Theoretical study of binuclear Cu-M complexes (M = Zn, Cu, Ni) with p-xylylene-bridged-bis(1,4,7-triazacyclononane) ligands: Possible CuZnSOD mimics

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Theoretical study of binuclear Cu-M complexes (M = Zn, Cu, Ni) with pxylylene-bridged-bis(1,4,7-triazacyclononane) ligands: Possible CuZnSOD mimics ⁎

Talis Uelisson da Silvaa, , Everton Tomaz da Silvaa,b, Camilo Henrique da Silva Limaa, Sérgio de Paula Machadoa a b

Instituto de Química, Universidade Federal do Rio de Janeiro, 21945-970 Rio de Janeiro, RJ, Brazil Instituto Federal do Rio de Janeiro, 25050-100 Caxias, RJ, Brazil

A B S T R A C T

DFT calculations were used to study a series of binuclear complexes with the general formula [CuM(pxbtacn-R2)Cl4] (pxbtacn = p-xylylene-bridged-bis(1,4,7triazacyclononane); M = Zn, Cu and Ni; R = -H, -CH3, -CH(CH3)2) as potential mimics of superoxide dismutase. The obtained results indicate that all complexes have similar structures to the experimental structure reported for [Cu2(pxbtacn)Cl4] complex. In the reduction process, the loss occurs of one of the Cl- ligands in which the generated Cu(I) show distorted tetrahedral geometry. An analysis of acceptor (oxidized complexes) and donor (reduced complexes) orbitals shows that these orbitals have significant participation from Cu (II) and Cu (I), respectively. This indicates that the reduction process occurs via Cu(II) receiving an electron and the oxidation process occurs with the removal of this electron from Cu(I), according to the process observed in the native enzyme. The Gibbs free energy shows that the catalysis is spontaneous for all of the complexes studied, and the reduction step is the predominant stage of the global process. For the three series studied here, the calculated values of the Gibbs free energy and electronic affinity indicate that complexes with R = -CH3 and -CH(CH3)2 have the greatest ability to reduce, in accordance with the reported experimental mimic activity. Complexes with these substituents should therefore have a higher mimic activity.

1. Introduction Superoxide dismutase (SOD, EC 1.15.1.1) is a metalloenzyme that promotes the dismutation reaction of the anion radical O2.− (a subproduct generated in the metabolism of oxygen) in H2O2 and O2 (Eqs. (1) and (2)) [1]. SODs are classified according to the Mn+1 metal that participates directly in the redox process, which may be manganese or the copper-dependent enzymes found in human cells [2]. SOD

Mn + 1 + O2. − → Mn + + O2 SOD

Mn + + O2. − + 2H+ → Mn + 1 + H2 O2

(1) (2)

In active site of CuZnSOD, the Cu(II) and Zn(II) ions are bridged by the imidazole ring of one histidine residue (imidazolate group, im), which is the distorted square pyramidal coordination sphere (SP) of Cu (II) completed with a further three histidine residues and an H2O molecule, weakly coordinated in the apical position (oxidized form). The Zn(II) ion is coordinated in a distorted tetrahedral geometry (TD) by two histidine residues, one carboxylate residue and the im group (Fig. 1A). The distance Cu-Zn is about 6.0–6.2 Å. In catalysis, the Cu-im bond is broken during the reduction of Cu(II) (Eq. (1)), and the

⁎

generated Cu(I) has a distorted trigonal geometry (reduced form) (Fig. 1B). The distance Cu-Zn is about 6.9 Å. After the reoxidation step (Eq. (2)), the Cu-im-Zn bridge is reestablished, and SP geometry is reestablished [3–5]. Studies suggest that Arg143 residue attracts negatively charged species (O2.−) to the channel entrance of activity site [6]. While Cu(II) undergoes the redox process, the Zn(II) ion has an indirect role in catalysis. Studies suggest that the presence of this ion in the active site makes the catalysis pH-independent over a wide range of pH, and stabilizes the sphere of coordination through the Cu-im-Zn bridge, meaning that the output of Cu-bonded H2O2 is faster [7]. It has also been shown that the removal of Zn from the CuZnSOD site reduces the catalytic activity, since the proper coordination of O2.− to Cu and the required reduction potential for catalysis can only be achieved in the presence of Zn(II) [8]. However, although Zn(II) makes a fundamental contribution to catalysis, studies have shown that substitution by the Ni(II) ion results in small changes in the enzymatic structure and catalytic activity, indicating that CuNiSOD analogues have similar activity to that of native CuZnSOD. In addition, Ni(II) ion has also proved to be a good mimic for the Cu(II) ion in this enzyme [9]. Although natural antioxidant systems are efficient, the generation of reactive oxygen species (ROS) can overcome the defensive antioxidant

