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. 2023 Jun 1;8(23):20423–20439. doi: 10.1021/acsomega.3c00645

Homobimetallic Au(I)–Au(I) and Heterotrimetallic Au(I)–Fe(II)–Au(I) Complexes with Dialkyldithiophosphates and Phosphine Ligands: Structural Characterization, DFT Analysis, and Tyrosinase Inhibitory and Biological Effects

Abdollah Neshat †,*, Atiyeh Mahdavi ‡, Mohammad Reza Yousefshahi †, Mahdi Cheraghi †, Ali Mousavizadeh Mobarakeh †, Saiedeh Mohammadi ‡, Vaclav Eigner §, Monika Kucerakova §, Michal Dusek §, Babak Kaboudin †
PMCID: PMC10268621  PMID: 37332817

Abstract

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The role of bridging and terminal ligand electronic and steric properties on the structure and antiproliferative activity of two-coordinated gold(I) complexes was investigated on seven novel binuclear and trinuclear gold(I) complexes synthesized by the reaction of either Au2(dppm)Cl2, Au2(dppe)Cl2, or Au2(dppf)Cl2 with potassium diisopropyldithiophosphate, K[(S-OiPr)2], potassium dicyclohexyldithiophosphate, K[(S-OCy)2], or sodium bis(methimazolyl)borate, Na(S-Mt)2, which afforded air-stable gold(I) complexes. In 1–7, the gold(I) centers adopt a two-coordinated linear geometry and are structurally similar. However, their structural features and antiproliferative properties highly depend upon subtle ligand substituent changes. All complexes were validated by 1H, 13C{1H}, 31P NMR, and IR spectroscopy. The solid-state structures of 1, 2, 3, 6, and 7 were confirmed using single-crystal X-ray diffraction. A density functional theory geometry optimization calculation was used to extract further structural and electronic information. To investigate the possible cytotoxicities of 2, 3, and 7, in vitro cellular tests were carried out on the human cancerous breast cell line MCF-7. 2 and 7 show promising cytotoxicity.

Introduction

The fascinating chemistry of gold dates back to ancient times, but some clinical successes with gold complexes in treating rheumatoid arthritis and tuberculosis, along with unique catalytic applications associated with gold(I) and gold(III), have been primarily driving the reemergence of molecular gold(I) and (III) chemistry in recent decades.1−10 The gold(I)/(III) coordination chemistry has been profoundly influenced by the phosphine and thiol ligands.11−16 For instance, auranofin (see Figure 1), containing both thiol and phosphate-based ligands, was the first gold-based drug approved as an antiarthritic agent in the late 1970s.7 This class of gold(I) heteroleptic complexes incorporated mixed ligands and was shown to have enhanced properties.17−27 While the number of biologically active monomeric heteroleptic gold(I) complexes in the literature are quite large, bi- or trimetallic alternatives that include a gold ion are limited. The hypothesis that the presence of two or more metal centers in a metal complex improves their activities, as compared with the monomeric metal complexes, has pushed forward the ligand design strategies to incorporate at least one gold atom in combination with other transition-metal ion or ions in the resulting heterometallic complexes.28−34 Some notable examples of heterometallic gold(I) complexes featuring carbon, phosphorus, and sulfur donors are shown in Figure 1. Unlike most platinum-based anticancer agents, gold complexes have different cellular targets. Some proven targets include deacetylases, protein kinases, and polymerases. The inhibition of thioredoxin (Trx)/thioredoxin reductase (TrxR) has also been considered an attractive strategy for the development of gold(I) therapeutic agents.35−38 A literature survey reveals that the majority of biologically active gold(I)/(III) complexes include phosphorus, N-heterocyclic carbene, or the sulfur donor ligand because these ligands are soft, suitable to stabilize low-valent gold(I) ions, and their electron-donation capabilities are tunable.

Figure 1.

