Electrochemical oxidation of phenanthrenequinone ...

Journal of Electroanalytical Chemistry 770 (2016) 84–89

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Electrochemical oxidation of phenanthrenequinone dioxime and its quantification using sensing at boron doped diamond electrode Dalibor M. Stanković a,⁎, Eda Mehmeti b, Kurt Kalcher b a b

Innovation Center of the Faculty of Chemistry, University of Belgrade, Studentski trg 12–16, Belgrade, Serbia Institute of Chemistry — Analytical Chemistry, Karl–Franzens University Graz, A-8010 Graz, Austria

a r t i c l e

i n f o

Article history: Received 1 February 2016 Received in revised form 28 March 2016 Accepted 29 March 2016 Available online 4 April 2016 Keywords: Phenanthrenequinone dioxime Oxidation Boron doped diamond electrode Blood samples

a b s t r a c t Nowadays, there is small number of analytical procedures for the quantification of the phenanthrene and its derivatives, quinones and quinonedioximes. In recent years, different studies shows that potential application of these compounds and their complexes possess important role in many search areas, medicine, catalysis, sensors and bioorganic systems. In this paper, for the first time, we offer fast, sensitive, selective and reliable electroanalytical procedure for quantification of phenanthrenequinone dioxime (PQD) based on its oxidation. Also, its electrochemical behavior in water acidic media is given. Possible electrode mechanism based on these measurements was proposed. It was found that by employing differential pulse voltammetry (DPV) in Britton–Robinson buffer solution (BRBS) at pH 3.0 using boron-doped diamond (BDD) electrode calibration curve for PQD quantification was linear in the range of 0.3 to 7.0 μM with detection limit of 0.22 μM. Proposed method was successfully applied for the determination of PQD in blood samples with satisfactory recovery (96–102%). Proposed method can be beneficial in the chemistry of dioximes due to advantages of BDD electrode and sensitivity and selectivity of the electroanalytical procedures. © 2016 Elsevier B.V. All rights reserved.

1. Introduction Today, worldwide, breast cancer causes death around 400,000 women every year [1]. Up to date, it presents the most common female cancer. In the literature are lots of synthetic or natural compounds which possess cytotoxic properties which are approved for the clinical treatment of the cancer cells. Quinones and its derivatives could be considered as second largest group of molecules which shows this behavior [2–4]. Breaking of DNA strands and their inhibition together with alterations of cell membrane function could be possible mechanism of their anticancer activities and cytotoxic properties [5,6]. Different group of the researchers have reported that naturally isolated phenanthrene, phenanthrenequinone and its synthesized metal complexes, due to its planar structure, shows antimicrobial, anti HIV, anti-inflammatory and potential anticancer effects [7–12]. Different studies reported that possible mechanism of the action, which could explain activities of this group of molecules and its complexes, could be attributed to the production of reactive oxygen species (ROS) [13–15]. The chemistry of cobaloximes and its chemical and electrochemical behavior, dominantly due to easy transaction between different states, together with (Co(III) – Co(II) – Co(I)) conversation could play important role in the chemistry of the vitamin B12 and may represent ⁎ Corresponding author. E-mail address: [email protected] (D.M. Stanković).

http://dx.doi.org/10.1016/j.jelechem.2016.03.041 1572-6657/© 2016 Elsevier B.V. All rights reserved.

potential use of this complex for the clarification of the mechanism that controls activity of this vitamin and has been extensively investigated in the recent years [16–19]. These compounds play important role in the treatment of soman poisoning and they are known to be acetylcholinesterase reactivators. However, although these compound demonstrate the wide range of applications there is small number of methods, reported in the literature, dealing with its determination, primarily based on their action on the reaction of Au(III) with potassium iodide [20–22]. Our research group extensively using the advantages of a borondoped diamond electrode, up to date one of the best electrode materials, which lies in its low and stable background current, extreme electrochemical stability in alkaline and acidic media, excellent long-term response stability and high response sensitivity, for the application in development of electroanalytical procedure for the quantification of the various biologically active compounds important in the area of environment, food and drug analysis [23–28]. The aim of this study was to show electrochemical behavior of phenanthrenequinone dioxime in acidic water media. For that purpose cyclic voltammetry was used at BDD electrode. The proposed electrochemical oxidation mechanism is given. Differential pulse voltammetry, after optimization of the experimental parameters, was employed for the quantification of PQD. Effect of possible interferences was evaluated. The proposed analytical procedure was successfully applied for the determination of PQD in human blood samples.

