title: Thiols oxidation and covalent binding of BSA by cyclolignanic quinones are enhanced by the magnesium cation.
abstract: A novel cyclolignanic quinone, 7-acetyl-3',4'-didemethoxy-3',4'-dioxopodophyllotoxin (CLQ), inhibits topoisomerase II (TOPO II) activity. The extent of this inhibition was greater than that produced by the etoposide quinone (EQ) or etoposide. Glutathione (GSH) reduces EQ and CLQ to their corresponding semiquinones under anaerobic conditions. The latter were detected by EPR spectroscopy in the presence of MgCl(2) but not in its absence. Semiquinone EPR spectra change with quinone/GSH mol ratio, suggesting covalent binding of GSH to the quinones. Quinone-GSH covalent adducts were isolated and identified by ESI-MS. These orthoquinones also react with nucleophilic groups from BSA to bind covalently under anaerobic conditions. BSA thiol consumption and covalent binding by these quinones are enhanced by MgCl(2). Complex formation between the parent quinones and Mg(+2) was also observed. Density functional calculations predict the observed blue-shifts in the absorption spectra peaks and large decreases in the partial negative charge of electrophilic carbons at the quinone ring when the quinones are complexed to Mg(+2). These observations suggest a possible role of Mg(+2) chelation by these quinones in increasing TOPO II thiol and/or amino/imino reactivity with these orthoquinones.
authors.affiliation: Department of Chemistry, University of Puerto Rico-Humacao, Humacao, Puerto Rico 00791, USA. ae_alegria@uprh.edu
authors.forename: Antonio E
authors.initials: AE
authors.lastname: Alegria
authors.forename: Pedro
authors.initials: P
authors.lastname: Sanchez-Cruz
authors.forename: Ajay
authors.initials: A
authors.lastname: Kumar
authors.forename: Carmelo
authors.initials: C
authors.lastname: Garcia
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Gonzalez
authors.forename: Aimee
authors.initials: A
authors.lastname: Orellano
authors.forename: Beatriz
authors.initials: B
authors.lastname: Zayas
authors.forename: Marina
authors.initials: M
authors.lastname: Gordaliza
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry; D002413:Cations, Divalent; D002614:Chelating Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D005047:Etoposide / Q000031:analogs & derivatives / Q000737:chemistry; D005978:Glutathione / Q000737:chemistry; D015636:Magnesium Chloride / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011809:Quinones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D012710:Serum Albumin, Bovine / Q000737:chemistry* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000378:metabolism; D059005:Topoisomerase II Inhibitors
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D002413:Cations, Divalent; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D011809:Quinones; D013438:Sulfhydryl Compounds; D059005:Topoisomerase II Inhibitors; D015636:Magnesium Chloride; D012710:Serum Albumin, Bovine; C025232:semiquinone radicals; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; D005978:Glutathione; D011034:Podophyllotoxin