Nitrobenzimidazoles as Substrates for DT-Diaphorase and Redox Cycling Compounds: Their Enzymatic Reactions and Cytotoxicity

Šarlauskas, Jonas; Dičkancait≐, Egl≐; Nemeikait, Auŝra; Anusevičius, Žilvinas; Nivinskas, Henrikas; Segura‐Aguilar, Juan; Č≐nas, Narimantas

doi:10.1006/abbi.1997.0285

Cited by 49 publications

(42 citation statements)

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“…However, in the presence of air, redox cycling occurs, whereby the nitroarene compound is recovered with the concomitant production of reactive oxygen species (Tocher et al, 1989, Krainev et al, 1998, Sarlauskas et al, 1997. Although the possibility exists that redox cycling by nitroarenes generates cytotoxic effects, the greatest cytotoxicity is usually observed under hypoxic or anaerobic conditions (Wardman, 2001).…”

Section: Discussionmentioning

confidence: 99%

Comparison of the nucleic acid covalent binding capacity of two nitro-substituted benzazolo[3,2-a]quinolinium salts upon enzymatic reduction

Zayas

Beyley

Terrón

et al. 2007

Toxicology in Vitro

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The DNA binding capacity of two nitro-substituted benzazolo[3,2-a]quinolinium chlorides (NBQs), NBQ-38 and NBQ-95, was evaluated upon their enzymatic reduction with hypoxanthine (HX)/ xanthine oxidase (XO) under anaerobic conditions. In the presence of 2'-deoxyguanosine (2'-dG) or calf thymus DNA, covalent-addition products were monitored. Reactions of each NBQ with 2'-dG or DNA differed in the NBQ to HX molar ratio. Control reactions, one without HX/OX and another under aerobic conditions, were also analyzed. Adducts were isolated and characterized by high performance liquid chromatography (HPLC) and electrospray ionization-mass spectrometry (ESI-MS). Authentic samples of the reduced forms of these NBQs, identified as ABQ-38 and ABQ-95, were synthesized as standards to monitor bioreduction processes. HPLC analysis showed that the yield of formation of an unknown product (possibly, 2'-dG-NHBQ-38 adduct) from the reaction of NBQ-38 with 2'-dG and DNA was proportional to the HX to NBQ-38 molar ratio. ESI-MS analysis of the DNA hydrolysates showed evidence of an adduct formed upon bioreduction of NBQ-38 by the ions detection at m/z 528.3 and 454.8, consistent with chemical structures of a 2'-dG-NHBQ-38 adduct and a fragment ion. DNA adducts were not observed with NBQ-95, although the corresponding bioreduction product ABQ-95 was detected by ESI-MS. This study provides mechanistic information of these bioreductively-activated pro-drugs with potential therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Comparison of the nucleic acid covalent binding capacity of two nitro-substituted benzazolo[3,2-a]quinolinium salts upon enzymatic reduction

Zayas

Beyley

Terrón

et al. 2007

Toxicology in Vitro

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“…Each of these active sites is composed of residues from both polypeptide chains [77]. The enzyme catalyses the NADH or NADPH-dependent reduction of a variety of organic compounds, including quinones [78][79][80][81][82]. Its cellular role is not wholly clear, but it seems likely that NQO1 participates in the detoxification of xenobiotic compounds and also in the cycling of quinones in the cell [75].…”

Section: Dicoumarol Also Inhibits Nqo1mentioning

confidence: 99%

Dicoumarol: A Drug which Hits at Least Two Very Different Targets in Vitamin K Metabolism

Timson

2017

CDT

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Dicoumarol, a symmetrical biscoumarin can be considered as the "parent" of the widely used anticoagulant drug, warfarin. The discovery of dicoumarol's bioactive properties resulted from an investigation into a mysterious cattle disease in the 1940s. It was then developed as a pharmaceutical, but was superseded in the 1950s by warfarin. Both dicoumarol and warfarin antagonise the blood clotting process through inhibition of vitamin K epoxide reductase (VKOR). This blocks the recycling of vitamin K and prevents the γ-carboxylation of glutamate residues in clotting factors.VKOR is an integral membrane protein and our understanding of the molecular mechanism of action of dicoumarol and warfarin is hampered by the lack of a three dimensional structure. There is consequent controversy about the membrane topology of VKOR, the location of the binding site for coumarin inhibitors and the mechanism of inhibition by these compounds. Dicoumarol (and warfarin) also inhibit a second enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1). This soluble, cytoplasmic enzyme may also play a minor role in the recycling of vitamin K. However, its main cellular roles as an enzyme appear to be detoxification and the prevention of the build-up of reactive oxygen species. NQO1 is well characterised biochemically and structurally. Consequently, structurebased drug design has identified NQO1 inhibitors which have potential for the development of anticancer drugs. Many of these compounds are structurally related to dicoumarol and some have reduced "off target" effects. Therefore, it is possible that dicoumarol will become the "parent" of a second group of drugs.

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“…In addition, benzimidazoles have been found to be antiallergic, antihistaminic, antidepressant, anesthetic, and antihypertensive [10][11][12]. Nitrobenzimidazoles can generate oxidative stress in vivo in rat [13]. Oxidative stress may occur when oxidant-antioxidant balance breaks down, and/or antioxidant potential is decreased [14].…”

Section: Introductionmentioning

confidence: 99%

Investigation of Oxidative Status of the 2-Furan-2-yl-1H-Benzimidazole in Rats

Karataş

Servi

Kara

et al. 2008

Biol Trace Elem Res

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We investigated the influence of 2-furan-2-yl-1H-benzimidazole regarding vitamins A, E, C, selenium (Se), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) levels on rats. 2-Furan-2-yl-1H-benzimidazole was given to rats by subcutaneous injection every other day for a total of 22 injections. At the end of the experiment, Se levels were determined by using a fluorimetric method. Serum levels of vitamins A, E, C, and malondialdehyde (MDA) were determined by high-performance liquid chromatography. Glutathione peroxidase (GSH-Px) levels of erythrocytes were spectrophotometrically determined. Our experimental results showed that vitamins A, E, C, and Se levels were found generally lower than the control groups, while serum MDA level and GSH-Px activity flexibly increased, which is dependent on injection days. The observed decreases in vitamins A, E, C, and Se levels in the blood might be causally related to the increased amount of free radicals that are generated with 2-furan-2-yl-1H-benzimidazole injection. However, further investigations are needed to clarify the significance of this observation in respect with the 2-furan-2-yl-1H-benzimidazole injection.

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Nitrobenzimidazoles as Substrates for DT-Diaphorase and Redox Cycling Compounds: Their Enzymatic Reactions and Cytotoxicity

Cited by 49 publications

References 0 publications

Comparison of the nucleic acid covalent binding capacity of two nitro-substituted benzazolo[3,2-a]quinolinium salts upon enzymatic reduction

Comparison of the nucleic acid covalent binding capacity of two nitro-substituted benzazolo[3,2-a]quinolinium salts upon enzymatic reduction

Dicoumarol: A Drug which Hits at Least Two Very Different Targets in Vitamin K Metabolism

Investigation of Oxidative Status of the 2-Furan-2-yl-1H-Benzimidazole in Rats

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