Corresponding author. [email protected] (T.U. da Silva).

https://doi.org/10.1016/j.ica.2019.119232 Received 14 September 2019; Received in revised form 27 October 2019; Accepted 27 October 2019 Available online 28 October 2019 0020-1693/ © 2019 Elsevier B.V. All rights reserved.

Please cite this article as: Talis Uelisson da Silva, et al., Inorganica Chimica Acta, https://doi.org/10.1016/j.ica.2019.119232

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Fig. 1. Structures of the oxidized (A) and reduced (B) states of the active site in CuZnSOD.

for the other atoms. This theory level has recently been employed in studies of complexes mimicking SOD and catalase, giving good results [27,28]. For the oxidized complexes, Cu(II)-Zn(II), Cu(II)-Cu(II) and Cu (II)-Ni(II) were considered in the doublet, singlet/triplet and doublet/ quartet spin states, respectively. For the reduced complexes, Cu(I)-Zn (II), Cu(I)-Cu(II) and Cu(I)-Ni(II) were considered in the singlet, doublet and singlet/triplet spin states, respectively. From the total energies of the oxidized and reduced optimized structures, we obtained the electronic affinities (EA) as EA = ERed– EOx, where ERed and EOx are the total energies of the reduced (anionic) and oxidized (neutral) forms of the complexes, respectively [29]. The variation in the corrected Gibbs free energy (ΔG) (thermal correction) was calculated for the oxidation and reduction processes in order to evaluate the spontaneity of these processes in each complex [30]. Calculations were done in a water solvent, using the polarized continuum model (PCM) solvation method [31]. Frequency calculations were employed to obtain the vibrational spectra. The absence of imaginary frequency values in the obtained optimized structures confirmed that the structures are at energetic minima on potential energy surface [32]. The experimental structure of C3CuCu [16] was used in the modeling of all structures. The Zn(II) and Ni(II) ions were kept as pentacoordinated during modeling, since pentacoordinated complexes of these ions with tacn ligands have already been reported in the literature [15,32].

ability of an organism, generating an oxidative stress condition, and this is related to various pathologies such as cardiovascular disease, cancer and neurological disturbance [1,10]. The use of exogenous SOD to treat diseases related to oxidative stress is therefore an important strategy [11]. However, natural SOD has some drawbacks for this application, such as weak tissue permeability and high molecular weight. There is therefore a need to synthesize small molecular complexes to mimic the structure and catalytic activity of SOD [12,13]. A number of Cu(II) complexes have been characterized as models of the CuZnSOD enzyme, including homo- and heterodinuclear Cu(II)-Zn (II) with imidazolate-bridged Cu-im-Zn [10,12,14]. In work by Daier et al., homodinuclear Cu-im-Cu was more active than the Cu-im-Zn complex [10]. After insertion of these complexes into the mesoporous form of silica, the heterodinuclear complex showed higher activity than the homodinuclear [15]. In addition, in natural SOD, the substitution of Zn(II) by Ni(II) showed little disturbance of the enzymatic structure, while the substitution of Cu(II) by Ni(II) generated an effective SODmimicking system, suggesting that the Cu-Ni analogues can show good mimic activity [9]. Coordination compounds with 1,4,7-triazacyclononane (tacn) macrocyclic ligand and their derivatives have been reported using enzymatic active site models. Ligands containing two or more bridge-connected tacn units can generate bi- or polynuclear complexes whose metal centers have free valences that can bind to substrates [16–18]. Recently, Tang’s group synthesized a series of Cu(II) binuclear complexes with p-xylylene-bridged-bis(1,4,7-triazacyclononane) ligands (Fig. 2), which had similar IC50 values to those of natural enzyme activity [19]. The crystal structure of one of these complexes was reported by Fry et al. (C3CuCu) [16]. C1CuCu and C2CuCu homodinuclear complexes are promising mimics of CuZnSOD, and have moderate catalase mimic activity, which is desirable since the H2O2 generated in SOD catalysis is toxic. Dual SOD/ catalase-mimicking systems have been sought [20,21]. In work by Tang et al., C1CuCu and C2CuCu were characterized by spectroscopic methods because, unfortunately, no single crystals of these complexes were suitable for X‐ray structural analysis could be successfully obtained [19], making the study of the structure and reactivity of these complexes essential. Hence, in this work, we theoretically examine the CuCu complexes obtained by Tang et al. and the proposed Cu-Zn and CuNi analogues (Fig. 2), in order to help in the synthesis of new CuZnSODmimicking complexes.