Figure 1

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Notable examples of mono- and heterometallic gold(I) complexes bearing phosphine, N-heterocyclic carbene, and sulfur donors.26,27,29,44

Recent examples of achieving mixed-ligand two-coordinated gold(I) complexes include functionalized phosphine-gold(I)-chloro or NHC-gold(I)-chloro complexes with thiol-based ligands. In this regard, different thiolate-based ligands such as alkyl thiols, aryl thiols such as mercaptopyridines, mercaptothiazolines, mercaptourines, mercaptotetrazolates, and other related thiol-based ligands have been used.39−43

The highly investigated and interesting class of sulfur donor ligands are organodithio derivatives of phosphorus, which include dithiophosphates, [S2P(OR)2]−, dithiophosphonate, [S2PR(OR)]−, and dithiophosphinates, [S2PR2]−.44−59 The dithiophosphorous chemistry of gold resembles that of diphenylmethylenethiophosphinato ligands, [CH2P(S)Ph2]2–, which was pioneered by Fackler et al.60 Among these three classes of dithiophosphorous ligands, dithiophosphates are particularly interesting because they are easily prepared and form stable gold complexes. While the synthesis, molecular structures, and photoluminescence of dithiophosphorous ligands and related gold complexes have been investigated, only a few reports are available on the chemistry of gold(I) complexes with mixed ligands, including bis-aryl phosphines and dithiophosphonates.57,61 Inspired by previous works, we aimed to synthesize and characterize seven novel gold(I) complexes by employing dppm, dppe, and dppf as bridging ligands and dithiophosphates as terminal ligands. Bidentate ligands, dppm, dppe, and dppf, play an important role in the intramolecular and intermolecular distances in the resulting two-coordinated gold(I) complexes. The unique physicochemical and biological properties of ferrocene have allowed its extensive investigation in the design of bioactive metal complexes. One common approach in this regard included the appendment of the ferrocene motif as part of the ligand coordinated to the second metal center.62−65 Studies have shown that such multimetallic systems incorporating ferrocene have improved biological activities as a result of improved lipophilicity and undergoing one-electron oxidation. Therefore, the dppf ligand was also included in the studies in a couple of cases. In addition to the full characterization, we present studies of in vitro activity against human breast cancer cell lines and tyrosinase inhibitory effects. Because of the initial satisfying results with 2, 3, and 7, in vitro cell toxicity analysis was carried out only with samples prepared from these complexes.

Results and Discussion

Synthesis and Characterization of the Metal Complexes

Tetrahydrofuran turned out to be an ideal solvent for synthesizing 1–7. Generally, the gold(I) precursor was reacted overnight with the potassium or sodium salt of a ligand precursor with a 1:2 stoichiometric ratio at room temperature. Then, the potassium or sodium chloride byproduct was removed by centrifugation, and the supernatant was concentrated under reduced pressure. The remaining solid was dissolved in dichloromethane. The foggy solution was centrifuged once more, and the clear supernatant was left in an open flask to obtain a crystalline solid. Using this general procedure, the reaction of (dppm)Au2Cl2, (ddpe)Au2Cl2, or (dppf)Au2Cl2 with potassium diisopropyldithiophosphate, K(S-OiPr)2, gave 1–3 in moderate yields, which are stable in the solid state or in dry solvents for weeks. Only 3 in tetrahydrofuran (THF) turns dark brown upon long exposure to air or moisture, most probably via oxidation of the Fe(II) center. The appearance of only one doublet at 1.35 ppm and a sharp septet at 4.93 ppm in the 1H NMR spectrum of 1 (Figure S1), with a mutual coupling of 8.0 Hz, reveals a symmetrical structure in solution. Two geminally coupled methylene protons from the dppm ligand appeared at 3.73 ppm. In the 13C NMR spectrum of 1 (Figure S2), signals at 23.9 and 72 ppm are attributed to isopropyl substituents. A weak signal at 29.7 ppm is attributed to the dppm ligand, which along with three sharp signals from an aromatic carbon at 129.3, 133, and 133.5 from the same ligand provided further evidence for the validity of the proposed structure. The 31P{1H} NMR spectrum of 1 (Figure S3) in CDCl3 showed one signal at 99.3 ppm assigned to two magnetically equivalent diisopropyldithiophosphate ligands and a second signal at 29.9 ppm from the dppm ligand. 2, a light green powder, showed a similar NMR absorption pattern (Figures S4 and S5), except a broad signal at 2.82 ppm, which is attributed to the ethylene linker from the dppe ligand. The 31P{1H} NMR spectrum of 2 (Figure S6) in CDCl3 also shows two sets of magnetically equivalent signals originating from dialkyldithiophosphate at 98.1 ppm and a signal at 37.1 ppm associated with the dppe ligand. Overall, these data are consistent with the literature data regarding linear gold(I) complexes stabilized with phosphine and sulfur donor ligands.44,46,66

