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Studies on the Synthesis, Characterization, DNA Binding, Cytotoxicity and Antioxidant activity of 2-methyl-4-nitrophenylferrocene.

Byline: Bhajan Lal, Amin Badshah, Ataf Ali Altaf, Shabeeb Hussain, Jahangeer Patujo, Saqib Kamal, Shafiq Ullah and Fazlul Huq

Summary:

We report herein the synthesis, structural characterization, DNA binding, BamH1 digestion, cytotoxicity and antioxidant activity of 2-methyl-4-nitrophenylferrocene. Structural characterization is based on multinuclear (1H and 13C) NMR, FT-IR spectroscopy and elemental analysis. Interaction of 2-methyl-4-nitrophenylferrocene with pBR322 plasmid DNA shows noncovalent interactions however these noncovalent interactions reveal the prevention of BamH1 restriction site (g/ggtcc). In the voltammogram, a negative shift in peak potential has been observed on addition of increasing concentration of CT-DNA, which shows electrostatic interaction for 2- methyl-4-nitrophenylferro with negatively charged phosphate of DNA backbone. The binding ratio, binding constant, binding free energy and diffusion coefficient of free and bound drug were calculated to understand the mechanism. The high negative value of -G signifies the spontaneity and high conformational stability of 2-methyl-4-nitrophenylferro with CT-DNA.

The compound has the ability to scavenge free radicals as have been revealed by DPPH findings.

Keywords: Ferrocene, DNA binding, BamH1 digestion, Cytotoxicity, Antioxidant Activity.

Introduction

Cisplatin, its derivatives (carboplatin, oxaplatin, nedaplatin, iproplatin) and several other metallopharmaceuticals have been found to be effective as anticancer agents [1]. However these drugs attain resistance and have side effects [2,3]. These compounds exert their cytotoxic effect by interacting with DNA, which leads to the inhibition of transcription and replication [4-9]. Interest in understanding the association of drug molecules with duplex DNA has been developed in the hope of overcoming problems of drug resistance and side effects associated with platinum based chemotherapy [10]. Ferrocene and its derivatives have been excessively studied in order to be used as chemotherapeutic drug [11]. In these molecules, the stability, well-characterized redox behavior and spectroscopic activity of the ferrocene moiety make them promising candidates for many biological applications [12].

The presence of ferrocenyl moiety significantly enhances the activity due to its reversible redox behavior and lipophilic nature, which also make these molecules to permeate cells [13].

In the present work, we report the synthesis, structural elucidation, DNA binding, antitumour potency and ability to scavenge free radicals of 2- methyl-4-nitrophenylferrocene. The compound has been found to possess significant anticancer activity against human ovarian cell lines and believed to better overcome the resistance operating mechanism in A2780cisR and A2780ZD0473R cell lines. The extent and mode of interaction with DNA and prevention of BamH1 restriction site is studied by using cyclic voltammetry and gel electrophoresis respectively. The free radical scavenging activity of title compound was obtained by using DPPH free radical scavenging activity.

Experimental

Materials

Ferrocene, 2-methyl-4-nitroaniline, and sodium salt of CT-DNA were purchased from Acros Organics (Geel, Belgium), sodium nitrite, hydrochloric acid, diethyl ether, cetyltrimethylammonium bromide (CTAB), potassium chloride (KCl), 2,2-Diphenyl-1- picrylhydrazyl (DPPH) and other solvents were purchased from Aldrich. All the chemicals purchased were of analytical reagent grade and used as such.

Synthesis of 2-methyl-4-nitrophenylferrocene (1)

2-methyl-4-Nitroaniline (0.82 g, 5.37 mmol) was added to 10 ml of 18 % aqueous hydrochloric acid to form the slurry and cooled to 0-5 C using salt water-ice bath. A solution of sodium nitrite (0.37 g, 5.37 mmol) in 10 ml of water was added drop wise to slurry under stirring. After complete addition the solution was stirred for additional 30 min and kept below 4 C during to form the respective diazonium salt. Ferrocene (1 g, 5.37 mmol) and 0.1 g hexadecyltrimethylammonium bromide (CTAB) were added to 50 ml ethyl ether and cooled to 0 C. The diazonium salt solution was added drop wise to ferrocene solution containing phase transfer catalysts CTAB under constant stirring and kept below 4 C. After the complete addition the reaction mixture was stirred overnight at room temperature. The mixture was concentrated by rotary evaporation and the residue washed with water then the crude solid was steam distilled to recover un-reacted ferrocene.

