synthesis and biological activities of polymer-iron (iii

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Apr 11, 2016 - Company Ltd. 2,2ʹ -Azobis (isobutyronitrile) (AIBN; initiator) was supplied ..... The decomposition step for 4-VP-Fe shows endothermic peak at ...
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Vol. 2, No. 2, April 11, 2016 ISSN: 2454-2490

SYNTHESIS AND BIOLOGICAL ACTIVITIES OF POLYMER-IRON (III) COMPLEX BASED ON 4-VINYL PYRIDINE Ahmed G. Ibrahim a , Mahmoud M. Elaasserb , Alaa Fahmy a, Ibrahim Osman a, Hussein H. El-Shiekhc , Farag Abd El-Hai a and Ahmed M. Salah. b a b c

Department of Chemistry, Faculty of science, Al-Azhar University, Nasr City, Cairo, Egypt

Regional Center for Mycology and Biotechnology, Al-Azhar University, Nasr City, Cairo, Egypt

Department of Botany and Microbiology, Faculty of Science, Al-Azhar University Nasr City, Cairo, Egypt

ABSTRACT Reaction of Fe (III) with 4-vinyl p yridine in non aqueous medium led to the formation of metal complex. This complex reacted with methyl methacrylate by using azobisisobutyronitrile (AIBN) as initiator to form the polymer metal complex. This metal complex and polymer metal complex have been characterized by elemental analyses, molar conductance, IR, 1 H-NMR, Mass spectra and thermal analyses (DTA and TGA). The molar conductance of the complex indicating that, the complex is not electrolytes. This confirms that, the anion is coordinated to the metal ion. The IR data show that the metal ion is coordinated via the nitrogen atom of 4-VP. The metal VP-Fe complex and Polymer Fe Complex have been tested in vitro against number of tumor and number of microorganisms in order to assess their anti tumor and antimicrobial properties. Interestingly, the tested compound MMA-VP-Fe also exhibited highest tendency to inhibit Gram positive bacteria than Gram negative bacteria along with its activity agai nst the tested filamentous fungi (Aspergillus fumigatus). Good antitumor activity against HCT-116 cells was detected for compound VP-Fe with IC 50 value of 17.8±1.3, compared with reference standard (24.6±0.3 µg/ml) followed by MMA-VP-Fe (88.3±1.2 µg/ml). The obtained results revealed the moderate biological activities of the synthesized VP-Fe complex and polymer Fe complex.

Keywords: Metal complexes, Polymer metal complexes, Spectral studies, anti tumor and antimicrobial activity. INTRODUCTION Vinyl p yridine is a heterocyclic six-member cyclic aromatic molecule with binding capabilities through its nitrogen electron lone pair which has inspired considerable interests in its bonding with metals [1–5]. Iron pyridine complexes are being studied intensely by many researchers as the constituents of catalytic systems for the polymerization of ethylene and othe r olefins [6, 7]. The Fe(II) and Fe(III) complexes have recently received considerable attention in chelation therapy and are cytoto xic to tumor cells in mice [8]. Recently we have reported the antiproliferative activity of Fe(III) complexes of a novel nitrogen donor ligand [9]. 4-vinyl pyridine complexes played a vital role in the development of coordination chemistry [10]. It also plays an important role in biological process as exemplified in many instances in which enzymes are known to be activated by metal ions [11]. These complexes have been occupied in the strongest and transport of active substances through membrane [12]. Many metal complexes are resulting application in the microelectronic industry, chemical vapor deposition of metals, and drugs [13]. Coordination compounds display diverse characteristic properties which depend on the metal ion to which they are bound. On the basis of nature of the metal as well as the type of ligand, these metal complexes have wide applications in different fields of human curiosity [14, 15].

2. EXPERIMENTAL SECTION 2.1. Materials The monomers, 4-vinyl pyridine (4-VP) and Methyl methacrylate (MMA), were used as provided by Sigma -Aldrich Company Ltd. 2,2ʹ -Azobis (isobutyronitrile) (AIBN; initiator) was supplied by Merck. FeCl 3.6H 2O (III) was used as received. Ethanol (Aldrich) was distilled from anhydrous stannous chloride. All other reagents were of analytical reagent grade and used as purchased without further purification.

