were studied in order to investigate their modes of DNA binding, in vitro DNA strand breaks, mechanism of topoisomerase (Topo I) inhibition and cellular accumulation. DNA model base studies have shown that complex 1a [Pt(HL1)Cl(2)] was capable of binding covalently to 9-ethylguanine (9-EtG) and 5'-GMP. (1)H NMR and mass spectrometry studies have shown that both chlorides were substituted by 9-EtG ligands, whereas 5'-GMP was able to replace only one chlorido ligand, due to steric hindrance. The chlorido Pt(2+) complexes [Pt(HL)Cl(2)] highly accumulate in prostate (PC-3) and melanoma (MDA-MB-435) cell lines, being able to induce DNA strand breaks in vitro and inhibit Topo I by a catalytic mode. On the other hand, the free 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinones HL and the amino Pt(2+) complexes [Pt(L(-))(NH(3))(2)]NO(3) neither cause DNA strand breakage nor exhibit strong DNA interaction, nevertheless the latter were also found to be catalytic inhibitors of Topo I at 100μM. Thus, coordination of the Mannich bases HL to the "PtCl(2)" fragment substantially affects the chemical and biophysical properties of the pro-ligands, leading to an improvement of their DNA binding properties and generating compounds that cleave DNA and catalytically inhibit Topo I. Finally, the high cytotoxicity exhibited by the free (uncomplexed) 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinones might be associated with their decomposition in solution, which is not observed for the Pt(2+) complexes.
authors.affiliation: Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284, USA.
authors.forename: Amanda P
authors.initials: AP
authors.lastname: Neves
authors.forename: Michelle X G
authors.initials: MX
authors.lastname: Pereira
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Peterson
authors.forename: Ralph
authors.initials: R
authors.lastname: Kipping
authors.forename: Maria D
authors.initials: MD
authors.lastname: Vargas
authors.forename: Floriano P
authors.initials: FP
authors.lastname: Silva
authors.forename: J Walkimar M
authors.initials: JW
authors.lastname: Carneiro
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Farrell
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D001692:Biological Transport; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry*; D053837:DNA Cleavage / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry*; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry; D006157:Guanosine Monophosphate / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008352:Mannich Bases / Q000737:chemistry*; D015394:Molecular Structure; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000494:pharmacology*; D010984:Platinum / Q000737:chemistry*; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D008352:Mannich Bases; D009285:Naphthoquinones; D059004:Topoisomerase I Inhibitors; D010984:Platinum; D006147:Guanine; D006157:Guanosine Monophosphate; C014542:9-ethylguanine; D004247:DNA; D004264:DNA Topoisomerases, Type I