3. Results and discussion 3.1. Structural characterization 3.1.1. Oxidized form Firstly, we calculated the possible spin states for the oxidized Cu-Cu (singlet and triplet) and Cu-Ni (doublet and quartet) structures, due to the possibility of coupling of both metal centers [16,19]. For the Cu-Cu structures, the calculated energy values (Table 1S) indicated that the triplet states (Figs. 3 and 1S) of the three complexes have lower energy than the singlet state within the range 35–38 kcal/mol (Table 1S). For the Cu-Ni, the doublet and quartet states have very close energies (Table 1S); the quartet spin state (Fig. 3) was chosen since it has the lowest energy SOMO orbital (SOMO acceptor), which is the orbital responsible for accepting one electron in the reduction step, with an energy lower than that of the singlet state (Table 2S). In addition, in the subsequent studies discussed in Section 3.3, the process reduction of the quartet and doublet states was spontaneous and non-spontaneous, respectively, thus reinforcing the choice of the quartet spin state. As shown in Fig. 3, all complexes are centrosymmetric about the center of the xylyl aromatic ring, and the metal centers adopt an anticonformation that gives rise to a large Cu-M separation of about 12 Å. The M(II) centers are in a distorted SP environment, with the one of nitrogen atoms of the ligand occupying the apical site, while the basal plane is defined by the two Cl− ligands and the two remaining nitrogen

2. Computational methods All calculations were performed using the Gaussian 09 computational package [22]. The optimized structures of complexes were obtained in the oxidized (Ox) and reduced (Red) forms with the functional B3LYP exchange-correlation hybrid [23,24]. The LanL2DZ pseudopotential [25] was used for transition metals and the D95V basis set [26] 2

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Fig. 2. General structure of the studied complexes.

3.1.2. Reduced form The optimized structures were obtained for all the reduced complexes (Fig. 4). For the Cu-Ni complexes, we evaluated the possible spin states, and the triplet state was chosen for the study as it had a lower energy than the singlet state, by 26 kcal/mol (Table 1S). For all complexes, the reduced structures (Figs. 4 and 2S) retained a centrosymmetric structure about the center of the xylyl aromatic ring, and the metal centers observed anti-conformation in the oxidized structures. The Cu-M distances found here were around 12 Å. However, one of the Cu-Cl bonds was broken, as evidenced by the Cu-Cl(exit) distance within 4–5 Å. In addition, the geometry around the Cu(I) became a distorted TD structure, with the remaining Cl− ligand occupying the apical site. As previously observed for oxidized structures, the Cu-Cl bond was longer than the others, suggesting weakness. Thus, the Cl− ligands are expected to be lost during the reduction process. This result is according with observed by Wilson and Lippard in their study of platinum complexes, which some specific M-L bonds in the reduced complexes were longer than the others, suggesting the loss of these Lligands on reduction process [33]. Further evidence for this is that the Cu-Cl binding is weaker in the complexes with the highest mimicking activity, C1CuCu and C2CuCu, suggesting that the greater ease of Cu-Cl breakage may be associated with higher reactivity. The metal site where there was no reduction retained the SP geometry. The analysis of the distances and angle values of the calculated structures for Cu-Cu, Cu-Zn and Cu-Ni analogues (Tables 7S, 8S and 9S, respectively) revealed that an increase occurs in the Cu-Cl bonds to values about 4–5 Å, indicating the breaking of this bond. Thus, in the reduction process of all the complexes studied here, there is the loss of one Cl- ligand, generating a distorted TD geometry around the Cu(I) ion, as evidenced by the values of the Cl(apical)-Cu-N(basal) angle in the range 119–135° and Cu-Cl distance values in the range 2.3–2.4 Å. These results suggest that the apical Cl should be weakly coordinated to Cu(I) and that the basal nitrogen atoms form an approximately trigonal pyramidal arrangement. The calculated data on the oxidized and reduced structures of the complexes indicate that in the reduction step, there is the loss of one Cl− ligand, and that the geometry around the central Cu changes from SP to TD. The coordination sphere of the other metal center remains virtually unchanged.