The residual crude product was recrystallized from heptane t o give 2-methyl-4-nitrophenylferrocene as violet plates [14]. Yield: 73.2%, 1H NMR (300 MHz, CDCl3, ppm): 7.52 (d, J=8.4Hz, H16), 6.58-6.51(m, H13,15), 4.42 (dd,J=1.5Hz, H7,8), 4.25 (dd,J=1.5Hz, H6,9), 4.14 (s, H1-5), 2.33 (s, H17): 13C NMR (75 MHz, CDCl3, ppm) 144.56 (C14), 136.85 (C11), 131.55 (C12), 127.40 (C16), 117.01 (C13), 112.63 (C15), 88.13 (C10), 69.42 (C1-5), 69.32 (C7,8), 67.42 (C6,9), 21.3 (C17) ppm. FT-IR ( cm-1) 3091, 2964, 2927, 1606, 1581, 1510, 1346, 1132, 1105, 1070, 1002, 876, 829, 802, 750, 717, 557, 472.Anal.Calc. (%) C17H15FeNO2: C, 63.58; H, 4.71; N, 4.36: (%) found: C, 63.57; H, 4.69; N, 4.41.

Physical Characterization

Multinuclear (1H and 13C) NMR and FT-IR spectra were obtained by using BRUKER AVANCE 300MHz NMR spectrometer and Thermo Scientific Nicolet-6700 FTIR spectrometer. Microanalysis was carried out with Leco CHNS 932 apparatus. Cyclic voltammetric (CV) measurements were performed by using Eco Chemie Auto lab PGSTAT 12 potentiostat/galvanostat (Utrecht, The Netherlands) with the electrochemical software package GPES 4.9. Pharmaspac UV-1800 UV-Visible Spectrophotometer Schimadzu was used to record UV-visible spectrometric measurements. The gel pictures were captured by Eastman Kodak Company, Molecular Imaging Systems (Carestream Health Inc. Rochester New York USA).

DNA Binding Studies by Cyclic Voltammetry

Cyclic voltammetric (CV) measurements were performed in a single compartment cell with a three electrode configuration using Eco Chemie Auto lab PGSTAT 12 potentiostat/galvanostat (Utrecht, The Netherlands) equipped with the electrochemical software package GPES 4.9. The three electrode system consisted of reference electrode; RE-1B silver-silver chloride (Ag/AgCl) saturated with sodium chloride (NaCl) of length 70 mm and outer diameter of 6.0 mm (ALS cat # 012167), a Beckman platinum wire of thickness 0.5 mm with an exposed end of 10 mm as the counter electrode and a bare glassy carbon electrode (surface area of 0.071 cm2) as working electrode. The voltammogram of a known volume of the test solution was recorded in the absence of calf thymus DNA (CT-DNA) after flushing out oxygen by purging with argon gas for 10 min just prior to each experiment.

The procedure was then repeated for systems with a constant concentration of the drug (1 mM) and increasing concentration of CT-DNA (0.6 1.8 M). All the sample solutions were prepared in 80 % DMSO (80 % DMSO : 20 % H2O) and buffered at pH 6 by phosphate buffer (0.1 M NaH2PO4 + 0.1 M NaOH), 0.12 mM potassium chloride (KCl) was used as supporting electrolyte. The working electrode was cleaned after every electrochemical assay [15, 16].

Gel Electrophoresis

Agarose gel electrophoresis method was applied to insight any conformational changes caused in pBR322 DNA structure with the interaction of title compound and also for the prevention of BamH1 digestion.

