Probing the interaction of iron complex containing N3S2 macrocyclic ligand with bovine serum albumin using spectroscopic techniques

Journal Pre-proof Probing the interaction of iron complex containing N3S2 macrocyclic ligand with bovine serum albumin using spectroscopic techniques

Hany El-Shamy, Shaban Y. Shaban, Ibrahim El-Mehasseb, Maged El-Kemary, Rudi van Eldik PII:

S1386-1425(19)31201-6

DOI:

https://doi.org/10.1016/j.saa.2019.117811

Reference:

SAA 117811

To appear in:

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy

Received date:

24 August 2019

Revised date:

16 November 2019

Accepted date:

17 November 2019

Please cite this article as: H. El-Shamy, S.Y. Shaban, I. El-Mehasseb, et al., Probing the interaction of iron complex containing N3S2 macrocyclic ligand with bovine serum albumin using spectroscopic techniques, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy(2019), https://doi.org/10.1016/j.saa.2019.117811

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© 2019 Published by Elsevier.

Journal Pre-proof Probing the interaction of iron complex containing N3S2 macrocyclic ligand with bovine serum albumin using spectroscopic techniques Hany El-Shamya,*, Shaban. Y. Shabanb, Ibrahim El-Mehassebb, Maged El-Kemaryc, Rudi van Eldikd a

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Chemistry Department, El Shaheed Ezzat El Shafei Secondary School for Girls, Kafrelsheikh, Egypt b Chemistry Department, Faculty of Science, Kafrelsheikh University, 33516 Kafrelsheikh, Egypt c Chemistry Department, Nano Science and Technology Institute, Kafrelsheikh University, 33516 Kafrelsheikh, Egypt d Chemistry, Institute of inorganic chemistry, Erlangen-Nuernberg University, Erlangen, Germany Abstract

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The interaction of bovine serum albumin (BSA) with seven-coordination iron (II) complex containing sulfur-based macrocyclic ligand was investigated by means of

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UV/vis absorption spectroscopy and fluorescence quenching technique. The accurate fluorescence spectra are obtained by using Inner filter effect (IFE) correction. The

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apparent association constant, kapp, the number of binding sites, n, and the apparent binding constant KSV were found to be 0.95 × 103 M1, 0.96, and 6.13 × 104 M−1,

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respectively. It found that BSA molecules are adsorbed on the surface of iron (II)

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complex by electrostatic interaction. The quenching mechanism is discussed involving energy transfer from BSA to iron (II) complex. Keywords: Inner filter effect, Energy transfer, Fluorescence quenching, Bovine serum albumin, Macrocyclic ligand, Iron (II) Complex Corresponding author. Tel: +2(0) 1008824963 (H. El-Shamy). E-mail addresses: [email protected], [email protected] (H. El-Shamy).

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Journal Pre-proof 1. Introduction Bovine serum albumin (BSA), is the most abundant protein in plasma, and is used in many biological studies. It is of great importance in many physiological functions, because it is the main component of the soluble protein in circulatory system [1]. It safeguards the pH buffer of the blood [2]. As pH changes, albumin undergoes structural changes very easily [3, 4]. BSA is a protein model with 3D structure thought to resemble the structure of human serum albumin [5]. BSA contains three types of intrinsic fluorophores including two residues of Tryptophan (trp), which can be quenched [6].

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The study of the mechanism of drug interaction and serum albumins attracted the

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attention of a large number of researchers [7-9]. One of the most appropriate techniques for determining the interaction between drugs and serum albumins is Fluorescence

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spectroscopy [10-12]. Much knowledge about structural modifications can be found in BSA by fluorescence spectroscopy. The binding characterizations of drugs and BSA have

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been scrutinized by many researchers [13,14]. Several methods such as Benesi–

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Hildebrand equation [15] and Stern–Volmer equation [16-18]. have been used to study the quenching of proteins and the interaction between proteins and drugs. The nature of

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binding between the drugs and the serum albumins has been recorded [19, 20]. From the point of view of biological pharmacy, one of the important functions of the albumin is to carry the medicines in addition endogenous and exogenous materials, the binding ability

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and sites of serum albumins have been described [21,22].