2.2. Preparation of Iron (III) complex 0.5 gm (0.0018 mol) FeCl 3.6H 2O was dissolved in 100 ml filtered ethanol with stirring. In this solution 0.582gm (0.0055 mol) of 4-vinyl pyridine was added dropwise with stirring [1M: 3L] (VP-Fe) Complex. The mixture was refluxed with stirring on a magnetic stirrer for one hour at 60 oC. Then the mixture is cooled to room temperature. The brown complex Precipitated and filtered off, washed several times with ethanol and dried under vacuum over P 4O 10. The possible mechanism of the produced complex was represented in Figure 1. The analytical and physical characteristics was determined (Table1).

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ISSN: 2454-2490 Table 1: The analytical and physical data of Fe complex Elemental analysis

complex

4-VP-Fe

Yield %

Molecular Formula

M.Wt

80

C21H33Cl 3FeN 3O 6

586

%C

m.p

Color

(oC)

285

Brown

%H

%N

Calcd

found

Calcd .

found

Calcd .

found

43.06

43.0

5.68

5.59

7.17

7.13

Molar conductivity

9.8

2.3. Preparation of polymer Iron (III) complex 1.0 g of VP-Fe complex and 4.0 g of Methyl methacrylate were mixed in dimethylsulfoxide (DMSO; 50 mL). Then, the flask of reaction mixture was refluxed with stirring for 3 h and immersed in a pre-heated oil bath at 70±1 ◦C. During the reaction, a small amount of azobisisobutyronitrile (AIBN; 100 mg, 0.6 mmol) initiator was added to flask. The reaction mixture was precipitated in methanol as brownish bowder. The product was filtered, washed with methanol and dried using a vacuum at 60 ◦C for 2 h. The product will be referred here in as MMA-VP-Fe. The possible mechanism of the produced polymer complex is represented in Figure 2.

2.4. Solubility test Solubility of the synthesized vinyl pyridine Fe complex and the synthesized polymer Fe(III) complex were tested in various polar and non-polar solvents. About 5–10 mg of the sample was added to about 2 ml of the respective solvent in a test tube and kept overnight with the tube tightly closed. The solubility of the compounds was noted after 24 hours.

2.5. Physical and spectroscopic techniques The Fourier transform infrared (FT-IR) spectroscopy of the prepared samples was performed on a Perkin–Elmer 683 spectrophotometer (4000–200 cm -1) using KBr pellets. The elemental analys is for the synthesized complex was undertaken at the National Research Center, Micro analytical Centre, Giza, Eg ypt. The molar conductivity of (10 -3 M) o 1 solutions of the complex in DMSO were measured at 25 C with a Bibby conductimeter type MCl. H-N MR spectra were obtained with Perkin–Elmer R32-90-MHz spectrophotometer using TMS as internal standard. Mass spectra of the metal complex were recorded using JEULJMS-AX-500 mass spectrometer provided with data system. The thermal analyses (DTA and TGA) were carried out on a Shimadzu (TGA-50H) thermal analyzer, the temperature range covered was 27– 1000 oC and the scanning rate 10 oC per minute, under nitrogen atmosphere.

2.6. Antimicrobial and antitumor studies 2.6.1. Antimicrobial activity All microbial strains were provided from culture collection of the Regional Center for Mycology and Biotechnology (RCMB), Al-Azhar University, Cairo, Egypt. The antimicrobial activity was investigated on a dozen of newly synthesized compounds in order to increase the selectivity of these derivatives towards test microorganisms using well diffusion method [16]. Briefly, 100 μl of the test bacteria/fungi were grown in 10 mL of fresh media until they reached a count of approximately 108 cells/ml for bacteria or 105 cells/mL for fungi. One hundred µL of each sample (at 1 mg/ml) was added to each well (10 mm diameter holes cut in the agar gel). The plates were incubated for 24 -48 h at 37 °C (for bacteria and yeast) and for 48 h at 28 °C (for filamentous fungi). After incubation, the mi croorganism's growth was observed. Ampicillin and gentamycin were used as standard antibacterial drugs while amphotricin B was used as standard antifungal drug. The resulting inhibition zone diameters were measured in millimeters and used as criterion for the antimicrobial activity. If an organism is placed on the agar it will not grow in the area around the well if it is susceptible to the chemical. This area o f no growth around the disc is known as a Zone of inhibition. The size of the clear zone is prop ortional to the inhibitory action of the compound under investigation. Solvent controls (DMSO) were included in every experiment as negative controls. DMSO was used for dissolving the tested compounds and showed no inhibition zones, confirming that it has no influence on growth of the tested microorganisms.