In the 1H NMR spectrum of 3 (Figure S7), two sets of multiplet signals in the 4.84–4.29 ppm range with pronounced upper field chemical shifts are observed for the cyclopentadienyl resonances from the dppf ligand. It is notable that the 31P signals from dppm, dppe, or dppf free ligands usually undergo a pronounced upfield chemical shift upon metal coordination in tetrahedral complexes, while in 1–3, due to the presence of a trans sulfur atom, these chemical shifts are not distinct. 3 is not stable in acetonitrile, and a portion of the orange solute precipitates shortly after its complete dissolution. The orange precipitate, however, is soluble in dichloromethane or THF and shows spectroscopic characteristics of 3. Borate-based sulfur donor ligands, owing to their flexibility, show different coordination modes, mostly ranging from κ1-SS to κ3-SS upon metal coordination. Therefore, a more flexible borate-based Na(S-Mt)2 ligand with a larger bite angle was also used. 4, a white powder and an orange luminescent material, is not stable in dichloromethane for a prolonged time period due to its reaction with dichloromethane and decomposition of the coordinated borate ligand.67 Therefore, in the general work-up procedure described above and after the dissolution of 4 in dichloromethane, the solvent was promptly evaporated under reduced pressure. In the 1H NMR spectrum of 4 in Figure S10, methyl and methylene signals appeared as singlets at 3.58 and 2.85 ppm, respectively, indicating a symmetrical structure in solution. In the 13C NMR of 4, a diagnostic C–S signal from the borate ligand is observed at 158 ppm. In addition, the solid-state IR spectra of 4 and Na(S-Mt)2 in Figures S23 and S25 show two and one diagnostic medium-intensity bands assigned to νB–H stretching frequencies. These bands are observed for Na(S-Mt)2 at 2455 and 2413 cm–1 with different intensities. In 4, these bands are merged and observed at 2361 cm–1. This observation indicates two identical B–H bonds in the solid-state structures of 4, as depicted in Scheme 1. The reaction of (dppm)Au2Cl2, (ddpe)Au2Cl2, or (dppf)Au2Cl2 with potassium dicyclohexyldithiophosphate, K(S-OiPr)2, gave 5–7 in moderate yields. The characteristic O–CH– signal from cyclohexyl substituent is observed in the 1H NMR of 5, 6, and 7 as complicated multiplets above 4 ppm (Figures S13, S16, and S19). 31P{1H} NMR spectra of 5–7 (Figures S15, S18, and S21) showed two magnetically equivalent phosphine signals related to the phosphate and phosphine ligands near 100 and 30 ppm.

Scheme 1. Preparation of Bimetallic and Trimetallic Gold(I) Complexes.

Scheme 1

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1, 2, 3, 6, and 7 have been characterized by single-crystal X-ray crystallography. The selected structural parameters of the characterized complexes are provided in Tables 1 and 2. Bond lengths and angles are listed in Table 3. 1 crystallizes by slow diffusion of n-hexane into a dichloromethane solution at room temperature. Similarly, slow diffusion of a few drops of ether into an acetonitrile solution of 2, 3, 6, and 7 afforded crystals of sufficient quality for the X-ray diffraction (XRD) analysis. The molecular structure of 1 is shown in Figure 2. 1 crystallizes in the monoclinic space group P21/c. As summarized in Table 3, the experimentally determined Au–S and Au–P bond lengths and angles are within the reported range of gold(I) thiolate and phosphine complexes.68−71 The short Au–Au interatomic distances in gold complexes, particularly due to attractive bonding interactions between closed-shell d10 Au(I) centers, known as aurophilic interactions, have had fascinating consequences in the coordination chemistry of gold. While several factors could be crucial for the presence of such interatomic interactions, a comparison of dihedral angles within phosphine ligands and steric demands of ligand substituents reveals the presence of a large variation in intramolecular Au···Au distances in 1–7.46