D.M. Stanković et al. / Journal of Electroanalytical Chemistry 770 (2016) 84–89

2. Experimental 2.1. Apparatus and reagents All reagents used in this study were of analytical grade. Phenanthrenequinone dioxime, glucose, boric acid, sodium hydroxide, ascorbic acid, uric acid, dopamine, acetic acid and phosphoric acid were purchased from Sigma Aldrich. Standard solution of PQD was prepared in ethanol at the concentration value of 1.0 × 10− 4 M. Britton–Robinson buffer solution was used as supporting electrolyte and it was prepared by mixing 0.04 M of the boric acid, phosphoric acid and acetic acid. The pH values of BRBS were adjusted with sodium hydroxide (0.2 M). Calibration solutions were prepared by appropriate dilution of the stock solution with supporting electrolyte. The voltammetric measurements were performed using a potentiostat/galvanostat (AUTOLAB PGSTAT 302 N, Metrohm Autolab B.V., The Netherlands) controlled by the corresponding electrochemical software (NOVA 1.9). The electrochemical cell (total volume 10 mL) was equipped with a boron-doped diamond electrode (Windsor Scientific Ltd., Slough, Berkshire, United Kingdom) as a working electrode, an Ag/AgCl (saturated KCl) as a reference electrode and a Pt wire as a counter electrode. At the beginning of working day prior to starting the first measurement, the BDD electrode was rinsed with deionized water and gently rubbed with a piece of damp silk cloth until a mirror-like appearance of surface was obtained (with minimal probability of mechanical damage of surface). Subsequently, it was anodically pretreated by setting + 2 V during 180 s in 1 M H2SO4 in order to clean the electrode surface (get rid of any impurities) followed by cathodic pretreatment at − 2 V during 180 s to renew the hydrogen terminated surface of the working electrode [24–26]. After every measurements electrode was slightly polished with piece of cotton. In order to confirm stability and advantages of the BDD electrode before starting measurements and at the end of working day, potential/current changes in the K4[Fe(CN)6 ]/K 3 [Fe(CN)6 ] couple was monitored. It was observed that during the day these changes are lower than 5%. All potentials reported in this paper are referred versus the above mentioned reference electrode. All measurements were done at an ambient temperature. All pH values were measured with a pH meter model Orion 1230 equipped with combined glass electrode model Orion 9165BNWP (USA). The used BDD electrode were embedded in a polyether ether ketone (PEEK) body with an inner diameter of 3 mm, a resistivity of 0.075 Ω cm and a boron doping level of 1000 ppm. These characteristics are declared by the supplier.