2.6.2. Antitumor activity assay The tested human carcinoma cell lines were obtained from the American Type Culture Collection (ATCC, Rockville, MD). The cells were grown on RPMI-1640 medium supplemented with 10% inactivated fetal calf serum and 50µg/ml gentamycin. The cells were maintained at 37 °C in a humidified atmosphere with 5% CO2 and were subcultured two to three times a week. For antitumor assays, the tumor cell lines were suspended in medium at cell density of 5x104 cells/well in Corning® 96-well tissue culture plates, then incubated for 24 hours. The tested compounds were then added into 96 -well plates (six replicates) to achieve eight concentrations for each compound. Imitanib is used as a standard drug. Six vehicle controls with media or 0.5 % DMSO were run for each 96 well plate as a control. After incubating for 24 h, the numbers of viable cells were determined by the MTT assay 51, 52. Briefly, the media was removed from the 96 -well plate and replaced with 100 µl of fresh culture RPMI 1640 medium without phenol red then 10 µl of the 12 mM MTT

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stock solution (5 mg of MTT in 1 mL of PBS) to each well including the untreated controls. The 96 well plates were then incubated at 37°C and 5% CO2 for 4 hours. An 85 µl aliquot of the media was removed from the wells, and 50 µl of DMSO was added to each well and mixed thoroughly with the pipette and incubated at 37°C for 10 min. Then, the optical density was measured at 590 nm with the microplate reader (SunRise, TECAN, Inc, USA) to determine the number of viable cells and the percentage of viability was calculated as [1-(ODt/ODc)]x100% where ODt is the mean optical density of wells treated with the tested sample and ODc is the mean optical density of untreated cells. The relation between surviving cells and drug concentration is plotted to get the survival curve of each tumor cell line after treatment with the specified compound. The 50% inhibitory concentration (IC50), the concentration required to cause toxic effects in 50% of intact cells, was estimated from graphic plots of the dose response curve for each conc. using Graphpad Prism software [17].

3. RESULTS AND DISCUSSION The VP-Fe complex and polymer-Fe complex are stable at room temperature, non hydroscopic, insoluble in water and common solvent, vi z: MeOH, EtOH, CHCl 3, CCl 4, (CH 3)2CO and DMF but soluble in DMSO. The analytical and physical data of the prepared complex are given in Table (1). The good agreement between the experimental and theoretica l values of the C, H and N levels reveals that the methods of synthesis and purification of the metal complexes were performed successfully. Reaction of 4-vinyl pyridine with Iron (III) salt in ethanol gives complex 4-VP-Fe. The reaction leading to the com plex is represented schematically in Figure 1. The prepared complex possesses three vinyl linkers which should be suitable for copolymerization. The methyl methacrylate (MMA) was chosen as a co -monomer for radicalinduced polymerization reactions Figure 2. The copolymerization reactions of pure MMA with the prepared complex led to the polymer MMA-VP-Fe.

HC

FeCl3.6H2O

+

CH2

3

N

Cl



N

N

Fe

N

.6H2O

Cl

Cl

Figure 1: Preparation of 4- Vinyl p yridine-Iron(III) complex

CH3

H 2C

C

Cl

+

N

COOCH3

N N

Fe

Cl

Cl

AIBN



O

O

Cl N

O

O

N

Cl

.6H2O

N

Fe

Cl

O

O

Figure 2 : Preparation of polymer Iron (III) complex

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3.1. Molar conductivity

The molar conductance values of the complex in DMSO (10-3 M) is 9.8 Ω mol-1cm 2, indicating that, the complex is not electrolytes. This confirms that, the anion is coordinated to the metal ion .

