title: 2-Bromo-1,4-naphthoquinone: a potentially improved substitute of menadione in Apatone™ therapy.
abstract: Apatone™, a combination of menadione (2-methyl-1,4-naphthoquinone, VK3) and ascorbic acid (vitamin C, VC) is a new strategy for cancer treatment. Part of its effect on tumor cells is related to the cellular pro-oxidative imbalance provoked by the generation of hydrogen peroxide (H2O2) through naphthoquinone redox cycling. In this study, we attempted to find new naphthoquinone derivatives that would increase the efficiency of H2O2 production, thereby potentially increasing its efficacy for cancer treatment. The presence of an electron-withdrawing group in the naphthoquinone moiety had a direct effect on the efficiency of H2O2 production. The compound 2-bromo-1,4-naphthoquinone (BrQ), in which the bromine atom substituted the methyl group in VK3, was approximately 10- and 19-fold more efficient than VK3 in terms of oxygen consumption and H2O2 production, respectively. The ratio [H2O2]produced / [naphthoquinone]consumed was 68 ± 11 and 5.8 ± 0.2 (µM/µM) for BrQ and VK3, respectively, indicating a higher efficacy of BrQ as a catalyst for the autoxidation of ascorbic acid. Both VK3 and BrQ reacted with glutathione (GSH), but BrQ was the more effective substrate. Part of GSH was incorporated into the naphthoquinone, producing a nucleophilic substitution product (Q-SG). The depletion of BrQ by GSH did not prevent its redox capacity since Q-SG was also able to catalyze the production of reactive oxygen species. VK3/VC has already been submitted to clinical trials for the treatment of prostate cancer and has demonstrated promising results. However, replacement of VK3 with BrQ will open new lines of investigation regarding this approach to cancer treatment.
authors.affiliation: Departamento de Química, Universidade Estadual Paulista, Bauru, SP, Brasil.
authors.forename: F S
authors.initials: FS
authors.lastname: Graciani
authors.forename: V F
authors.initials: VF
authors.lastname: Ximenes
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000737:chemistry / Q000494:pharmacology*; D004338:Drug Combinations; D057915:Drug Substitution; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D017382:Reactive Oxygen Species; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects; D024483:Vitamin K 3 / Q000737:chemistry / Q000494:pharmacology
chemical_list: C529217:2-bromo-1,4-naphthoquinone; D000970:Antineoplastic Agents; D004338:Drug Combinations; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D024483:Vitamin K 3; D006861:Hydrogen Peroxide; D001205:Ascorbic Acid