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Macrocyclic chelators can form highly stable complexes with transition metals [23] and multidentate ligands is an interesting field in chemistry and has been the subject of extensive research due to their potential applications in building block macrocyclicbased biomedical [24]. Iron is a widespread chemical element that is involved in the biological activity of living organisms. Iron is involved in the formation of blood, respiration, and biological immune processes, and involves the formation of more than a hundred enzymes. Iron concentration in human blood varies greatly. It has a daily rhythm and changes in its serum level to human health within 24 hours can be as great as ~ 100%. Some diseases

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Journal Pre-proof cause change of iron content in the serum; for example, iron content decreased in case of anemia but increased in blood pigmentation [25]. We recently reported on the new crystalline and interactive structure of iron(II) complex,[(pyN3S2)FeII(ClO4)2]

([pyN3S2=

{6,7-dihydro-15,19-nitrilobenzo(e,p)

(1,4,7,15)dithiadiazacycloheptadecine-N,N´,N´´,S,S´}),

represented

in

Scheme

1).

Complex was structurally characterized as a seven-coordinate iron center with the slightly distorted pentagonal-bipyramidal, structure in each case with the macrocycle occupying the pentagonal plane and the axial positions being filled by two perchlorate

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ions. The iron-OClO3 bond lengths are slightly long compared to related complexes. It

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was found to be an active catalyst in the oxidation of triphenyl phosphine as substrate [26]. While relatively rare, seven-coordinate complexes of first row transition metals are

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nevertheless well-established [27]. However, we are not aware of any studies of bovine serum albumin interaction with these complexes. This is largely because the complexes

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are high-spin and paramagnetic; thus, “conventional wisdom” deems the interaction

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processes to be intractable by NMR spectroscopic investigation. In this paper, we report the interaction of BSA with iron (II) complex in details by

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means of fluorescence and ultraviolet-visible (UV-Vis) spectroscopic measurements. Because the binding ability of drug-albumin has an important impact on metabolism of

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drug, the investigation of such an interaction is very important.

Scheme 1. Schematic representation of macrocyclic ligand together with its iron (II) complex adopted from reference 26. 2. Experimental Section 2.1. Materials and physical techniques

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Journal Pre-proof All reagents and solvents used for this work were commercial products and are of reagent quality unless otherwise stated. Methanol was purified and dried by passing via a double alumina column. The conductivity of the complex was obtained using an industrial instrument model RC T68 Conductivity Bridge. Measurements were taken at room temperature at 1000Hz on solutions that were ~10-3 M. Fe-complex was synthesized following the reported procedures [26] and used in different concentrations (2, 4, 6, 8, 10, 12, 14, 16, 18) × 106 M in a mixture of methanol and distilled water (1:4).

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Caution: Metal perchlorate salts are potentially explosive and should be handled

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with care.

BSA (fatty acid free, Sigma) was dissolved in double distilled water to prepare the

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stock solution (5 × 106 M). All measurements were performed at ambient temperature. The fluorescence quenching measurements were recorded out with a Shimadzu RF-

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5301PC spectrofluorometer. The excitation wavelength of BSA was 278 nm and the

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emission was monitored at 340 nm. Absorption spectral measurements were recorded using a Shimadzu UV-2450 spectrophotometer.

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3. Results and discussions

3.1. Synthesis of [(pyN3S2)FeII(ClO4)2].

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Iron complexes [(pyN3S2)FeII(ClO4)2] has been synthesized as reported previously [26] via template condensation of pyridine-2,6-dicarbaldehyde and 1,2-bis(o-

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aminophenylthio) ethane in methanol in the presence of a stoicheiometric amount of iron perchlorate. [(pyN3S2)FeII(ClO4)2] was structurally characterized as a seven-coordinate iron center with the slightly distorted pentagonal-bipyramidal, structure with the macrocycle occupying the pentagonal plane and the axial positions being occupied by two perchlorate ions. The iron-OClO3 bond lengths are slightly long compared to related complexes. [(pyN3S2)FeII(ClO4)2] is high-spin d6 with magnetic moments close to the value of 4.9 BM. The electronic spectra of [(pyN3S2)FeII(ClO4)2], recorded in methanol solution, exhibited two absorption bands at 210 (ε = 15 × 103 M-1cm-1) and 310 nm (ε = 2.7

× 103

M1cm-1),

which

can

be

assigned

4

to

ππ*

ligand

transitions.