3.2. Infrared spectra The mode of bonding between the ligand and the metal and the monomer can be revealed by comparing the IR spectra of the solid metal complex and ligand with that of the polymer metal complex. The IR spectrum of the 4-VP-Fe and MMA-VPFe compounds are presented in figures 3 and 4, respectively. In the spectra of 4-vinyl pyridine, bands in the region 16001380 cm-1 were attributed to C=C, C=N stretching and ring vibration [18]. On complexation these frequencies are shifted to the higher wave numbers, clearly indicating that the ligand is bonded to the central metal atom through the hetero Natom. This is also confirmed by the appearance of new bands at 261 and 265 cm−1 this have been assigned to the M-N in 4-VP-Fe and MMA-VP-Fe, respectively [19]. The peaks at 1632,1520 and 1456 cm −1 are attributed to characteristic vibration of the pyridine ring on 4-VP/Fe [20] and the intensity of the beaks in polymer complex MMA-VP-Fe decrease. The beaks of the C=N stretching band of the pyridine ring displaced to 1618 and 1402 [21] .The absorption band at 1068 cm −1 is assigned to the C- H bending in the in-plane rings in Ligand and it shifted to 1170 cm−1 in 4-VP-Fe indicating that −1 the ligand is bonded to the central metal atom through the hetero N-atom [22]. The absorption band at 1726 cm is −1 assigned to the C=O in MMA-VP-Fe and this band not found in 4-VP-Fe [23]. The absorption band at 1021 cm is assigned to the C-O in MMA-VP-Fe [24]. We have found that the absorption band at 465 and 544 cm −1 is due to the stretching vibration of Fe-Cl bond in 4-VP-Fe and it shifted to 478 and 599 cm _1 due to polymerization in MMA-VP-Fe [20].

Figure 3: IR spectrum of VP-Fe(III) complex

Figure 4: IR spectrum of MMA-VP-Fe(III) complex

3.3. 1H – NMR studies 1

H-NMR spectra of the 4VP, 4-VP-Fe and MMA-VP-Fe in deuterated DMSO show signals consistent with the proposed structure. For Ligand, the peak at 8.3 ppm are assigned to proton of CH=N. The aromatic proton observed at 7.1 ppm. The peak at 6.5 ppm is assigned to proton of CH=C which attach to pyridine ring. The peaks at 5.8 and 5.3 ppm are assigned to protons of C=CH 2. For 4-VP-Fe, the peak at 8.9 ppm is assigned to protons of CH=N. The aromatic protons observed in 6.65-7.6 ppm range. The peak at 6.19 ppm is ass igned to proton of CH=C which attach to pyridine ring. The peak at 5.55 is assigned to proton of C=CH 2. However, for MMA-VP-Fe, the peak at 8.56 ppm is assigned to proton of CH=N. aromatic proton observed at 7.5 ppm [24]. The peak at 3.295 ppm is assigned to proton of C–CH-C which attached to pyridine ring. The peaks at 2.529 and 2.495 ppm are assigned to protons of C-CH2-C-C=O and the peak at 1.737 and 1.708 ppm is assigned to proton of C-CH 2-C [25].

3.4. Mass spectra of metal complex studies The mass spectra of Fe (III) complex 4-VP-Fe confirmed their proposed formulations. It reveals the molecular ion peaks (m/z) at 586 amu, consistent with the molecular weight of the Fe(III) complex. Furthermore, the fragments observed at 105,108, 162, 267, 372, 478 and 481 are due to C 7H7N, H12O6, FeCl 3, C 7H7 Cl3FeN , C 14 H 14Cl3FeN2, C21H 21Cl 3FeN 3 and C14H 26Cl 3FeN 2O 6, moieties respectively. The spectral data of the Fe(III) Complex (4-VP-Fe) are presented in table 2.