Interaction with pBR322 plasmid DNA

With a fixed concentration of pBR322 plasmid DNA (1 L), the increasing concentration (17 L of 5 to 80 M) of 1 was added. The total volume was made up to 20 L by adding mQ water. The resulting solution was incubated on shaking water bath at 37 C for 4 h. The reaction was stopped by rapid cooling to less than 0 C. 2 L of marker dye ethidium bromide (1 mg/ml) was added. 16 L aliquots of drug-DNA mixture was loaded onto the 2% gel and electrophoresis were run under TAE buffer containing ethidium bromide (1 mg/ml) for 40 min at 150 V cm-1. The gel was photographed with Eastman Kodak Company, Molecular Imaging Systems [17].

BamH1 Digestion

An identical set of drug-DNA mixture as described in the previous section for interaction with pBR322 plasmid DNA was incubated in a shaking water bath for 4 h at 37 C and then subjected to BamH1 digestion. 2 L of 10 x digestion buffer SB was added to each 18 L of the incubated drug-DNA mixture, followed by the addition of 0.1 L BamH1 (1 unit). The mixtures were kept for 1 h at 37 oC in a shaking water bath the reaction was terminated at the end by rapid cooling.Electrophoresis was carried out and the gel was subsequently stained with ethidium bromide, visualized under UV light and photographed as described previously [18].

Cytotoxicity

The cytotoxicity of 1 was determined along with cisplatin (as reference) against human ovarian tumour model: A2780 (parent), A2780cisR (resistant to cisplatin) and A2780ZD0473R (resistant to cisplatin analogue denoted as ZD0473) using the 3-(4,5- dimethylthiazol -2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Each cell line plated at a density of 4000 to 6000 cells/ well and incubated for 24 h in a humidified atmosphere (37 C, 5% carbon dioxide in the air, pH 7.4) to allow the cells to attach. The cells in the 96 well plates (10% FCS/RPMI 1640 culture medium) were treated with different concentrations of 1 and cisplatin. A serial fourfold dilutions of the 1 ranging from 0.64 to 80 M in 10% FCS/RPMI 1640 medium were prepared and added to equal volumes of cell culture in quadruplicate wells, then left to incubate under normal growth conditions for 72 h.

After the period, growth inhibition of cell was determined. 50 L per well of 1 mg mL-1 freshly prepared MTT solution was added to each plate. After 4 h; the formazan crystals formed in each well were dissolved in 150 L of DMSO and read with Bio-Rad Modal 3550 Microplate Reader (BioRad Sydney Australia) set at 550 nm [19, 20].

Antioxidant Activity

Free Radical Scavenging Activity of the 1 was performed by using 167 M concentration of 1,1-Diphenyl-2-picryl-hydrazyl (DPPH) in ethanol. Test samples of 3.125, 6.25, 12.5, 25, 50 and 100 g/ml concentrations of 1 with constant DPPH concentration were prepared in ethanol and buffered at pH 6 by phosphate buffer (0.1 M NaH2PO4 + 0.1 M NaOH). The absorbance of the DPPH solution without any additions of 1 was stable over 30 min. Test samples were incubated at 40 C for 30 min and the absorbance at 517 nm was measured by (Pharmaspac UV-1800 UV-Visible Spectrophotometer Schimadzu) under dim light. All the samples were prepared in triplicates and results were obtained as mean [21, 22].

Result and Discussion

Synthesis and Characterization

Synthetic pathway adopted for 2-methyl-4- nitrophenylferrocene (1) sketched in Scheme-1. The title compound was characterized by using FT-IR and multinuclear (1H and 13C) NMR that confirms the structure whereas elemental analysis justifies the purity.

Equation

The compounds (1) was synthesized by the reaction of ferrocene with the diazonium salt of 2- methyl- 4-nitroaniline. The 1H NMR spectrum of 1 showed that unsubstituted cp-ring of ferrocene displayed singlet for five protons at 4.14 ppm, however the substituted cp-ring of ferrocene splited into two signals and appeared in the region of 4.25- 4.42 ppm. The substituted aromatic ring gave rise signals in the region of 6.54-7.52ppm. The methyl protons (attached to phenyl ring) appeared in the region of 2.33 ppm. The multiplicity and intensity of signals were used to identify the nonequivalent protons. The integration curve revealed that protons present in the molecule and the area under the curve were in agreement with each other.