Table 1. Crystal and Structure Refinement Data of 1 and 2.

identification code 1 2
empirical formula C37H50Au2O4P4S4 C38H52Au2O4P4S4
formula weight 1204.9 1218.86
T, K 180 95
λ, Å 1.54184 1.54184
crystal system monoclinic triclinic
space group P21/c P1̅
a, Å 14.1294(3) 9.4923(2)
b, Å 30.6226(7) 10.3310(2)
c, Å 11.4565(2) 13.2261(3)
α, deg 90 97.2410(17)
β, deg 111.745(2) 99.7940(17)
γ, deg 90 114.035(2)
V, Å3 4604.26(18) 1139.47(5)
Z 4 1
ρcalc, g cm–3 1.7382 1.7763
μ, mm–1 15.027 15.258
F(000) 2344 594
crystal size, mm 0.134 × 0.077 × 0.039 0.067 × 0.050 × 0.029
θmin, θmax, deg 2.89, 67.61 3.47, 73.24
index ranges –16 < = h < = 16 –11 < = h < = 11
–34 < = k < = 36 –12 < = k < = 12
–13 < = l < = 9 –16 < = l < = 16
reflections collected 27 150 15 869
independent reflections, Rint 8217, 0.028 4483, 0.037
θfull, deg (completeness 98%) 67.61 72.78
data/restraints/parameters 8217/12/459 4483/0/235
goodness-of-fit on F2a 1.0981 1.3200
R1 [I > 3σ(I)] 0.0212 0.0194
wR2 [I > 3σ(I)] 0.0619 0.0469
R1 (all data) 0.0267 0.0208
wR2 (all data) 0.0663 0.0476
Δρmin, Δρmax, e Å–3 –0.44, 0.41 –0.69, 0.36
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a

Refinement software Jana2020 does not refine the weighting scheme. Therefore, S is rarely close to 1, especially for the well-exposed data.

Table 2. Crystal and Structure Refinement Data of 3 and 6.

identification code 3 6 7
empirical formula C46H56Au2FeO4P4S4 C50H68Au2O4P4S4 C58H72Au2FeO4P4S4
formula weight 1374.9 1379.1 1535.1
T, K 150 95 95
λ, Å 0.71073 0.71073 1.54184
crystal system monoclinic triclinic triclinic
space group P21/c P1̅ P1̅
a, Å 8.4513(3) 9.5977(3) 9.6981(2)
b, Å 27.2691(14) 11.1499(3) 10.5928(2)
c, Å 11.3171(5) 13.5415(4) 14.6410(3)
α, deg 90 96.644(2) 88.8080(15)
β, deg 103.783(4) 101.627(2) 72.8570(16)
γ, deg 90 112.082(2) 82.2580(15)
V, Å3 2533.0(2) 1285.67(7) 1423.86(5)
Z 2 1 1
ρcalc, g cm–3 1.8026 1.7813 1.7903
μ, mm–1 6.395 6.029 14.305
F(000) 1360 682 760
crystal size, mm 0.356 × 0.288 × 0.174 0.130 × 0.059 × 0.036 0.100 × 0.031 × 0.0185
θmin, θmax, deg 2.38, 29.4 2.02, 29.53 3.16, 73.17
index ranges –8 < = h < = 11 –13 < = h < = 12 –12 < = h < = 11
–24 < = k < = 37 –15 < = k < = 15 –12 < = k < = 12
–13 < = l < = 15 –18 < = l < = 18 –18 < = l < = 18
reflections collected 12 240 21 685 19 963
independent reflections, Rint 5925, 0.0238 6327, 0.0366 5602, 0.0665
θfull, deg (completeness 98%) 27.07 27.61 73.17
data/restraints/parameters 5925/9/283 6327/0/289 5602/0/283
goodness-of-fit on F2a 1.3959 1.0067 1.1668
R1 [I > 3σ(I)] 0.0357 0.0226 0.0323
wR2 [I > 3σ(I)] 0.0701 0.0395 0.0756
R1 (all data) 0.0505 0.0332 0.0380
wR2 (all data) 0.0753 0.0421 0.0789
Δρmin, Δρmax, e Å–3 –0.77, 0.78 –0.24, 0.34 –1.28, 0.84
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a