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ISSN: 2454-2490 Table 2: Mass fragmentation of Iron(III) complex Fragment

m/z

Rel. Int.

C7H 7N

105

100

H12O6

108

2.62

FeCl 3

162

1.06

C 7H7 Cl 3FeN

267

0.57

C14 H14Cl 3FeN 2

372

0.49

C21H21Cl 3FeN 3

478

1.4

C14H 26Cl 3FeN 2O 6

481

1.6

C21H 33Cl 3FeN 3O 6

586

3.2

3.5. DTA and TGA (Thermal analyses) Since the IR spectra indicate the presence of water molecule, thermal analyses (DTA and TGA) were carried out to a certain their nature. The thermal curves in the temperature 27 -1000°C range for metal complex and polymer complex are thermally stable up to 60°C. Dehydration is characterized by endothermic peak within the temperature 85 -122°C range. The decomposition step for 4-VP-Fe shows endothermic peak at 85°C with 11.76 % weight loss is due to loss of s ix hydrated water molecules [26]. , however, endothermic peak observed at 257°C with 22.68 % weight loss, is correspond to the loss of VP unit [19] . However, the endothermic peak appears at 285°C with 23.53% weight loss may be assigned to the melting point. Oxidative thermal decomposition occurs at 578°C with exothermic peaks, leaving Fe 2O3 with 15.87% weight loss. MMA-VP-Fe shows endothermic peak at 122°C with 4.77% weight loss, are assigned to elimination of six hydrated water molecules. The endotherm ic peak observed at 238.3°C with 17.5 % weight loss may be assigned to the loss of VP unit [27]. The endothermic peak observed at 267°C with 19.25 % weight loss may be assigned to the melting point. Oxidative thermal decomposition occurs at 468°C with exothermic peaks, leaving Fe 2O3 with 16.73 % weight loss. The thermal data are shown in table 3 and the thermo grams of 4-VP-Fe and MMA-VP-Fe are shown in figures 5 and 6, respectively.

Table 3: DTA and TGA data for Iron(III) complex and polymer- Iron(III) complex

Compound

metal complex (VP-Fe)

Polymer complex (MMA-VP-Fe)

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TGA (Wt.loss%)

Temp. (oC)

Assignment

85

Loss of six hydrated water

Endo

11.76

257

Loss of VP unit

Endo

22.68

578

Thermal decomposition with the formation of Fe2O3

Exo

15.87

122

Loss of six hydrated water

Endo

4.77

238

Loss of VP unit

Endo

17.5

468

Thermal decomposition with the formation Fe2O3

Exo

16.73

DTA (Peak)

Found

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Figure 5 : Thermogram of VP-Fe (III) complex

Figure 6 : Thermogram of MMA-VP-Fe (III) complex.

3.6 Antimicrobial activity The antibacterial activity was tested against four pathogenic bacterial strains (Escherichia coli, Pseudomonas aeruginosa, Bacillus sub tilis and Streptococcus pneumoniae) and compared with standard drugs (Ampicillin and Gentamicin). The results of the antimicrobial activities showed variations in activities among the tested compounds. Interestingly, the tested compound MMA-VP-Fe also exhibited highest tendency to inhibit Gram positive bacteria than Gram negative bacteria. The mode of action of the compounds may involve the formation of a coordinate bond groups with the active centers of the cell constituents resulting in an interference with the cell process. This activity can be explained on the basis of chelation theory [28]. All compounds were found with no antibacterial activity against the Psedomonas aeruginosa under the screening conditions. Additionally, none of the tested compounds exhibited antifungal activity ag ainst the Candida alb icans under the screening conditions. On the other hand, the tested compound VP-Fe was found with no antibacterial or antifungal activities under the screening conditions (Table 4 and 5).