The 13C NMR spectrum of 1 revealed that unsubstituted cp-ring of ferrocene showed singlet for five carbons in the range of 69.42 ppm whereas the substituted cp-ring of ferrocene splited into three signals, the ipso carbon (directly attached to phenyl ring) displayed signal in the range o f 88.13 ppm. The other two signals of the substituted cp-ring appeared in the range of 69.32- 67.42 ppm. The methyl carbon attached to the phenyl ring appeared in the region of 21.3ppm. The compounds 1exhibited six different signals for aromatic carbons in the region of 144.56-112.63 ppm, justifying the pattern of substitution of the phenyl ring. The nitro (-NO2) moiety of compounds (1) displayed two peaks i.e. asymmetric peak in the region of 1581 cm-1 and symmetric peak in the region of 1346 cm-1.

The FT-IR of title compound 1 showed no peak above 3200 cm-1 confirms the coupling of nitroaniline with the ferrocene. However, Fe- cpvibrational stretching peak appeared in the region of 472 cm-1 and other C=C and C-H (sp3 and sp2) bands were observed in their usual region. FT-IR spectrum for 1 shows two peaks in the range of 2900- 3100 cm-1 for sp3 and sp2 (C-H stretching). The diagnostic peak for NO2 appeared at 1581-1346 cm-1. The characteristic peak of the Fe-cp is appeared at 472 cm-1.In experimental section; full data and procedure can be followed [12, 23].

DNA Binding Studies by Cyclic Voltammetry

Voltammetric measurements were performed to understand the redox behavior and the DNA binding affinities of 2-methyl-4- nitrophenylferrocene [24-26]. The voltammogram of the compound shows a couple of well-defined and stable redox peaks in the potential range of 0.2-0.8 V, that is an anodic (oxidation) at 0.59 V as well as a cathodic (reduction) peak at 0.52 V. Simple ferrocene has formal potential peak at 0.55 V. The positive shift of 37 mV in potential was observed for 1 which is believed to be due to the electron withdrawing effect of nitrogroup attached to the phenyl ring at the para position from the cyclopentadienyl ring of ferrocene. The electrochemical signals reflected that the oxidation of the Fe2+ to Fe3+ was difficult and it steadily oxidized in the synthesized compounds. The cyclic voltammetric behavior of 1 mM compound 1 in the absence and presence of 0.6 M, 1.2 M and 1.8 M CT-DNA at a glassy carbon electrode (GCE) as shown in Fig. 1.

On addition of increasing concentration of CT-DNA to the solution of 1 mM title compound, drop in peak current along with a change in peak potential is observed. The variation in peak current and shift in potential of compounds is used to calculate the binding ratio (Kred./Koxd.), binding constant (M-1), free binding energy (kJ mol-1) and mode of interaction with the double helical structure of DNA.The drop in peak current is due to a slow but steady diffusion of the compound into double helical DNA resulting in the formation of 1-DNA supramolecular complex. The consumption of the compound in the formation of a supramolecular complex with DNA is responsible for the decrease in the transfer of electrons that results in the decrease of current. However a change in peak potential is attributed to the different mode of interaction between the compound and DNA [27].

The negative shift in formal potential is believed to be due to the presence of electrostatic interaction between cationic iron moiety and anionic phosphate of the DNA backbone whereas positive shift is indicative of the presence of an intercalative mode of interaction [28].

The shift in both cathodic and anodic peak potentials reveals that both forms are interacting with CT-DNA but Fe3+ form intercalate more predominantly. The binding ratio of reduced and oxidized species reveals that ferrocenium moiety interacts strongly with anionic DNA compared to ferrocene revealed by equation (1) [29].