Refinement software Jana2020 does not refine the weighting scheme. Therefore, S is rarely close to 1, especially for the well-exposed data.

Table 3. Selected Geometrical Parameters (Å, deg) of 1, 2, 3, 6, and 7.

bond lengths (Å)
 bond angles (deg)
complex specified atoms DFT X-ray specified atoms DFT X-ray
1 Au2–S3 2.343 2.3277(9) S3–Au2–P2a 177.09 177.20(4)
Au2–P2a 2.293 2.2595(8) Au2–S3–P2 98.21 100.28(5)
P2–S3 2.070 2.0372(14) S3–P2–S4 116.78 114.89(6)
P2–S4 1.960 1.9444(19) O3–P2–O4 95.47 94.58(15)
Au1–Au2 3.143 3.0945(2)      
2 Au1–S1 2.365 2.3234(3) S1–Au1–P1 177.35 177.584(7)
Au1–P1 2.298 2.2512(2) Au1–S1–P2 98.87 100.24(3)
P2–S1 2.057 2.0429(6) S1–P2–S2 118.22 117.07(4)
P2–S2 1.964 1.9423(11) O1–P2–O2 99.49 99.59(12)
3 Au1–S1 2.366 2.3189(17) S1–Au1–P1 178.67 177.40(9)
Au1–P1 2.298 2.2555(16) Au1–S1–P2 97.43 98.61(8)
P2–S1 2.054 2.001(2) S1–P2–S2 118.22 113.59(19)
P2–S2 1.965 1.994(4) O1–P2–O2 100.27 93.2(2)
6 Au1–S1 2.366 2.3162(3) S1–Au1–P2 179.16 177.948(6)
Au1–P2 2.299 2.2501(2) Au1–S1–P1 96.86 99.881(17)
P1–S1 2.062 2.0461(6) S1–P1–S2 118.96 118.97(3)
P1–S2 1.956 1.9319(10) O1–P1–O2 104.59 104.97(11)
7 Au1–S1 2.360 2.3100(6) P1–Au1–S1 175.90 176.48(3)
Au1–P1 2.303 2.2547(2) Au1–S1–P2 103.62 100.86(5)
P2–S1 2.050 2.0310(14) S1–P2–S2 112.55 112.46(7)
P2–S2 1.957 1.9433(14) O1–P2–O2 99.24 100.45(14)
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Figure 2.

Figure 2

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(left) Representation of the X-ray crystal structure of 1 with thermal ellipsoids for nonhydrogen atoms at a 30% probability level. Hydrogen atoms are omitted for clarity. (right) Side view of 1 showing two crossing P–Au–S units. Au1–S1 2.3162(9), Au1–P1a 2.2542(9), Au2–S3 2.3277(9), Au2–P2a 2.2595(8), S1–P1 2.0306(14), S2–P1 1.9465(15), S3–P2 2.0372(14), S4–P2 1.9444(19), P1–O1 1.590(3), P1–O2 1.588(3), P2–O3 1.577(3), P2–O4 1.579(3), S1–Au1–P1a 170.02(4), S3–Au2–P2a 177.20(4), Au1–S1–P1 96.86(4), Au2–S3–P2 100.28(5), S1–P1–S2 112.24(5), S1–P1–O1 110.61(12), S1–P1–O2 105.50(12), S2–P1–O1 113.26(12), S2–P1–O2 114.70(13), O1–P1–O2 99.64(13), S3–P2–S4 114.89(6), S3–P2–O3 108.59(14), S3–P2–O4 106.52(14), S4–P2–O3 114.52(15), S4–P2–O4 115.68(15), and O3–P2–O4 94.58(15).