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The applicability of the proposed procedure was tested for the quantification of PQD in human blood samples. The samples were prepared as it is mentioned below. Adequate aliquots of each sample solution were added in electrochemical cell (10.0 ml) and diluted with supporting electrolyte. In order to provide recovery of analyte and matrix effects standard addition method was used. All concentrations were determined in triplicate using calibration curve previously obtained under the optimum experimental conditions. 2.3. Preparation of blood samples Blood samples were obtained from two apparently healthy, nonsmoking male volunteers, and stored frozen until the analysis process. Samples were prepared by slightly modifying previously described procedure [29]. First, blood was centrifuged for 30 min at 15,000 rpm to get serum sample. 0.8 mL of acetonitrile was added to a 1.0 mL blood sample to remove serum protein. After vortexing for 45 s, the mixture was centrifuged for 10 min at 15,000 rpm to remove the serum protein residues. Supernatant was taken carefully and 1.0 mL of this supernatant was transferred into a 10.0 mL flask and diluted up to the volume with the BRBS (pH 3.0). 3. Results and discussions 3.1. Electrochemical behavior of PQD Evaluation of electrochemical behavior of the PQD and optimization of pH of the Britton–Robinson buffer solution was performed by employing cyclic voltammetry. Concentration of the PQD of 2.0 × 10−5 M was used. The cyclic voltammogram obtained for the BDD electrode in the presence of mentioned concentration of the PQD in BRBS at pH 3.0, is presented in Fig. 1. Also, the corresponding CV for the measurement of the supporting electrolyte is presented in Fig. 1 (dash line). As can be seen from these measurements, the oxidation process of the PQD under these conditions occurs as two processes. First process was obtained at around +0.70 V and second at around +0.95 V. The oxidation of PQD was more pronounced at pH 3.0, and analytical signal decreased gradually with further increasing of the pH. Thus the BRBS solution at pH 3.0 was selected for the development electroanalytical procedure, once the best peak shape and highest oxidation peak current were obtained. In the reverse scan after the inversion of the potential scanning, no corresponding reduction processes were observed. It could be

2.2. Analytical procedure Electrochemical behavior of PQD on BDD electrode was evaluated by cyclic voltammetry at the scan rate of 50 mV s−1 (if not stated otherwise). pH of supporting electrolyte was selected from these measurements. In order to provide highest analytical signal we optimized DPV parameters, such as pulse amplitude and pulse time. For these measurements potential was swept from 0 to 1.3 V. After optimization of parameters, with the best experimental conditions (pulse time 10 ms and pulse amplitude 40 mV) the calibration curve was obtained from the addition of known amounts of stock solution of PQD in the electrochemical cell containing supporting electrolyte. Corresponding equation, limit of detection (LOD) and linear range were determined from these measurements. The LOD was calculated using the expression: LOD ¼ 3 σ ðblankÞ − intercept =slope: The selectivity of the proposed method was evaluated from measurements of main containing compounds presented in investigated matrices in the presence and absence of PQD.

Fig. 1. Cyclic voltammograms obtained in absence (dotted line) and presence of the 2.0 × 10−5 M PQD in BRBS at pH 2.0 (blue line), pH 3.0 (purple line) and pH 6.0 (red line) using BDD electrode. Inset curve present of peak potential of the second oxidation wave of the PWD vs. pH of supporting electrolyte.

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concluded that these processes are irreversible oxidation of PQD. Scan rate used for these measurements was 50 mV/s. At lower scan rate (Fig. 2) oxidation of PQD gives three signals, where can be concluded that second signal oxidation current observed at higher scan rate present superposition of these two signals. Increasing of the pH of the supporting electrolyte leads to the disappearance of the first oxidation process and causes shift of the peak potential of the second peak to the more negative values (inset of Fig. 1). The corresponding equation obtained for these measurements is: E (V) = − 0.058 pH + 1.062 (R2 = 0.9937). The obtained slope value of 58 mV is close to the ideal value of 59 mV, indicating that same number of protons and electrons participate in the electrode reaction. These statement and data are in accordance with previously reported data for some dioximes [30]. Based on these measurements and reported data full oxidation mechanism is proposed in this paper. First oxidation step probably leads to the formation of the dinitrozo form, which spontaneously isomerized to the furoxan, including the transfer of two electrons and two protons. Second wave can be attributed to the formation of iminoxyl radicaloxoimmonium cation system, which is a stable product of the oxidation of dioximes [31,32]. The proposed mechanism of the electrochemical oxidation of dioximes is presented in Scheme 1. In Fig. 2a. CVs at different scan rates for the oxidation of PQD in the same supporting electrolyte are presented, ranking from 25 to 300 mV/s. These experiments were done in order to determine the electrochemical behavior of the PQD oxidation. Linear dependence of the corresponding oxidation current from the square root of the scan rate, calculated for both oxidation peaks are shown in Fig. 2b. This linearity following the regression equations: I ð10–8AÞ ¼ ð−0:678Þ þ 0:286 v1=2 ; R2 ¼ 0:982 I ð10–8AÞ ¼ ð−0:705Þ þ 0:538 v1=2 ; R2 ¼ 0:970 indicating that the electrochemical processes occur at the BDD electrode surface belongs to the diffusion control processes. 3.2. Optimization of the determination parameters Differential pulse voltammetry offers fast, simple, low cost, and in same time high selective and sensitive technique, for the quantification a number of biological important compounds. Due to these, nowadays, its present one of the most used electroanalytical methods. In order to provide best conditions for quantification of PQD, relevant experimental parameters of the DPV method were optimized. The evaluated parameters were pulse amplitude (10–100 mV) and pulse time (10–100 ms). All experiments were done in BRBS at pH 3.0 containing 5.0 μM of PQD using BDD electrode. During one parameter was varied, others were kept constant. It was found that increase of the pulse amplitude