Journal Pre-proof [(pyN3S2)FeII(ClO4)2] exhibits an absorption band in the visible region at 581nm (ε = 15 M1cm1) attributed to dd transitions. Electrical conductivity measurements in methanol showed that [(pyN3S2)FeII(ClO4)2] is 1:2 electrolyte, indicating the displacement of the two perchlorate anions by methanol and the structure in methanol could be formulated as [(chelate)FeII(CH3OH)2]2+ + 2ClO4-. 3.2. Interaction of BSA to iron-complex The interaction of the iron-complex with BSA was probed by a combination of biophysical techniques as outlined below:

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3.2.1. Absorption spectroscopy

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UV–vis absorption spectroscopy is a simple technique to explore the structural changes of BSA molecules and to recognize the complex formation between BSA and

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iron-complex. The absorption spectra of BSA in the absence and presence of Fe-complex at different concentrations are shown in Fig. 1. Absorption of BSA at around 280 nm, is

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attributed to all types of chromophores (Phe, Tyr and Trp) [28]. The addition of different

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concentration of Fe-complex to the BSA leads to regular increase in the absorption peak at 278 nm with slightly blue shift (5 nm). The increase in the absorption with blue shift

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can be assigned to the interaction of bovine serum albumin with Fe-complex by mean of

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ground state complex formation [29].

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The equilibrium for the BSA∙∙∙∙Fe-complex can be given as shown by scheme 2 and the apparent association constant can be given as illustrated by Eq. 1: 𝐵𝑆𝐴 + 𝐹𝑒 − 𝑐𝑜𝑚𝑝𝑙𝑒𝑥 ⇌ 𝐹𝑒 − 𝑐𝑜𝑚𝑝𝑙𝑒𝑥 … 𝐵𝑆𝐴 (𝑆𝑐ℎ𝑒𝑚𝑒 2) 𝐾𝑎𝑝𝑝 =

[𝐵𝑆𝐴 ∙∙∙∙ 𝐹𝑒 − 𝑐𝑜𝑚𝑝𝑙𝑒𝑥] [𝐵𝑆𝐴][𝐹𝑒 − 𝑐𝑜𝑚𝑝𝑙𝑒𝑥]

(1)

The change in intensity of the absorption peak at 278 nm, as a result of formation of the surface complex, were utilized to obtain Kapp according to the method reported by Benesi and Hildebrand [15] as expressed by Eq. 2 as follow:

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Journal Pre-proof 𝐴𝑜𝑏𝑠 = (1−∝)𝐶0 𝜀𝐵𝑆𝐴 1+ ∝ 𝐶0 𝜀𝐶 1 (2) Where Aobs is the observed absorbance of the solution containing different concentration of Fe-complex at 278 nm, α is the degree of association between BSA and Fe-complex, εBSA and εC are the molar extinction coefficients at the defined wavelength (278 nm) of BSA and the formed complex. Eq. 2 can be reformulated to Eq. 3: 𝐴𝑜𝑏𝑠 = (1−∝)𝐴0 + ∝ 𝐴𝑐

(3)

Where A0 and AC are the absorbance of BSA and the complex at 278 nm with the

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concentration C0, respectively. At relatively high complex concentration, α can be equated to the following:

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𝐾𝑎𝑝𝑝 [𝐹𝑒 − 𝑐𝑜𝑚𝑝𝑙𝑒𝑥] 1 + 𝐾𝑎𝑝𝑝 [𝐹𝑒 − 𝑐𝑜𝑚𝑝𝑙𝑥]

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𝛼=

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In this case Eq. 3 can be reformed to Eq. 4 as follow:

(4)

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1 1 1 = + 𝐴𝑜𝑏𝑠 − 𝐴0 𝐴𝑐 − 𝐴0 𝐾𝑎𝑝𝑝 (𝐴𝑐 − 𝐴0 )[𝐹𝑒 − 𝑐𝑜𝑚𝑝𝑙𝑒𝑥]

By plotting of 1/(A0bs – A0) vs. reciprocal concentration of the Fe-complex, the

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apparent association constant was calculated and found to be 0.95 × 103 M1. The apparent association constant between BSA and Fe-complex indicates that BSA has

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affinity towards Fe-complex [30].

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Journal Pre-proof 0.78

-6

-6

0 x 10 M

0.52 0.39

1/A-A 0

Fe-comp

0.65

Absorbance

40

18 x 10 M

30 20 10 0 0.0

0.26

0.1 0.2 0.3 0.4 0.5 -6 1 / [Fe-Complex] x 10 M

0.13 0.00 270

300

330

360

390

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240

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Complex

-p

Wavelength/nm

Fig. 1. Absorption spectrum of BSA (5 × 106 M) in the absence (black) and presence

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(dark cyan) of Fe-complex in the concentration range of (2-18 × 106 M). Inset is the plot

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of 1/A-A0 vs. 1/ [complex] at 278 nm as a function of number of Fe-complex equivalents.