The two Au(I) atoms in 1 (Figure 2) are separated by 3.0945(2) Å. Considering the distance of 3.351 Å in dppm-Au2Cl2,70 substituting the chloro ligand with dialkyldithiophosphate ligands has caused a stronger interaction in gold centers. As shown as a side view in Figure 2, two planes containing S–Au–P units have the torsion angle Au(2)–P(1a)–P(2a)–Au(2), which is 9.26(4)°. To reduce steric congestion between the two dialkyldithiophosphate units, the two planes containing S1–Au1 and S3–Au2 bonds are out of phase, and the torsion angle between them is 13.16(4)°.

The crystal structure of 2 was determined to be triclinic (space group P1̅) with Z = 1 formula units in the unit cell. The packed form of two individual monomeric chain-like units is shown in Figure 3. In contrast to 1, the dppe dihedral angle of 180° allows for a large distance of 7.0133(2) Å between gold(I) metal centers. However, an intermolecular bond distance of 4.3001(2) Å is observed in 2 between symmetrically related molecular units. Shorter intramolecular Au···Au contacts have been reported for similar complexes with bridging phosphine ligands with chloro ligands situated in the trans position to the phosphine ligands.72−74 Complex 6 (Figure 4) with the bridging dppe ligand and cyclohexyl substituents on the terminal ligands has a comparable intramolecular Au···Au distance of 7.0511(3) Å to 2. This observation indicates no influence from terminal ligands on the intramolecular gold(I) contacts. However, the intermolecular Au···Au distance of 4.4728(2) Å observed in 6 is comparable to that found in 2.

Figure 3.

Figure 3

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Representations of the X-ray crystal structure of 2 showing thermal ellipsoids for nonhydrogen atoms at a 30% probability level. The intramolecular and intermolecular Au···Au distances are 7.013 and 4.3 Å, respectively. Hydrogen atoms are omitted for clarity. Selected geometrical parameters (Å, deg): Au1–S1 2.3234(3), Au1–P1 2.2512(2), S1–P2 2.0429(6), S2–P2 1.9423(11), P2–O1 1.5948(17), P2–O2 1.585(3), S1–Au1–P1 177.584(7), Au1–S1–P2 100.24(3), S1–P2–S2 117.07(4), S1–P2–O2 100.16(7), and S2–P2–O2 116.39(9).

Figure 4.

Figure 4

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Representations of the X-ray crystal structure of 6 showing thermal ellipsoids for nonhydrogen atoms at a 30% probability level. Au1–S1 2.3162(3), Au1–P2 2.2501(2), S1–P1 2.0461(6), S2–P1 1.9319(10), P1–O2 1.589(3), S1–Au1–P2 177.948(6), Au1–S1–P1 99.881(17), S1–P1–S2 118.97(3), S1–P1–O2, 98.75(7), and S2–P1–O2 116.50(9).

The non-coplanarity of the two phosphorus atoms in the bridging dppf ligand allows even for a larger intramolecular separation of 8.6660(17) and 8.4771(3) Å between the two gold(I) centers in 3 and 7 (Figure 5), respectively. Indeed, a certain relationship exists between the steric bulk of the bridging and terminal ligands on one hand and inter- or intramolecular Au···Au separations in these molecules on the other hand.

Figure 5.

Figure 5

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Representations of the X-ray crystal structure of 7 showing thermal ellipsoids for nonhydrogen atoms at a 30% probability level. Hydrogen atoms are omitted for clarity.