from 10 to 40 mV, at fixed pulse time of 10 ms, leads increase of peak current. Further increase causes decrease of the peak current, so for further experiment pulse amplitude of 40 mV was chosen. On the other hand, immediately with increasing pulse time from 10 ms, at previously optimized pulse amplitude of 40 mV, peak current started to decrease. Based on these facts, for all further experiments, analytical study, interferences study and application in real sample analysis, these found optimum values were used.

3.3. Construction of calibration curve Recording PQD by DPV under previously obtained experimental conditions two oxidation peaks were observed, similar as for CVs measurements. Second peak, obtained at higher potential was observed at the concentrations of 1.0 μM and higher. As this work present for the first time one electroanalytical procedure for the quantification of dioximes, in order to provide best analytical performances, calibration curve for the determination of PQD was constructed by plotting oxidation current of the first peak against concentration. The DP voltammograms recorded for different PQD concentrations ranking from 0.3 to 7.0 μM are presented in Fig. 3a. The corresponding linear calibration curve (Fig. 3b) can be expressed with the following linear regression equation I (× 10− 7 A) = 2.602 c (PQD) μM – 0.535; R2 = 0.9987. Linearity was also estimated by employing analysis of residual (data not shown). The residual plot shows a typical random pattern, indicating a good fit for a linear model. Calibration curve were linear in the range of 0.3 to 7.0 μM and the calculated limit of detection was 0.22 μM. The obtained results proposed by Kishikawa et al., by employing high-performance liquid chromatography with postcolumn fluorescence derivatization using 2-aminothiophenol was the linear range from 0.013 to 50 μM with detection limit of 3.4 nM and they are similar to those proposed by Delhomme et al., for HPLC-MS/MS with negative ionization [33,34], and it is obvious that they are better than obtained from this study. Results from this study are comparable with results proposed by Cho et al. and Delhomme et al., for HPLC-MS/MS with positive ionization [34,35]. However, electrochemical approach offers simplicity in sample preparation, low cost instrumentation in comparison with used methods. The repeatability and the precision of the proposed method were studied for all concentrations from calibration curve. As it is expected, the relative standard deviations (RSDs), for n = 5 measurements of each concentration, decreased with the increase of concentration from 3.4 to 1.9%. Also, for the concentration of 1.0 and 3.0 μM interday studies were done. It was found that RSD values for five days measurements of these concentration were 3.8 and 2.1%. These results demonstrate advantages of BDD electrode and a good precision of proposed analytical procedure.

Fig. 2. a) CVs recorder at different scan rated for a 2.0 × 10−5 M PQD in BRBS at pH 3.0 using BDD electrode (25, 50, 75, 100, 150, 200 and 300 mV/s); b) peak current vs. square root of the scan rate.


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Scheme 1. Proposed oxidation mechanism of PQD in BRBS at pH 3.0 using BDD electrode.