Table 4: Antibacterial activity of the synthesised compounds tested at 10 mg/ml Gram-negative bacteria Tested

Gram-positive bacteria

Escherichia coli

Psedomonas aeruginosa

Staphylococcus pneumoniae

Bacillus sub tilis

0

0

0

0

Polymer complex (MMA-VP-Fe)

17.3 ± 0.63

0

17.4 ± 0.64

20.2 ± 0.58

*Ampicillin

--

--

23.8 ± 0.2

32.4 ± 0.3

*Gentamicin

19.9 ± 0.3

17.3 ± 0.1

--

--

compounds metal complex (VP-Fe)

* Ampicillin and Gentamicin were used as standard antibacterial drugs against Gram positive and Gram negative bacteria respectively.

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ISSN: 2454-2490 Table 5. Antifungal activity of the compounds at 10 mg/ml Fungi

Compounds Candida alb icans

Aspergillus fumigatus

metal complex (VP-Fe)

0

0

Polymer complex (MMA-VP-Fe)

0

15.2 ± 0.58

25.4 ± 0.1

23.7 ± 0.1

Amphotricin B*

* Amphotricin B was used as standard antifungal drug

3.7. Antitumor activities The activity of the compounds was performed against tumor cell line using viability assay on two carcinoma cells (i.e. cervical cancer cell line (HeLa cells) and human colon carcinoma cell line (HCT-116 cells). The in vitro growth inhibitory rates (%) and inhibitory growth activity (as measured by IC 50) of the synthesized compounds were investigated in comparison with the well-known anticancer standard drug Imatinib (2-substituted aminopyrimidine derivative; Gleevec®). Data generated were used to plot dose response curves and presented in Fig. ( 7a,b). However, the results revealed that the tested compounds showed high variation in the inhibito ry growth rates and activities against the tested tumor cell lines in a concentration dependent manner (Fig. 7 a,b). The difference between inhibitory activities of all compounds with different concentrations was statistically significant P < 0.001. Furthermore, the activity against HCT-116 cells was detected for compound VP-Fe (with IC50 value 17.8±1.3 µg/ml), compared with reference standard (24.6±0.3 µg/ml) followed by MMA-VP-Fe (88.3±1.2 µg/ml). Lower sensitivity was detected for HeLa cell line showing higher IC 50 values in the same trend of activity measured for HCT-116.This can be explained as Metal binds to DNA. It seems that, change the anion and the nature of the metal ion has effect on the biological behavior, due to alter binding ability of the DNA binding. Antitumor effect of the compounds may be attributed to the central metal atom which was explained by Tweedy's chelation theory [29]. Also, the positive charge of the metal increases the acidity of coordinated ligand that bears protons, leading to stronger hydrogen bonds which enhance the biological activity. Also, metal could act as a double-edged, sword by inducing DNA damage and also by inhibiting their repair. The OH radical reacts with DNA sugars and bases and the most significant and well-characterized of the OH reactions is hydrogen atom abstraction from the C 4 on the deoxyribo unit to yield sugar radicals with subsequent β-elimination, by this mechanism strand breakage occurs as well as the release of the free bases. Another form of attack on the DNA bases is by solvated electrons, probably via a similar reaction to those discussed below for the direct effects of radiation on DNA [29].

Figure 7 : Acti vity of the prepared complexes against (a) HCT-116 cell line and (b) HeLa cell line

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Table 6: Acti vities of the compounds with reference standard drug evaluated on colon and cervical cancer cell lines

compounds

IC 50 values (µg/ml) HCT-116

HeLa

Metal complex (VP-Fe)

17.8±1.3

21.5±1.4

Polymer complex (MMA-VP-Fe)

88.3±1.2

135.9±3.4

Imitanib

24.6±0.3

30.1±0.7

CONCLUSION In this contribution radical induced copolymerization reactions of Iron(III) complex with pure methyl methacrylate (MMA) in DMSO using azobisisobutyronitrile (AIBN) as initiator led to formation of polymer Iron(III) complex. The suggested structures of the Iron(III) complex and polymer Iron (III) complex were confirmed by using spectroscopic measurements. IR, elemental analysis, DTA, and TGA results show that the polymer–Iron (III) complex was successfully synthesized. The prepared compounds have been tested against number of tumor and number of microorganisms giving promising results that needs further pharmaceutical and in vivo studies to explore their action.

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Vol. 2, No. 2, April 11, 2016 ISSN: 2454-2490

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