A comparative study of the spectral, fluorometric

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 183 (2017) 439–450

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A comparative study of the spectral, fluorometric properties and photostability of natural curcumin, iron- and boron- complexed curcumin Fatima Mohammed, Fiza Rashid-Doubell, Seamas Cassidy, Fryad Henari Department of Basic Medical Sciences, Royal College of Surgeons in Ireland, Medical University of Bahrain, P.O. Box 15503, Adliya, Bahrain

a r t i c l e

i n f o

Article history: Received 15 February 2017 Received in revised form 11 April 2017 Accepted 17 April 2017 Available online 21 April 2017 Keywords: Curcumin Iron-complexed curcumin Boron-complexed curcumin Spectroscopy Fluorometry Quantum yield Photostability Fluorescence intensity

a b s t r a c t Curcumin is a yellow phenolic compound with a wide range of reported biological effects. However, two main obstacles hinder the use of curcumin therapeutically, namely its poor bioavailability and photostability. We have synthesized two curcumin complexes, the first a boron curcumin complex (B-Cur2) and the second an iron (Fe-Cur3) complex of curcumin. Both derivatives showed high fluorescence efficiency (quantum yield) and greater photostability in solution. The improved photostability could be attributed to the coordination structures and the removal of β-diketone group from curcumin. The fluorescence and ultra violet/visible absorption spectra of curcumin, B-Cur2 and Fe-Cur3 all have a similar spectral pattern when dissolved in the same organic solvent. However, a shift towards a lower wavelength was observed when moving from polar to non-polar solvents, possibly due to differences in solvent polarity. A plot of Stokes' shift vs the orientation polarity parameter (Δf) or vs the solvent polarity parameter (ET 30) showed an improved correlation between the solvent polarity parameter than with the orientation polarity parameter and indicating that the red shift observed could be due to hydrogen-bonding between the solvent molecules. A similar association was obtained when Stokes' shift was replaced by maximum synchronous fluorescence. Both B-Cur2 and Fe-Cur3 had larger quantum yields than curcumin, suggesting they may be good candidates for medical imaging and in vitro studies. © 2017 Elsevier B.V. All rights reserved.

1. Introduction Curcumin, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene3,5-dione is a hydrophobic phenolic compound obtained from the plant Curcuma longa [1]. The chemical structure of curcumin consists of three moieties; two aromatic rings with hydroxy and methoxy substituents, linked by a seven carbon unit containing a β-diketone moiety [2–5]. The β-diketone structure can undergo keto-enol tautomerism in solution, with the di-keto/keto-enol ratio dependent on both solvent characteristics and temperature [6,7]. The enolic form predominates in non-polar and moderately polar solvents [1]. It has been reported that curcumin possesses a variety of biologically significant properties, including antibacterial, anti-inflammatory and antioxidant effects [8–10], as well as having potential anti-cancer activity [11]. However, a major obstacle when using curcumin therapeutically is its poor aqueous solubility and the lack of photostability [12]. Curcumin is poorly soluble in water, but is readily soluble in polar and non-polar organic solvents, such as methanol and xylene, respectively [13,14].

E-mail address: [email protected] (F. Mohammed).

http://dx.doi.org/10.1016/j.saa.2017.04.027 1386-1425/© 2017 Elsevier B.V. All rights reserved.