3.2.2.1 Inner filter effect

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3.2.2. Fluorescence quenching studies

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Accurate fluorescence spectra are obtained by using Inner filter effect correction [31] by the following Eq. 5.

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Fcorr = Fobs * 10[

(𝐴𝑒𝑥 + 𝐴𝑒𝑚 ) ] 2

(5)

Where Fcorr is the corrected fluorescence spectrum, Fobs is the measured or observed fluorescence intensity, Aex is the absorbance at the excitation wavelength and Aem is the absorbance of the sample at the emission wavelength. The corrected intensities are shown in Fig. 2

3.2.2.2 Stern-Volmer analysis

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Journal Pre-proof The interaction of BSA with Fe-complex was studied by spectrofluorometer at room temperature [32]. An aqueous solution of BSA (5 × 10−6 M) was titrated with increasing concentration of Fe-complex solution as shown in Fig. 2. As seen from Figure 2, the fluorescence intensity of BSA showed a significant decrease with increasing the concentrations of the added complex. The strength and type of the quenching process in BSA/Fe-complex was determined using Stern-Volmer analysis according to Eq. 6. 𝐼0 = 1 + 𝐾𝑆𝑉 [𝑄] 𝐼

(6)

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Where I0 and I are fluorescence intensities in the absence and presence of quenchers, respectively. KSV is the Stern-Volmer constant and [Q] is the quencher

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concentration, Fe-complex. The ratios I0/I were calculated and plotted against quencher concentration according to Eq. 6 as shown in Fig. 2 (inset) and the calculated quenching

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constant, KSV is 6.13 × 104 M−1. The stability constant for BSA and Fe-complex could be

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represent the static quenching [33]. The Stern–Volmer constant is related to quenching rate constant by the relation kq = KSV/τ. The measured average lifetime value of BSA in

lP

methanol is equal to 5.28 ns (See supporting information, Figure S1). Then the calculated quenching rate constant, kq is equal to 1.16 × 1013 M−1s−1 which is much greater than the

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maximum collision quenching constant of various kind of quencher to biopolymer (2 × 1010 M−1 s−1) [34]. This indicates the static mode is mainly involved in the mechanism of

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quenching process [35].

8

2.25

450

-6

0 x 10 M 1.80

Fe-comp

375

I0 / I

-6

300

18 x 10 M

1.35 0.90 0

225

4 8 12 16 -6 [Fe-Complex] x 10 M

150 75 0

IFE Correction Applied

280

320

360

400

440

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Fluorescence intensity(a.u)

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480

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Wavelength/nm

Fig. 2. Correction of emission intensity for inner filter effect according to Eq.(5),

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fluorescence quenching of BSA (5 × 106 M) in the absence (black) and presence (dark

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cyan) of Fe-complex in the concentration range of (218 × 106M), and inset is the

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Stern-Volmer plot for the steady-state fluorescence quenching of BSA by Fe-complex. 3.2.3. Binding constant and binding sites

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If it is supposed that there are similar and independent binding sites in BSA, the relationship between fluorescence intensity and the quencher medium can be assumed

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from the following Eq. 7:

nQ + B → Qn . . . B

(7)

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Where B is the fluorophore, Q is the quencher, nQ + B is the postulated complex between a fluorophore and n molecules of quencher. The constant K is given by the following Eq. 8:

K = [Qn . . . . B] / [Q]n . [B]

(8)

If the total amount of biomolecules (bound or unbound with the quencher) is B0, then [B0] = [Qn...B] + [B], here [B] is the concentration of unbound biomolecules, then the relationship between fluorescence intensity and the unbound biomolecule as [B]/[B0] = I/I0 that shown in Eq. 9: log [(I0-I)/I] = log Ka + n log [Q]

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(9)

Journal Pre-proof where Ka is the binding constant or the apparent association constant for drug–protein interaction, and n is the number of binding sites. The values of Ka and n were determined from the slope and the intercept and were found to be 0.35 × 104 M−1 (R2 = 0.9882) and 0.96, respectively (Fig. 3). 0.4

0.0 -0.2

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log [ I0- I / I ]

0.2

-0.4

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-0.6

2

R = 0.9882

-4.8

-5.0

-5.2

-5.4

-p

-0.8 -4.6

-5.6

-5.8

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log [Q]

Fig. 3. Plot of log [(I0 − I)/I] vs. log [Q].