atoms. An analysis of the bond distance and angle values of the calculated structures for Cu-Cu analogues (Table 3S) revealed that the theoretical and experimental structures for C3CuCu show good agreement, with a maximum percentage error of only 5%. C1CuCu and C2CuCu have maximum percentage errors of only 6% and 8%, respectively, indicating that the experimental structures of C1CuCu and C2CuCu must be similar to that of C3CuCu. The Cu-Cl bond is longer than the apical and basal Cu–N bonds in the three complexes, with an approximate value of 2.4 Å. The Cu-Cl distances in the C1CuCu and C2CuCu complexes are higher than in the C3CuCu complex, indicating that this bond is weaker in complexes with higher mimic activity. The -CH3 and -CH (CH3)2 substituents distort the coordination environment around Cu(II), such as the decreased Cu–N(apical) bond and the N(apical)-Cu-Cl angle. The repulsion caused by substituents on the Cl-ligands is expected to weaken the Cu-Cl bonds. The structures obtained for the Cu-Zn and Cu-Ni analogues also showed good agreement with the experimental structure for C3CuCu (Tables 4S and 5S, respectively). For the Cu(II) centers in the Cu-Zn analogues, we found maximum percentage errors of 6%, 7% and 5% for C1CuZn, C2CuZn and C3CuZn, respectively, indicating that the Cu(II) centers retain an SP geometry. The same results were obtained for the Cu-Ni analogues, with maximum percentage errors of 6%, 7% and 5% for C1CuNi, C2CuNi and C3CuNi, respectively. The Zn(II) and Ni(II) ions also showed SP geometry in the complexes, with bond distances and angles similar to those found for Cu(II). In all complexes, the SP geometry is evidenced by values of the N(apical)-Cu–N(basal) and N (apical)-Cu–N(basal) angles in the range 80–90°. The infrared spectra were calculated for C1CuCu, C2CuCu and C3CuCu (Figs. 3S, 4S and 5S, respectively), and the more important vibrational modes obtained (Table 6S) were compared to the respective experimental values [19]. A maximum error of 8% was observed between the calculated and experimental values, indicating good agreement between these data. In C3CuCu, N-H stretching shows absorption at 3521.2 cm−1. In the three complexes, C-N and Cu-N stretching shows absorption in the ranges 1107.8–1114.6 and 424.2–446.1 cm−1, respectively.

3

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Fig. 3. Optimized structures obtained for C2CuZn, C2CuCu and C2CuNi oxidized. The hydrogen atoms have been omitted.

3.2. Electronic characterization The first step of the redox process involves the Cu(II)/Cu(I) reduction, and the electron received by the mimetic occupies the acceptor SOMO. In the second stage, the electron will be removed from the SOMO orbital of highest energy (donor SOMO) for the Cu-Cu and Cu-Ni complexes. For Cu-Zn complexes, the electron will be removed from the HOMO orbital. An analysis of the acceptor SOMO via a graphical representation of the studied complexes (Fig. 5 and 6S) and the percentage of Cu(II) participation in this orbital (%SOMOacceptor) (Table 1) showed that, for all complexes, this orbital is located over the Cu(II) sites. For heteronuclear complexes, there is a contribution of about 11–12%. In Cu-Cu analogues, this contribution is split between the two Cu(II) sites, and each Cu(II) contributes about 6–7% to the formation of this orbital. These results suggest that in the reduction step, the electron will be received by one of the Cu(II) ions present. An analysis of the donor SOMO/HOMO via a graphical representation of the reduced structures (Figs. 6 and 7S) and the percentage Cu(I) participation in these orbitals (%SOMO/HOMOdonor) (Table 1) showed that the donor orbital is located over the Cu(I) site for all studied complexes. The contribution of Cu(I) to the formation of the donor orbital is in the range 29–34%. These results suggest that in the oxidation step, the electron will be removed from the present Cu(II) ion. Since the CuZnSOD mimic needs to be able to reproduce the reactions of the natural enzyme, the significant contribution of Cu(II) to the the acceptor SOMO (reduction step) and Cu(I) to the donor SOMO/HOMO

Fig. 4. Optimized structures obtained for C2CuZn, C2CuCu and C2CuNi reduced. The hydrogen atoms have been omitted.