Wang and co-workers found that curcumin is both pH sensitive and light sensitive [15,16]. It degrades upon exposure to alkaline pH into; trans-6-(4′-hydroxy-3-methoxyphenyl)-2,4-dioxo-5-hexenal, vanillin, ferulic acid and feruloyl methane [15]. Both curcumin solution (ethanolic and methanolic extracts) and solid decomposes when exposed to sunlight into the following degradation products: vanillin, vanillic acid, ferulic aldehyde and ferulic acid [17]. In spite of the fact that mechanism of curcumin degradation is not fully understood, it is believed to be through α,β-unsaturated β-diketo moiety [1]. The former phenomenon can be reduced by conjugating curcumin to lipids, liposomes, albumins, cyclodextrin, surfactants and polymers [2]. Curcumin exhibits a strong absorption in both ultraviolet and visible (UV/Vis) regions of the spectrum, with an absorption peak at 430 nm [18]. The absorption spectrum of curcumin is solvent dependent. The maximum absorption peak for curcumin in polar solutions shows a big red shift, e.g. the maximum in dimethyl sulfoxide is at 429 nm while that in cyclohexane is at 408 nm [19]. Curcumin also exhibits fluorescence with low quantum yield [6]. We have coordinated curcumin with the elements boron and iron in an attempt to improve its solubility and stability. Boron was chosen because it is a metalloid and forms a negative charged tetrahedral complex with curcumin. In contrast iron (III) forms a neutral octahedral complex. In this study, we investigated the behaviour of the boron and iron

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F. Mohammed et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 183 (2017) 439–450

curcumin complexes in different organic solvents. The photostability and the fluorometric properties of curcumin, and its respective complexes with boron and iron were investigated in different organic solvents using different spectroscopic techniques. 2. Materials and methods 2.1. Synthesis of curcumin, B-Cur2 and Fe-Cur3 Curcumin was synthesized from vanillin and acetyl acetone, following EP 1999097 B1 European Patent protocol with some modifications [20]. The solvent used was a mixture of dimethyl formamide and toluene; boric acid was used as a protecting group; and 1-butylamine as a base. The boron and iron complexes were synthesized according to the Khalil et al. protocol [21]. This involved the addition of aqueous solution of the relevant metal salt quantity of curcumin dissolved in methanol. This was done by dissolution of curcumin in methanol followed by the addition of metal derivative in aqueous solution. The molar ratios of curcumin: metal reactant was 1:2 for boron and 1:3 for iron. The reaction mixtures were refluxed for 3 h, followed by cooling. The precipitated complex was then filtered off, before being washed, first with cold water and then ethanol. Finally, the synthesized complexes were dried and purified by column chromatography. Fig. 1 shows the chemical structure of curcumin and the relevant complexes. 2.2. UV/Vis spectroscopic measurements Solutions of 0.01 mM curcumin, boron-curcumin and iron-curcumin were prepared. A variety of solvents were used, including 2-butanone, chloroform, dimethyl sulfoxide (DMSO), ethyl acetate and xylene. The concentrations (0.01 mM) were kept low to avoid aggregation. The absorption spectra of freshly prepared curcumin and derivatives solutions were measured over the wavelength range of 200–1000 nm. The stability of the complexes was monitored over a period of 96 h by observing the relative change in the absorption peak upon exposure of the compounds (0.01 mM) to ambient room light and temperature.

2.3. Fluorometric measurements and quantum yield Fluorometric measurements of curcumin and its derivatives were obtained using a Shimadzu-RF-6000 fluorometer with a 10 mm quartz cuvette. The excitation source was a Xenon arc lamp. The bandwidths for excitation and emission were 5 nm. For the synchronized spectrum Δλ was 5, 10, 50, 100, 150 and 200, of that Δλ = 100 was adopted. The synchronous fluorescence range was 200–700 nm. An enhancement of fluorescence was observed for both metal complexes of curcumin when they were compared with curcumin itself. The fluorescence quantum yields (ɸ) for curcumin and its two complexes were determined from the spectrum integrated fluorescence, using software available with the instrument (Shimadzu-RF-6000 fluorometer). A 0.01 mM ethanolic solution of coumarin 102 laser dye was used as a reference compound. The calculated quantum yield of curcumin and its derivatives was corrected for differences in peak absorbance and the refractive indices of solvents. The data obtained from spectroscopy and fluorometry were later analyzed using OriginPro 9 software. 3. Results and discussion 3.1. UV/Vis spectra of curcumin and curcumin derivatives in various solvents The difference in the UV/Vis absorption spectra observed when curcumin and its derivatives were dissolved in organic solvents of varying polarity was explored. On this basis the dielectric constant (ε) of each solvent could be ranked according to their increasing polarity as follows: xylene b chloroform b ethyl acetate b 2-butanone b DMSO, (see Table 1). The ability of a solvent to accept or donate H bonds can be designated as an acidity parameter (α) and or a basicity parameter (β), respectively [22]. When α and β parameters were used, the solvents could be ranked from weakly to strongly hydrogen-bonding (Hbonding), as follows; xylene b chloroform b ethyl acetate b 2-butanone b DMSO. Fig. 2A shows curcumin UV/Vis absorption occurs over the range 300–550 nm, extending across both the visible and UV regions.

