The generation and reactions of quinone methides

Podsiadly

Free Radical Biology and Medicine

et al. 2016

Peroxy-caged luciferin (PCL-1) probe was first used to image hydrogen peroxide in living systems (Van de Bittner GC et al. Proc Natl Acad Sci U S A. 2010; 107:21316–21). Recently this probe was shown to react with peroxynitrite more potently than with hydrogen peroxide (Sieracki et al. Free Radic Biol Med. 2013; 61:40–50) and was suggested to be a more suitable probe for detecting peroxynitrite under in vivo conditions. In this work, we investigated in detail the products formed from the reaction between PCL-1 and hydrogen peroxide, hypochlorite, and peroxynitrite. HPLC analysis showed that hydrogen peroxide reacts slowly with PCL-1, forming luciferin as the only product. Hypochlorite reaction with PCL-1 yielded significantly less luciferin, as hypochlorite oxidized luciferin to form a chlorinated luciferin. Reaction between PCL-1 and peroxynitrite consists of a major and minor pathway. The major pathway results in luciferin and the minor pathway produces a radical-mediated nitrated luciferin. Radical intermediate was characterized by spin trapping. We conclude that monitoring of chlorinated and nitrated products in addition to bioluminescence in vivo will help identify the nature of oxidant responsible for bioluminescence derived from PCL-1.

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

On the use of peroxy-caged luciferin (PCL-1) probe for bioluminescent detection of inflammatory oxidants in vitro and in vivo – Identification of reaction intermediates and oxidant-specific minor products

Podsiadly

Free Radical Biology and Medicine

et al. 2016

“…The reductive activation of mitomycins providess electivity in the targeting of solid tumors because it is favored in the oxygen-deprived environment of tumor cells and inhibited by the oxygen-rich environment of healthy tissues. [36] To teva and Richard [37] published av ery comprehensive review on the reductivee limination that leads to QMs and, by using naphthoquinones, Wellington [38] showed the importance of this mechanism in medicinal chemistry.H owever, no electrochemical evidencew as presented, as shown in the presentc ase. Brimble and co-workers proposed as imilarp athway for kalafungin, an atural quinone, by using homogeneous reduction [30] and theoretical investigations in the presence of DNA.…”

Section: Spectroelectrochemical Experimentsmentioning

confidence: 99%

“…[41] Investigationo ft he reductivea nd oxidative metabolisms that form QM is av ery important topic in drug designa nd safety. [4,11,30,[36][37][38][39][40][41] The UV/Vis spectroelectrochemistry herein revealed the in situ generation of QM, which is relevant because, very often,m olecular proofsc ame from analysis of productbased results [30] together with computationalsimulations. [39,42] By taking into consideration the experimental data from CV, UV/Vis spectroelectrochemistry,e lectrolysis,c hemical reduction followed by thiophenol addition, and the effects of acetic anhydride in CV,t he electron-transfer process of LQB-118 in nonaqueous DMF + 0.1 mol L À1 TBABF 6 corresponds to the scheme displayed in Figure 9A.…”

Section: Spectroelectrochemical Experimentsmentioning

confidence: 99%

Reactive Oxygen Species Release, Alkylating Ability, and DNA Interactions of a Pterocarpanquinone: A Test Case for Electrochemistry

et al. 2016

The electrochemistry of a redox‐based bioactive pterocarpanquinone, designated as LQB‐118, and its precursor chromenquinone (CQ) was investigated in protic and aprotic media with a focus on the reduction mechanism in both media, the reactivity with oxygen, and the interaction with biological targets, such as DNA. UV/Vis spectroelectrochemistry clarified the proposed mechanism. The appearance of bands at λ=331, 400, and 600 nm suggests the generation of transient quinonemethides (QM). Electrochemical experiments revealed homogeneous electron transfer to oxygen. LQB‐118 itself interacts with calf‐thymus DNA and ssDNA in solution. It, and its electrogenerated intermediates, have been shown to decrease the diagnostic oxidation peaks of guanosine and adenosine residues. These results, together with electrochemical evidence for the formation of QMs and the reductive addition of thiols, partly explain the reported cytotoxic and parasiticidal effects of this quinone. Overall, the electrochemical methods do well to predict the molecular mechanism of the biological activity of the present class of compounds. As an additional competitive advantage, electrochemistry allows reductive cleavage in situ, the characterization of the generated intermediate, the calculation of the number of transferred electrons, and positively mimics in vitro and in vivo experiments.

“…This oxidation-isomerization pathway occurs, for example, with hydroxychavicol [11, 12], catechol estrogens [13], and quercetin [5, 14]. Finally, quinone methides can be formed by base-catalyzed elimination of facile leaving groups such as halides and protonated alkylamines [15–17] as shown for the anesthetic phencyclidine [16] and for NO-ASA analogs [17–19]. …”

Section: Introductionmentioning

confidence: 99%

Quinone Methide Bioactivation Pathway: Contribution to Toxicity and/or Cytoprotection?

Bolton¹

2014

COC

The formation of quinone methides (QMs) from either direct 2-electron oxidation of 2- or 4-alkylphenols, isomerization of o-quinones, or elimination of a good leaving group could explain the cytotoxic/cytoprotective effects of several drugs, natural products, as well as endogenous compounds. For example, the antiretroviral drug nevirapine and the antidiabetic agent troglitazone both induce idiosyncratic hepatotoxicity through mechanisms involving quinone methide formation. The anesthetic phencyclidine induces psychological side effects potentially through quinone methide mediated covalent modification of crucial macromolecules in the brain. Selective estrogen receptor modulators (SERMs) such as tamoxifen, toremifene, and raloxifene are metabolized to quinone methides which could potentially contribute to endometrial carcinogenic properties and/or induce detoxification enzymes and enhance the chemopreventive effects of these SERMs. Endogenous estrogens and/or estrogens present in estrogen replacement formulations are also metabolized to catechols and further oxidized to o-quinones which can isomerize to quinone methides. Both estrogen quinoids could cause DNA damage which could enhance hormone dependent cancer risk. Natural products such as the food and flavor agent eugenol can be directly oxidized to a quinone methide which may explain the toxic effects of this natural compound. Oral toxicities associated with chewing areca quid could be the result of exposure to hydroxychavicol through initial oxidation to an o-quinone which isomerizes to a p-quinone methide. Similar o-quinone to p-quinone methide isomerization reactions have been reported for the ubiquitous flavonoid quercetin which needs to be taken into consideration when evaluating risk-benefit assessments of these natural products. The resulting reaction of these quinone methides with proteins, DNA, and/or resulting modulation of gene expression may explain the toxic and/or beneficial effects of the parent compounds.