Equation

Eb and Ef are the formal potentials of the bound and free forms of drug respectively. The negative shift indicates that 1 in oxidized form interacts strongly with DNA. The mechanism of interaction with DNA may involve oxidation of Fe2+ to Fe3+ and that the oxidized form may be responsible for the interaction with negatively charged phosphate of double helix DNA backbone [30]. However another possibility of binding with DNA may also exist. Fe2+ may first bind with DNA followed by oxidation of Fe2+ to Fe3+ which may generate reactive oxygenated species (ROS) in vivo that cause oxidative stress and damage to DNA as shown in scheme-2 [31, 32].

Equation

The binding constant is calculated by the equation (2) [33]. The plot of 1/[DNA] versus 1/(1-i/i0) yielded binding constants1.84 x 104.

Equation

where i and i0 are the peak currents with and without CT-DNA, A is the proportionality constant and K is the binding constant. The binding free energy change (-G= RT ln K) in 24.33kJ/molat 25 C signifies the spontaneity of Drug-DNA interaction [34]. The diffusion coefficient of 1 in both absence and presence of DNA was determined by the application of Randles-Sevick expression (3) [27].

Equation

where Ipa is the peak current (A), A is the geometric area of electrode surface (cm2), Cois the bulk concentration of the electro active species (mol cm-3), D is the diffusion coefficient (cm2 s-1) and is the scan rate (V s-1).

The plot of Ipavs 1/2 shows a linear trend. The linear dependence of the peak current of free drug (1) and bound drug (1-DNA) on the square root of scan rate suggests that the main mass transport of title compound to the electrode surface is kinetically controlled by diffusion step as shown in Fig. 2. From the slope of Randles-Sevick plot, the diffusion coefficient of free drug (2.77 x 10-7) and DNA bound drug (1.11 x 10-7) is calculated. However, the lower Ipavs 1/2 slope of DNA bound drug compared to free drug confirms the 1-DNA adduct formation. The decrease in diffusion coefficient on adding DNA suggests an increase in molecular weight of title compound (due to adduct formation with DNA) confirms the idea that a heavy molecule diffuses slowly to the electrode [35].

Interaction with pBR322 plasmid DNA

Fig. 3. shows the interaction of 2-methyl-4- nitrophenylferrocene compound with pBR322 plasmid DNA. As pBR322 plasmid DNA exists in three forms, a super coiled form I, a singly nicked relaxed circular form II and a doubly nicked linear form III. When potential is applied, DNA will migrate from negative to positive electrode as it bears negative charge. Three forms of pBR322 plasmid DNA show difference in mobility when electrophoresed which is attributed to the difference in their structures. When platinum drugs interact with pBR322 plasmid DNA they cause significant change in the mobility and intensity of DNA as they form intra-strand bifunctional 1,2-Pt (AG) and 1,2-Pt (GG) adducts [36]. The electrophoretogram of untreated pBR322 plasmid DNA shows two bands for form I and form II (Fig. 3.).

When pBR322 plasmid DNA is interacted with increasing concentrations of 1, no change in intensity and mobility of either form I or form II band is observed showing that the 1 is unable to cause any change in DNA conformation, which is expected because compounds tend to bind with DNA non-covalently.

BamH1 Digestion

BamH1 is a restriction enzyme that recognizes the G/GATTCC sequence and cuts the phosphodiester bond between two consecutive guanines that alters the supercoiled form I, singly nicked relaxed circular form II to doubly nicked linear form III [37]. As cisplatin is known to bind covalently to 1,2-Pt (GG) forming intra-stand bifunctional adduct resulting in the prevention of BamH1 digestion. 1 is believed to undergo non covalent interaction and does not cause any conformational changes when interacted with pBR322 plasmid DNA so BamH1 digestion is used to gain further insight into the binding of the 1 with pBR322 DNA. Untreated and undigested pBR322 plasmid DNA shows two bands attributed to form I and form II whereas untreated but BamH1 digested pBR322 plasmid DNA displays one band corresponding to form III (Fig. 4).