Considering the van der Waals radii of 3.46 Å for gold and sulfur, the Au–S2 distance of 3.7412(7) Å in 2 indicates no interaction, although that of 3.183(6) Å in 3 could indicate a weak bonding interaction.74 Short intramolecular contacts in gold(I) chemistry, including dithiocarbamate compounds between free sulfur and metal center, have been reported previously.44

The proximity of intramolecular Au···S contact is controlled/dominated by the steric demands of the substituents. In 2, with Au···S contact of 3.7412(7) Å, the torsion angle Au1–S1–P2–S2 is 47.16(5)°. In 6, with a comparable torsion angle of 59.01(4)°, the Au···S contact is 3.9384(9) Å. On the other hand, in 3 (Figure 6), with a small torsion angle of 3.58(19)°, the Au···S contact is 3.183(6) Å. This analogy shows that the degree of torsion and the resulting Au···S contact in 2, 3, and 6 are directly related.

Figure 6.

Figure 6

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Representations of the X-ray crystal structure of 3 showing thermal ellipsoids for nonhydrogen atoms at a 30% probability level. Hydrogen atoms are omitted for clarity. Au1–S1 2.3189(17), Au1–P1 2.2555(16), S1–P2 2.001(2), S2–P2 1.994(4), P2–O1 1.561(3), P2–O2 1.598(4), S1–Au1–P1 177.40(9), Au1–S1–P2 98.61(8), and S1–P2–S2 113.59(19).

The geometry at gold centers is almost linear with P–Au–S angles of 177.584(7)°, 177.40(9)°, 177.948(6)°, and 176.48(3)° for 2, 3, 6, and 7, respectively. In 1, two different bond angles around gold are observed, which are S1–Au1–P1a 170.02(4)° and S3–Au2–P2a 177.20(4)°. The Au–P distances of 2.2542(9) and 2.2595(8) Å in 1, 2.2512(2) Å in 2, 2.2555(16) Å in 3, 2.2501(2) Å in 6 and 2.2547(2) Å in 7 are comparable to those measured experimentally in trans phosphine-Au(I)-thiolate complexes.62 It is notable that the Au–P distances in the (dppm)Au2Cl2, (dppe)Au2Cl2, and (dppf)Au2Cl2 precursors are shorter than those observed for 2, 3, 6, and 7 (vide supra) and this suggests that the phosphine ligand exerts a higher trans influence over chloride in precursors (e.g., dppe-Au2Cl2) than sulfurs in 1–7. The stronger bond lengths in the precursors are explained by a greater degree of dπ–dπ interaction between gold and a phosphine ligand. However, upon substitution of a chlorine ligand with sulfur donor ligands, the extent of this metal to ligand π backdonation is decreased. This observation also explains the downfield chemical shifts in the 31P NMR signals of the abovementioned complexes compared with gold precursors such as dppm-Au2Cl2.

Ground-State Geometry and Frontier Orbitals

The molecular structures of 2, 3, 6, and 7 were optimized in their electronic ground state (S0) using density functional theory (DFT) at the PBE0/Def2-TZVP (Au,Fe)/Def2-SVP (C, H, O, P, S) level.75−77 The Perdew–Burke–Erzenrhof parameter-free hybrid functional (PBE0) is well-known to properly describe the electronic properties of gold(I) complexes. Four views of the optimized geometry for 2, 3, 6, and 7 and the isodensity surface plots for the most relevant Kohn–Sham molecular orbitals (MOs) closer to the frontier region for the investigated complexes are shown in Figure 7.

Figure 7.

Figure 7

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Highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of 1–3, 6, and 7 using the PBE0 functional with Def2-TZVP/Def2-SVP basis sets.

The energy diagram of molecular orbitals (MO) of the studied complexes is shown in Figure 8. The energies of the corresponding orbitals from HOMO–5 to LUMO+5, along with the HOMO–LUMO energy gap, are given in Figures S26–S40.

Figure 8.

Figure 8

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Energy diagram of molecular orbitals (MO) of the studied complexes.