Fig. 1. Chemical structures of curcumin (A), boron curcumin complex, (B-Cur2) (B) and iron curcumin complex, (Fe-Cur3) (C). *The red circle indicates the keto-enol tautomeric group [14]. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

F. Mohammed et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 183 (2017) 439–450 Table 1 Properties of organic solvents. ε: Dielectric constant, α: acidity parameter-H+ donor, β: basicity parameter-H+ acceptor [27]. Solvents Non polar Polar weakly H-bonding Strong-H acceptors

Xylene Chloroform Ethyl acetate 2-Butanone DMSO

ε

α

β

2.38 4.81 6.02 18.50 47.24

0 0.44 0 0.06 0

0 0 0.45 0.48 0.76

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Curcumin and its boron and iron complexes displayed similar aqueous solubility and spectral patterns when dissolved in the same organic solvent (Fig. 2B and Fig. 2C respectively). For all the three compounds, the peak wavelength (λmax) were located in 2 main regions. In the 2-butanone, chloroform, ethyl acetate and xylene solutions this was in the 416–421 nm region; whereas in DMSO the λmax was at 437 nm. It can be seen that the λmax of curcumin and its derivatives shifted towards the lower wavelength (the blue region, 418–421 nm, for curcumin) when the solvent was changed from the most polar to non-polar and from strongly H-bonding to weakly H-bonding. In the case of curcumin, this was thought to be attributed to the dominance of the bis-keto form of curcumin in non-polar solvents, while in polar solvents the tautomeric equilibrium shifted towards the bis-enolic species [23]. However, this phenomenon cannot explain the spectral shift observed with the boron and iron complexes because the β-diketone moiety is absent in these compounds. No linear relationships were found between ε, α, β and λmax. When xylene was used as a solvent for curcumin or its metal complexes, the spectra obtained exhibited more than one shoulder, (Fig. 2), indicating either the presence of more than one isomer in the ground state [16, 22], or that different types of bonds exist between solute and solvent molecules. These bonds are less stable in non-polar solvents than in polar solvents [26]. 3.2. Fluorescence intensity of curcumin and its derivatives The fluorescence intensities of curcumin and its two derivatives were investigated at different excitation wavelengths. Fig. 3, shows that the iron complex had the highest fluorescence intensity (except for excitation at 450 and 550 nm), followed by the boron complex, while pure curcumin had the lowest intensity. This is in keeping with the literature, since aromatic compounds are generally reported as being more strongly fluorescent than aliphatic, and the fluorescence intensity rises as the number of aromatic rings increases [24,25]. 3.3. Photostability of curcumin and its derivatives The stability of curcumin, boron and complexes upon exposure to light was assessed by measuring the absorbance and the fluorescence intensity after each 24 h for a period of 4 days. Fig. 4 (A and B) shows that iron curcumin complex is the most stable compound, followed by the boron curcumin complex and then curcumin. The iron complex presents a minor decline in the fluorescence intensity after 96 h of light exposure, while a significant decrease is noticed in the absorbance panel.

Fig. 2. Absorption spectrum of 0.01 mM curcumin (A), B-Cur2 (B), and Fe-Cur3 (C) in different organic solvents.