(oxidation step) indicate that the systems studied in this work are capable of reproducing the CuZnSOD catalysis. An analysis of ESOMO acceptor (Table 1) revealed that this parameter decreases in the order C2 > C1 > C3. In addition, all values are between −6.51 and −6.33 eV, and these values are similar to the C1 and C2 complexes for all analogues. An analysis of ESOMO/HOMOdonor (Table 1) revealed that these values are between −4.46 and −4.37 eV, and that the complexes of each analogue series have ESOMO/HOMOdonor values that are very similar. The C2 complexes for the Cu-Cu and Cu-Ni analogues have the highest ESOMO/HOMO donor values, as observed for the ESOMO acceptor. Since C1CuCu and C2CuCu have highest ESOMO acceptor values than C3CuCu, this result may indicate that the electron received during reduction step is not stabilized to the point of compromising the oxidation step, in which this electron will be removed. The EA has been used as a theoretical parameter to measure the SOD mimic activity of metallic complexes. The lower the EA is, the higher the SOD-like activity [29]. The calculated values of the absolute (EAabsol) and relative (EArel) electronic affinities for each series of complexes (Table 2) indicate that the C1 and C2 complexes have a greater ability to reduce than C3, according to the experimental 4

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Fig. 5. Graphical representation of acceptor SOMO for C2CuZn, C2CuCu and C2CuNi in their oxidized forms. The hydrogen atoms have been omitted. Table 1 Electronic parameters calculated for the studied complexes: %SOMOaceptor, % SOMO/HOMOdonor, energy of acceptor orbital (ESOMO acceptor) and energy of donor orbital (ESOMO/HOMO donor). Complex

Ox ESOMO

Table 2 Calculated electronic affinity values (kcal/mol).

Red aceptor

(eV)

%SOMOacceptor

ESOMO/ HOMO donor

(eV)

%SOMO/ HOMOdonor

C1CuZn C2CuZn C3CuZn

−6.35 −6.33 −6.41

12.28 11.55 11.52

−4.44 −4.45 −4.46

28.85 29.51 32.00

C1CuCu C2CuCu C3CuCu

−6.39 −6.37 −6.46

6.82 6.24 6.71

−4.45 −4.46 −4.46

29.57 28.72 32.97

C1CuNi C2CuNi C3CuNi

−6.43 −6.43 −6.51

11.92 11.21 11.18

−4.40 −4.46 −4.37

33.98 28.15 32.02

Complex

EAabsol

EArel

IC50 (µM) [19]

C1CuZn C2CuZn C3CuZn

−88.76 −97.36 −82.70

−6.07 −14.67 0.00

– – –

C1CuCu C2CuCu C3CuCu

−88.69 −88.35 −82.61

−6.08 −5.73 0.00

0.087 0.068 0.250

C1CuNi C2CuNi C3CuNi

−87.85 −89.44 −85.95

−1.90 −3.48 0.00

– – –

similar reducing ability. 3.3. Gibbs free energy The absolute (ΔGabsol) and relative (ΔGrel) ΔG values (Table 3) for the reactions promoted by these complexes were calculated (Eqs. (3) and (4)).

CuZnSOD activity obtained for the Cu-Cu analogues (Fig. 2). The C2CuZn complex showed the lowest EAabsol value (highest reducing ability). The calculated EArel for the Cu-Cu analogues shows that C1 and C2 have similar reducing abilities, which are higher than C3; these results agree with the experimental results for mimicking activity (Fig. 2). In addition, the C1CuZn, C1CuNi and C2CuNi complexes have EAabsol values close to C1CuCu and C2CuCu, suggesting that these complexes have

Oxidized complex + O·2− → Reduced complex + O2

Reduced complex +

O·2−

+ 2H+ → Oxidized complex + H2 O2

(3) (4)

The ΔGabsol values (Table 3) show that both stages of catalysis

Fig. 6. Graphical representation of donor SOMO/HOMO for C2CuZn, C2CuCu and C2CuNi in their reduced forms. The hydrogen atoms have been omitted. 5

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positive inductive effect of -R substituents increases mimic activity by decreasing the bond distance Cu-N(apical) and increasing the bond distance Cu-N(basal). In addition, the repulsion caused by R-substituents on the Cl-ligands is weaken the Cu-Cl bonds on oxidized complexes, making easy Cl-output (as discussed earlier in Section 3.1.1). The influence of -R substituents were verified on ΔG values of reduction process (Table 3), determinant step of catalysis. For Cu-Cu analogues there is a minimal difference on ΔG values to C1 and C2. C3CuCu have lowest mimic activity and haven’t positive inductive effect, suggesting that increase of positive inductive effect increase spontaneity on reduction process of Cu-Cu analogues. Similar tendency was observed to heteronuclear series. The order of spontaneity on reduction process C2 > C1 > C3 was equal to order of increasing positive inductive effect: C2 > C1 > C3. These results reinforce the role of -R substituents effect on increase mimic activity.