In the case of pBR322 plasmid DNA interacted with increasing concentrations of 1 followed by BamH1 digestion, three bands corresponding to forms I, II and III are seen at all concentrations of the compound. 1 is found to be effective in preventing BamH1 digestion as results indicates which conclude that even non- covalent interactions can induce significant conformational changes in the DNA so that BamH1 fails to recognize the sequence.

Cytotoxicity

Table-1 shows the IC50 values and resistance factor of 2-methyl-4-nitrophenylferrocene and cisplatin (used as reference) as applied to A2780 (parent), A2780cisR (resistant to cisplatin) and A2780ZD0473R (resistant to picoplatin). It has been observed that 1 has shown significant activity against human ovarian cell lines. Against A2789 parent cell line compound exhibited much less activity than cisplatin; however against drug resistant cell lines compound is equally or nearly equally active as cisplatin. More importantly our compound has shown better ability to triumph over resistance operating in A2780cisR and A2780ZD0473R. One of possible reasons for difference in resistance factor (Rf) shown by the compound may lie in the difference in nature of interaction with DNA [38].

As cisplatin is believed to bind covalently with nucleobases in the DNA whereas 2-methyl-4-nitrophenylferrocene (1) undergo only electrostatic interaction with the same. The mechanism of action is explained in section 3.2.

DPPH Free Radical Scavenging Activity of 2-methyl- 4-nitrophenylferrocene

Antioxidants had ability to trap the free radicals. Highly reactive free radicals and oxygen species are being found in biological systems from different sources. These free radicals are responsible for the oxidation of nucleic acids, proteins, lipids or DNA and can initiate degenerative disease [39, 40] and thus antioxidant inhibit the oxidative mechanisms that lead to degenerative diseases [41]. The free radical scavenging activity of 2-methyl-4- nitrophenylferrocene (1) was performed by using 1,1- diphenyl-2-picryl-hydrazyl (DPPH) assay in ethanol at different concentration on UV-Visible spectrophotometer. A deep violet solution of DPPH gives a strong absorption band at 517 nm which is attributed to its odd electron. As this electron is paired up by free radical scavenger the decolorization occurs in accordance to the number of electrons taken up. The decrease in absorbance at 517 nm is used to evaluate the antioxidant potency of 1 [42].

From mean value % inhibition of 1 was calculated. Ascorbic acid was used as standard.The trend in free radical scavenging profile of 1 was found to be fairly impressive when compared to standard (ascorbic acid) as shown in Fig. 5. The antioxidant activity obtained for 1shows the scavenging activity between 4.01% to 90.12% for applied concentration ranges from 3.25 to 100 g/ml. As the concentration is increasing the % inhibition is also increasing showing that the odd electron is getting paired up with1.

Table-1: IC50 value and resistance factor (Rf) for 2-methyl-4-nitrophenylferrocene (1) and cisplatin.

###A2780###A2780cisR###IC50A2780cisR/ IC50A2780###A2780ZD0473R###IC50A2780cisR/ IC50A2780

Compounds

###IC50(M)###IC50(M)###Rf###IC50(M)###Rf

###Cisplatin###1.00 0.46###9.95 2.07###9.95###10.22 1.65###10.22

###1###8.16 0.40###9.94 0.95###1.21###11.41 1.64###1.39

Conclusion

The interaction of 2-methyl-4- nitrophenylferrocene (1) with pBR322 plasmid DNA showed noncovalent interactions however these noncovalent interactions reveal the prevention of BamH1 restriction site (g/ggtcc) at higher concentration to some extent. In the voltammogram, a negative shift in peak potential was observed on interaction of increasing concentration of CT-DNA, which is evident of electrostatic interaction for 2- methyl-4-nitrophenylferrocene with negatively charged phosphate of DNA backbone. The synthesized compound was found to have impressive ability to scavenge free radicals as revealed by DPPH findings.

Acknowledgments

Dr. Bhajan Lal is grateful to Higher Education Commission Pakistan for the award of an Indigenous PhD scholarship combined with IRSIP scholarship. This research is partly funded by Biomedical Science Research Initiative Grant and Biomedical Science Cancer Research Donation Fund, School of Medical Sciences, The University of Sydney, Australia.

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