Fig. 3. Fluorescence peak intensity of 0.01 mM curcumin, (B-Cur2) and (Fe-Cur3), in dimethyl sulfoxide (DMSO), upon excitation at different wavelengths.

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Fig. 4. Measurement of the absorption spectra (A) and fluorescence intensity (B) of 0.01 mM curcumin, B-Cur2 and Fe-Cur3 in DMSO upon exposure to ambient room light.

These results are in line with previous studies on the photostability of curcumin and its metal complexes [30]. Curcumin is symmetrical molecule with three chemical groups namely; two o-methoxy phenolic groups connected by a seven carbon chain which has an α,β-unsaturated β-diketo moiety showing keto-enol tautomerism. And it readily undergoes photodegradation [1]. Singh et al. found that exposure of curcumin to light promotes a triplet excited state with consequent degradation to vanillin, (E)-3-(4-hydroxy-3-methoxy-phenyl)prop-2enoic acid and small phenolic entities [31]. The curcumin molecule is a bidentate chelating agent that is capable of forming stable complexes with metals through the 1.3 β-diketo moiety [32]. The ready availability of electrons in the β diketo group for complexation arises because the curcumin molecule is a resonant conjugated system. Curcumin reacts with Fe(NO3)3·9H2O to produce a stable octahedral high-spin iron(III) complex, see Fig. 1 [32]. The Fe3+ cation has a high charge density and the curcumin enol oxygen is a small electronegative atom. The bonding in this complex will have a high degree of ionic character resulting in a more photostable complex than the curcumin ligand itself. Boric acid reacts with curcumin to give a cationic 2: 1 complex in which the central boron atom is tetrahedrally coordinated by two curcumin anions, see Fig. 1 [33]. The stability of the boron curcumin complex will be less than that of the iron-curcumin complex because of lower charge density associated with boron. However, both iron and boron curcumin complexes are stabilized by the formation of six membered ring structures around the central metal atom. When curcumin is complexed with a metal the β diketo group will be absent in the product. Li et al. have reported that curcumin analogues without the 1.3 β-diketo moiety are more photostable [30]. 4. Fluorometric measurements of curcumin and its derivatives in various solvents Variation in emission and excitation spectra for curcumin and its complexes dissolved in a variety of organic solvents was investigated. Overall, a similar pattern of emission spectrum was observed in the three compounds, (see Fig. 5), indicating that the emission maximum depends on the solvent rather than the compound itself. This emission maximum shifted towards the lower wavelengths when non-polar/weaker H-bonding solvents were used, (see Fig. 5). Non-polar solvents gave low emission maxima. Curcumin in xylene (non-polar) had a peak emission of 460 nm, while in DMSO (polar) it was 545 nm, showing a red shift in a highly polar solvent. In addition,