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The value of Ka is in the order of 104, which indicates that there is a moderate interaction between Fe-complex and BSA and the value of “n” is approximately equal to

[36-38].

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1 and this value indicates that there is only one binding site in the BSA for Fe-complex

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3.2.4. Scheme of interaction

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The fluorescence of BSA is due to the presence of tyrosine, tryptophan and phenylalanine residues. Hence spectroscopic methods are usually applied to study the conformation of the serum protein. According to Miller [39], the difference between the excitation and emission wavelength (Δλ = λemi - λexc) reflects the spectra of chromophores with the different natures. With larger Δλ (60 nm), the fluorescence of BSA is characteristic for the tryptophan residue, and smaller Δλ (15 nm), are characteristic for tyrosine [40]. The fluorescence spectra of BSA with various concentrations of complex were recorded at (Fig 2). With an increasing concentration of complex the tryptophan fluorescence emission decreased regularly, but no significant change in wavelength was

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Journal Pre-proof observed. It suggests that the interaction of complex with BSA affects only the conformation of the tyrosine region, but not the tryptophan region and this is because tyrosine contains one aromatic hydroxyl group, unlike tryptophan. Hence it is clear that the presence of a hydroxyl group in the tyrosine residues may be responsible for the interaction of BSA with iron complex, a scheme of interaction can be presented in

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Scheme 3.

Scheme 3. Interaction between BSA and Fe-complex.

3.3. Mechanism of quenching It is most likely that the quenching process is due to the energy-transfer reaction between BSA and Fe-complex. It should be noted that the possibility of the electron transfer reaction was excluded due to the presence of clear overlap between the emission spectrum of BSA and absorption spectrum of Fe-complex (Fig. 4). Moreover, the excited state energy of BSA (~3.6 eV, was calculated from the emission wavelength of BSA by using the equation E = hν, where ‘E’ is excited state energy of BSA, ‘h’ is the Plank’s

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Journal Pre-proof constant and ‘ν’ is equal to c/λ, in which ‘c’ is speed of light and ‘λ’ is the fluorescence maximum wavelength of BSA) [36,41] is greater than the band gap energy of complex (Eg= 3.04 eV). From the above results the fluorescence intensity of BSA is reduced by energy transfer from BSA (donor) to Fe-complex (acceptor) [42]. Energy transfer efficiency (E) is given through the following Eq. (10) [43] :

E = 1-

I

(10)

I0

Where, I is the emission intensity of BSA (donor) in the presence of Fe-complex

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(acceptor) and I0 is the emission intensity of BSA. Energy transfer efficiency increases with increasing the concentration of Fe-complex as shown in Fig. 5. As the concentration

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of Fe-complex increases, the number of BSA molecules adsorbed on the surface of Fe-

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complex also increases [33].

1.0

0.5

lP

150

0.0

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300

(B)

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(A)

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Absorbance

(C)

(D)

300

400 Wavelength/nm

0 500

Fluorescence intensity(a.u)

-p

complex is also increase and as a result, the amount of energy transfer from BSA to Fe-

Fig. 4. (A)- Absorption of BSA (B) - Emission spectrum of BSA (C) - Absorption of Fecomplex and (D)- Emission spectrum of Fe-complex.

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Journal Pre-proof 0.8

E

0.6 0.4 0.2

0

4

8

12 -6

16

20

of

0.0

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[Fe-complex] x 10 M Fig. 5. Energy transfer efficiency of BSA with various concentration of Fe-complex (2-

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18 × 106 M). 4. Conclusion

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The interaction of Fe-complex with BSA has been investigated by spectroscopic

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measurements. Of the synchronous fluorescence spectra, the binding constant, number of binding sites and the quenching rate constant have been studied by mean of the relevant

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fluorescence data. The results clearly indicated that: i) the interaction of BSA with Fecomplex by mean of ground state complex formation; ii) the quenching of the intrinsic

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fluorescence of BSA is attributed to energy transfer from bovine serum albumin to iron (II) complex; iii) a static mode is mainly involved in the mechanism of quenching. The

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present investigations demonstrate that the investigated Fe-complex may find biomedical and therapeutic applications.

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Graphical abstract

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Journal Pre-proof Highlights Seven-coordination iron - complex containing sulfur-based macrocyclic ligand.

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Interaction of bovine serum albumin with iron complex via ground state complex.

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Flourscence quenching BSA through energy transfer from BSA to iron (II) complex.

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a static mode is mainly involved in the mechanism of quenching.

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