Table 3 Calculated ΔG values (kcal/mol). Complex

Reduction process (Eq. (3))

Oxidation process (Eq. (4))

ΔGabsol

ΔGrel

ΔGabsol

ΔGrel

C1CuZn C2CuZn C3CuZn

−7.89 −18.05 −1.85

10.17 0.00 16.21

−361.51 −351.34 −367.55

6.04 16.21 0.00

C1CuCu C2CuCu C3CuCu

−7.78 −7.71 −2.56

0.00 0.08 5.23

−361.61 −361.69 −366.84

5.23 5.15 0.00

C1CuNi C2CuNi C3CuNi

−7.33 −11.13 −6.39

3.80 0.00 4.74

−362.06 −358.26 −363.00

0.94 4.74 0.00

promoted by the complexes are spontaneous, and that the oxidation step is much more spontaneous than reduction step. In addition, the ΔGabsol values of the oxidation step are close, meaning that the reduction step is the determinative step in the CuZnSOD-mimicking activity of these complexes (from a thermodynamic point of view). The high value of ΔGabsol observed in the oxidation step indicates that the reduced complex will be easily oxidized, regenerating the first species and continuing the catalytic cycle. The ΔGrel values (Table 3) for the homonuclear series reported by Tang's group [19] show that the values for the spontaneity of the reduction step for C1 and C2 are close to each other, and are about 5.00 kcal/mol lower than for C3, indicating that the reduction of C1CuCu and C2CuCu is more spontaneous than that of C3CuCu. These results are in agreement with the calculated results for EA and the reported mimetic activity (Fig. 2). For the Cu-Zn complexes, C2 has the highest reducing ability, followed by C1. In addition, of all the complexes studied, C2CuZn showed the lowest ΔGabsol, indicating that C2CuZn has the highest reducing ability. This result is in agreement with the calculated results for EA. For the Cu-Ni complexes, C2 also has the highest reduction ability, followed by C1. Thus, the reduction order C2 > C1 > C3 is observed for all series in the study, and the ΔGrel value for each series is highest for the Cu-Zn complexes and lowest for the Cu-Cu complexes. An analysis of the ΔGabsol values calculated for the doublet/singlet spin state Cu-Ni complexes (Table 10S) revealed that the oxidation step gave similar values to those obtained for the quartet/triplet isomers. However, the reduction step (the determinant step for the global process) gave positive ΔGabsol values, indicating that the reduction step in these isomers is nonspontaneous, and reinforcing the choice of quartet/triplet isomers for the study. The C2 heteronuclear complexes presented the lowest values for ΔGabsol, indicating that these complexes have higher mimicking activity than the homonuclear complexes. The C1 heteronuclear complexes have ΔGabsol values that are close to those of C1CuCu and C2CuCu, suggesting that these complexes must have similar mimicking activity. The results obtained in this study suggest that the heteronuclear analogues have structural and electronic features that are similar to the homonuclear analogues, indicating that the heteronuclear Cu-Zn and Cu-Ni analogues are good CuZnSOD-mimicking candidates.