3.4. Interferences studies The whole our previous study and study of other authors about possibilities of this kind of compounds and their complexes in the treatment of cancer cell leads to the conclusion that proposed analytical procedure could have the widest application in determination of PQD in human body fluid samples, urine and blood serum. Some of typical contaminants present in both samples were considered as potential interferents. Application of proposed method for quantification of PQD

in the presence of vitamin C, uric acid, dopamine, NaCl, KCl and glucose was investigated. It was considered that contaminant strongly interfere with determination of PQD if gives signal changes more than 10%. The concentration of PQD during these measurements was 1.0 μM and ratio analyte/contaminant was 1: 10 and higher. Representative voltammograms obtained for these measurement are presented in Fig. 4a–d. As can be seen from Fig. 4a–c the presence of 10 time higher concentration of vitamin C, dopamine and uric acid disable quantification of PQD as all three tasted compounds gives oxidation peak at the

Fig. 3. a) DP voltammograms obtained for different concentration of PQD starting from 0.3 to 7.0 μM in BRBS at pH 3.0 using BDD electrode. b) Corresponding analytical curve obtained from these measurements.

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Fig. 4. a–d. DP voltammograms recorder for the evaluation of the effect of possible interferences for the quantification of the 1.0 μM of PQD, under optimized experimental conditions.

similar values as PQD, under proposed experimental conditions. From these results it is obvious that proposed method is not suitable for application in urine samples as all three compounds are major component of urine. However, presence of glucose as component of blood samples do not causes signal change in the ratio of 1:20 and 1:50 and with further increase of amount of glucose up to the ratio of 1:100 it is noticed that starting from this value quantification of PQD is disabled as there is change in peak current of 25% (Fig. 4d). Also, presence of NaCl and KCl in all tasted ratios do not causes signal changes more than 5% from where can be concluded that this two compound do not affecting on the determination of PQD. These results suggest that proposed analytical procedure has appropriate selectivity toward determination of PQD in blood serum samples.

dioxime based on differential pulse voltammetry with BDD electrode was introduced. The excellent repeatability appropriate selectivity enables application of the method in human blood serum samples. Promising operating parameters, linear range from 0.3 to 7.0 μM and limit of detection of 0.22 μM, were obtained. Effect of possible interfering compounds such as vitamin C, uric acid, dopamine, NaCl, KCl and glucose was evaluated. Also, this study present for the first time application of electrochemical methods in quantification of this kind of compounds and could be beneficial for the researcher which are dealing with this topic.

3.5. Analytical application for the determination of PQD in blood serum samples The applicability of the developed method was evaluated for the quantification of PQD in blood serum samples from two different apparently healthy people. Addition of different amount of the standard solution of the PQD, were used to causes peak current increase and enable its quantification. Voltammograms for these measurements are depicted in Fig. 5. Recovery performed to evaluate matrices effects after standard-solution addition yielded average recoveries from 96 to 102% (Table 1). Based on these results, we could conclude that this investigated matrix do not present any significant interference on the proposed electroanalytical procedure and indicating that novel voltammetric method for the PQD quantification could be successfully used in human blood serum samples. 4. Conclusions In this study, a simple, fast, cost-effective and very sensitive electrochemical procedure for quantification of phenanthrenequinone

Fig. 5. Voltammograms obtained under optimized experimental conditions for the quantification of PQD in blood serum samples (black line); after addition of 0.5 μM (red line); and after addition of 1 μM (blue line) of the PQD.

D.M. Stanković et al. / Journal of Electroanalytical Chemistry 770 (2016) 84–89 Table 1 Results for the determination of PQD in blood serum samples and recovery valuesa. Sample

Found (μM)

Added/found (μM)

Recovery (%)b

Added/found (μM)

Recovery (%)

1. 2.

0.00 0.00

0.50/0.51 0.50/0.49

102 98

1.00/0.96 1.00/0.99

96 99

a b

n = 3. Recovery was calculated as: PQDfound / PQDadded × 100%.

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