the spectral bandwidths became narrower when moving to the less polar solvents. As with the UV/Vis absorbance spectra, dissolving curcumin (or derivatives) in xylene gave a prominent structured emission spectra. The excitation spectra of curcumin and its derivatives in different organic solvents exhibited a noticeable 2-shoulder profile, (Fig. 6). Interestingly, the excitation spectra were similar to the UV/Vis absorption spectrum in that two different regions were observed; the DMSO region and the 2-butanone, chloroform, ethyl acetate and xylene region. In contrast to the emission spectrum which showed a red shift in all polar solvents, however in the excitation spectra a red shift was only obtained with highly polar solvents; 2-butanone and DMSO, (see Fig. 5 (A, B, C)). The synchronous fluorescence spectrum (SFS) of curcumin and its two complexes in different organic solvents is shown in Fig. 7. Synchronous fluorescence spectroscopy is a simple technique in which the excitation and emission monochromators are simultaneously scanned, keeping a constant Δ λ between them (in this study Δλ = 100 was used) [34]. Two main regions are seen in SFS spectra: the DMSO region and the 2–butanone–chloroform–ethyl acetate–xylene region. In Fig. 7 (A, B, C) two peaks were seen after dissolving curcumin or its boron or its iron complex in DMSO and ethyl acetate. In DMSO, a major peak occurred at 550 nm with a secondary peak at 370 nm, while in ethyl acetate a prominent peak occurred at ≈ 505 nm with a second peak at ≈360 nm. In addition, in the xylene solution, curcumin and its boron complex displayed two peaks, one at 490 nm with a secondary peak at 390 nm, shown in Fig. 7 (A, B). When curcumin and its complexes were dissolved in a solvent other than xylene, only a single peak was seen, around 510 nm. The data obtained indicated that the fluorometric measurements (emission, excitation and synchronous) of curcumin and its derivatives were dependent on the type of organic solvent used and not on the compound itself, see Fig. 8. The significant red shift seen in the absorption, emission and excitation spectra of polar solvents such as DMSO can be attributed to both solvent polarity and to the H-bonding ability of the excited curcumin molecules [19]. To evaluate the contributions of these two factors we plotted Stokes' shift against two parameters, namely orientation polarity (Δf) and solvent polarity parameter (ET 30) [6,26]. Δf was estimated using Lippert equation derivative below:

Δf ¼

ε−1 η2 −1 − 2 2ε þ 1 2η þ 1

ð1Þ


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Fig. 5. Emission spectra (i) and quantitative fluorometric measurements (ii) of 0.01 mM curcumin (A), B-Cur2 (B) and Fe-Cur3 (C) in different organic solvents. *Using xylene as a reference.

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Fig. 6. Excitation spectra (i) and quantitative fluorometric measurements (ii) of 0.01 mM curcumin (A), B-Cur2 (B) and Fe-Cur3 (C) in different organic solvents. *Using xylene as a reference.


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Fig. 7. Synchronous fluorescence spectra (i) and quantitative fluorometric measurements (ii) of 0.01 mM curcumin (A), B-Cur2 (B) and Fe-Cur3 (C) in different organic solvents. *Using xylene as a reference.

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Fig. 8. A comparison of the fluorometric measurements namely, emission (A), excitation (B) and synchronous(C) of curcumin and boron and iron complex, in chloroform.


where ε is the dielectric constant, ɳ the refractive index of the solvent [6, 35]. ET 30 is a measure of molecule's charge transfer tendency. ET 30 values for the different solvents were obtained from the literature [27–29]. Since the solution concentrations used were so low, no change was expected in dielectric constant, ɳ and ET 30 values. Therefore, values from the literature were quoted. Fig. 9 shows Lippert plot of curcumin, boron and iron derivative. The figure shows a clear relationship between Stokes' shift and both Δf and ET30 for all the compounds. The stoke shift increases as the orientation

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polarity (Δf) (except for xylene) and ET30 increases. However, the Stokes' shift correlates better with ET30 than that with Δf for all the three compounds. This can be expressed numerically, and the coefficients between the Stokes' shift of curcumin and its boron and iron complexes with ET30 were 0.82, 0.85 and 0.98, respectively; while those with Δf were 0.68, 0.66 and 0.95, respectively. According to Patra and Barakat [6], synchronous fluorescence spectra (SFS) is a very selective method for fluorometric measurements. It gives perceptible results because of the reduction in

Fig. 9. Relationships between solvents Stokes shift of curcumin, B-Cur2 and Fe-Cur3 complex with Δf (A) and ET30 values (B).

