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

dc.creatorNeves, Amanda P.
dc.creatorPereira, Michelle X. G.
dc.creatorPeterson, Erica J.
dc.creatorKipping, Ralph
dc.creatorVargas, Maria D.
dc.creatorSilva Jr., Floriano P.
dc.creatorFarrell, Nicholas P.
dc.date2016-01-01T14:23:16Z
dc.date2016-01-01T14:23:16Z
dc.date2013
dc.date.accessioned2023-09-26T21:11:43Z
dc.date.available2023-09-26T21:11:43Z
dc.identifierNEVES, Amanda P.; et al. 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. Journal of Inorganic Biochemistry, v.119, p.54–64, Feb. 2013.
dc.identifier0162-0134
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/12470
dc.identifier10.1016/j.jinorgbio.2012.10.007
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8870639
dc.descriptionSeveral chlorido and amino Pt2+ 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 theirmodes of DNA binding, in vitro DNA strand breaks, mechanismof topoisomerase (Topo I) inhibition and cellular accumulation. DNA model base studies have shown that complex 1a [Pt(HL1)Cl2] was capable of binding covalently to 9-ethylguanine (9-EtG) and 5′-GMP. 1H 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 Pt2+ complexes [Pt(HL)Cl2] 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 Pt2+ complexes [Pt(L−)(NH3)2]NO3 neither cause DNA strand breakage nor exhibit strongDNA interaction, nevertheless the latter were also found to be catalytic inhibitors of Topo I at 100 μM. Thus, coordination of the Mannich bases HL to the “PtCl2” 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 Pt2+ complexes.
dc.formatapplication/pdf
dc.languageeng
dc.publisherElsevier
dc.rightsrestricted access
dc.subjectNaphthoquinone
dc.subjectPt2+ complexes
dc.subjectDNA binding
dc.subjectDNA strand breaks
dc.titleExploring the DNA binding/cleavage, cellular accumulation and topoisomerase inhibition of 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone Mannich bases and their platinum(II) complexes
dc.typeArticle


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