4. Conclusion A structural analysis of the series of complexes obtained by Tang et al. revealed that the calculated C3CuCu structure shows good agreement with the experimental data (with a maximum percentual error of 5%). In addition, these calculations suggest that C1CuCu and C2CuCu are similar to the reported C3CuCu structure [16], with maximum percentual errors of 6% and 8%, respectively. The heteronuclear complexes also showed a similar structure to that of C3CuCu, with Zn(II) and Ni(II) adopting the same SP geometry adopted by Cu(II) in these complexes. An analysis of the reduced structures revealed that in the reduction process of these complexes, the loss of one Cl− ligand occurs and the Cu (I) generated has a coordination sphere distorted TD. An electronic analysis of the oxidized structures revealed that the acceptor SOMO for all complexes is located specifically in the Cu(II) sites. In the heteronuclear analogues, the acceptor SOMO is located in the only present Cu(II) site, with %SOMOacceptor values in the range 11–12%. For the Cu-Cu analogues, these values are divided between the two Cu(II) sites. In the reduced structures, the donor SOMO is located at the Cu(I) site. Thus, in these complexes, the electron should be inserted in the Cu(II) and removed from the Cu(I), suggesting that the studied complexes are capable of reproducing the redox process carried out by CuZnSOD, and must therefore be potential mimics. The values found for the EA showed that the C1 and C2 complexes of each analogue series had a higher reduction ability than the respective C3 complex. The values found for ΔGabsol showed that both steps of the redox process are spontaneous for all of the studied complexes. The values found for the oxidation step were very close, and were higher than the values for the reduction step, indicating that the reduction step is the determinant step of the catalytic process (from a thermodynamic point of view). The reduction step is more spontaneous for the C1 and C2 complexes, and this is in accordance with the reported experimental mimicking activity for the homonuclear complexes. The increase positive inductive effect caused by R-substituents increase spontaneity of reduction process (determinant step of catalysis) on all complexes. The results obtained here suggest that the C1 and C2 heteronuclear analogues must have CuZnSOD mimicking activity that is higher than and similar to those of the C1 and C2 homonuclear complexes, respectively, reported by Tang et al. Thus, the results obtained in this study suggest promisor candidates to future studies of synthesis of new potential CuZnSOD mimics.

3.4. Influence of R-substituents The -CH3 and -CH(CH3)2 substituents donate electron density (positive inductive effect). The analysis of influence of -R substituents on bond distances revelated that increase of positive inductive effect make the Cu-N(apical) bond stronger, evidenced by decrease of distance Cu-N (apical) on all complexes (Tables 3S, 4S and 5S). The reverse effect is observed on distance Cu-N(basal) which decrease with increasing positive inductive effect, evidenced by increase of distance Cu-N(apical) on all complexes (Tables 3S, 4S and 5S). These results suggest that the

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 6

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Acknowledgments

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This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES) (Finance Code 001; Doctorate fellowships to T. U. da Silva). The authors also thank Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (grant E-26/010.001003/2016) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (grant 304402/ 2017). Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ica.2019.119232. References [1] A. Bafana, S. Dutt, A. Kumar, S. Kumar, P.S. Ahuja, J. Mol. Catal. B: Enzym. 68 (2011) 129. [2] B. Mohan, A. Jana, N. Das, S. Bharti, M. Choudhary, J. Mol. Struct. 1171 (2018) 94. [3] R.W. Strange, S. Antonyuk, M.A. Hough, P.A. Doucette, J.A. Rodriguez, P.J. Hart, L.J. Hayward, J.S. Valentine, S.S. Hasnain, J. Mol. Biol. 328 (2003) 877. [4] R.W. Strange, S.V. Antonyuk, M.A. Hough, P.A. Doucette, J.S. Valentine, S.S. Hasnain, J. Mol. Biol. 356 (2006) 1152. [5] V. Pelmenschikov, P.E.M. Siegbahn, Inorg. Chem. 44 (2005) 3311. [6] P.J. Hart, M.M. Balbirnie, N.L. Ogihara, A.M. Nersissian, M.S. Weiss, J.S. Valentine, D. Eisenberg, Biochemistry 38 (1999) 2167. [7] I.A. Abreu, D.E. Cabelli, Biochemica et Biophysica Acta (BBA) – Proteins and Proteomics 1804 (2010) 263. [8] S. Nedd, R.L. Redler, E.A. Proctor, N.V. Dokholyan, A.N. Alexandrova, J. Mol. Biol. 426 (2014) 4112. [9] L.J. Ming, J.S. Valentine, J. Biol. Inorg. Chem. 19 (2014) 647. [10] V.D. Daier, E. Rivière, S. Mallet-Ladeira, D.M. Moreno, C. Hureau, S.R. Signorella, J. Inorg. Biochem. 163 (2016) 162. [11] L. Guo, L. Xu, T. Wu, S. Fu, Y. Qui, C.A.A. Hu, X. Ren, R. Liu, M. Ye, Can. J. Microbiol. 63 (2017) 312. [12] Q. Yuan, K. Cai, Z.P. Qi, Z.S. Bai, Z. Su, W.Y. Sun, J. Inorg. Biochem. 103 (2009) 1156.

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