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spectral range, a narrowing of the spectral band and a simplification of the emission spectrum. In this study we used SFS to determine the correlation between synchronous λmax and Δf and ET 30. This can be seen in Fig. 10, with highly polar, H+-accepting solvents having the highest maximum synchronous spectra, while those dissolved in non-polar solvents had the lowest. Correlation coefficients between SFS λmax and Δf were calculated. These had a lower value (Cur = 0.73, B-Cur2 = 0.71, Fe-Cur3 = 0.66,) than the equivalent values

calculated between SFS λmax and ET30 (Cur = 0.95, Fe-Cur3 = 0.92, B-Cur2 = 0.95). The irregular relationships shown in Figs. 9 and 10 between Stokes' shift/SFS λmax and Δf of curcumin and its derivatives suggests that the significant solvatochromic red shift associated with the different organic solvents was not solely dependent on solvent polarity, but was also influenced by intermolecular hydrogen bonding between the solvent molecules [19].

Fig. 10. Correlation between the synchronous fluorescence spectrum of curcumin, B-Cur2 and Fe-Cur3 complex with Δf (A) and ET30 values (B).

F. Mohammed et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 183 (2017) 439–450 Table 2 Quantum yields of curcumin, Fe-cur and B-cur in different organic solvents. Solvents Non polar Polar weakly H-bonding Strong-H acceptors

Xylene Chloroform Ethyl Acetate 2-butanone DMSO

Curcumin

B-curcumin

Fe-curcumin

0.019 0.111 0.103 0.127 0.022

0.123 0.494 0.446 0.493 0.022

0.156 0.258 0.315 0.079 0.023

4.1. Quantum yields Fluorescence quantum yield (ɸf) is the ratio of the number of photons emitted to the number of photons absorbed by a molecule. ɸf is an indicator of the fluorescence efficiency, and the higher the quantum yield the greater the fluorescence of that compound [36]. ɸf is influenced both by the physicochemical character of the fluorophore itself and by its surroundings [37]. In the present study, the fluorescence quantum yields (ɸf) of curcumin, B-Cur2 and Fe-Cur3 in different organic solvents were measured, (see Table 2). In general curcumin had the lowest quantum yield, followed by Fe-Cur3, with B-Cur2 having the highest (Fig. 11). This overall pattern might be explained by fluorophore size; curcumin is the smallest molecule, having one basic unit; B-Cur2 has two fluorophore units; and Fe-Cur3 with three. However, such an explanation does not explain why B-Cur2 has a higher ɸf value than Fe-Cur3. In the case of curcumin, the lowest ɸf (0.019) was found with the non-polar solvent xylene. This is in keeping with the literature, where it has been reported that the non-polar solvent cyclohexane gave rise to a low ɸf value [38]. With the next lowest value (ɸf = 0.022) found when the polar solvent DMSO was used as a solvent. With both B-Cur2 and Fe-Cur3, the lowest quantum yields (ɸf = 0.022 and ɸf = 0.023 respectively) were seen when dissolved in DMSO. These low quantum yield values with DMSO are in line with observations made by Barika and his colleagues [39]. The proposed underlying cause of such low quantum yields was that the fluorophore molecule in polar media was excited, then lost some of its energy to reorient the dipole of the media (solvent), before it emits the photons. The reorientation, or the relaxation, results in photon emission at low energy, and thus a lower quantum yield [37]. The previous principle could also explain the difficulty mentioned earlier concerning the B-Cur2 and Fe-Cur3 quantum yields. In this case, the metal complex, Fe-Cur3, is more polar than the pseudometal compound, B-Cur2, with the former expected to have a lower quantum yield.

Fig. 11. Quantum yield values of curcumin, B-Cur2 and Fe-Cur3 in different organic solvents (ordered from non-polar to most polar).

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5. Conclusion Modification of the curcumin molecule by complexation with boron and iron gave compounds with enhanced photostability, fluorescence intensity and quantum yield. The UV/Vis spectra and fluorometric properties of these two compounds were influenced by solvent polarity and the hydrogen bonding between the solvent molecules. The improved fluorescence of B-Cur2 and Fe-Cur3 when compared to that of curcumin may prove to be useful for medical imaging as well as be a good candidates for further in vitro therapeutic and oncological studies. Experiments are in progress to examine the effect of these metal complexes on cell metastatic behaviour in breast cancer.

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