For complex 1, as illustrated in Figure 7, HOMO is dominantly delocalized on the π of the (S-OiPr)2 ligands and marginally on S and dx2-y2 orbitals of Au(I) atoms. LUMO is mainly delocalized on dppm (π*) and involves a minimal amount of π* of both Au(I) atoms. The HOMO in 2 is composed of π orbitals from (S-OiPr)2 and a slight contribution from dx2-y2 orbital from both gold atoms. LUMO, on the contrary, does not show contributions from S-OiPr and is mainly composed of a π orbital from the dppe ligand. Identical contributions from dppe and metal π (mostly py) orbitals are also observed in LUMO from 6 with 2. HOMO in 3 and 6 is mainly localized on π orbitals of the (S-OCy)2 ligand and partially from dx2-y2 of one metal center. LUMO in 3, on the other hand, is primarily localized on one of the phenyl rings of the dppf ligand. HOMO and LUMO in 7 are less localized and are combinations of the Fe dxz orbital, π orbitals from dppe, and π orbitals from (S-OCy)2. Furthermore, HOMO and LUMO energy levels are influenced by the nature of terminal and bridging ligands. For example, in 2, 6, and 3, 7 pairs, owing to the more electron-donating property of (S-OCy)2, HOMO is stabilized by 0.053 and 0.088 eV in 6 and 7, respectively. However, the LUMO level is destabilized by 0.007 eV. In 2, 3 and 6, 7 pairs, the complexes with similar terminal ligands, the replacement of dppe with dppf causes stabilization of the HOMO by 0.073 eV and on the contrary, destabilization of the LUMO by 0.107 eV, and this observation is in accordance with previous studies.78 In 1 and 2, with identical ligands but different linkers, the bridging dppm ligand causes stabilization of both HOMO and LUMO levels. A portion of this stabilization arises from aurophilic interactions.79,80

The calculated S0 structures in the dichloromethane phase are in good agreement with the geometrical parameters obtained from single-crystal X-ray diffraction analyses. In all cases, the computed geometries display a linear two-coordinated geometry around gold(I) atoms, with C1 point group symmetry for all complexes. The selected DFT-optimized structures reproduced the experimental Au–S and Au–P distances. These parameters are provided in Table 3.

Likewise, the computed S–Au–P bond angles are 177.35, 178.67, 179.16, and 175.90° for 2, 3, 6, and 7, respectively, which are in good agreement with crystallographic data. These data confirm the suitability of the computational model used in this study for describing the geometrical parameters of the complexes.

Electronic Spectroscopy and Time-Dependent (TD)-DFT

The photophysical properties of all complexes were investigated in dilute dichloromethane (2 × 10–5 molar concentration) at room temperature. The overlaid experimental and calculated absorbance spectra are displayed in Figure 9. For better clarity, the assigned molecular fragments are shown in Figure 10. According to the outcome of TD-DFT studies, there is an acceptable agreement between theoretical and experimental spectra. For the investigated complexes, the most relevant computed transitions involved in the vertical excitation processes, along with their energy, character, and oscillator strengths, are given in Figures S26–S40. The experimental absorption spectra of complexes show nearly identical features except for 2, which shows a second medium-intensity band around 270 nm, while in others, a weak shoulder around 270 nm appears. Based on TD-DFT results, the common transitions in the studied complexes are ILCT, MLCT, LMCT, and LLCT. The Au(I) ion as an electron-rich metal center, transfers some of its electron density to the π* of the coordinated ligands (MLCT) or accepts some electron density via the LMCT process. Ligands can also transfer their electron densities from their π orbitals to their π* orbitals called ILCT or to π* of other ligands named LLCT. In order to find the nature of transitions and involved fragments (metals and ligands) in the absorption process (UV–vis), TD-DFT calculations were carried out. 3 and 7 with bridging dppf show lower oscillator strength (f) compared to 2 and 6 having dppe linkers. Considering the high f value in complex 1, three important transitions are as follows: L2LCT at 312 nm, L1LCT, L2LCT at 293 nm, and MLCT, M′LCT, ILCT at 262 nm. For complex 2 (same as in 3, 6, and 7), three important transition bars are observed at 225, 240, and 278 nm. These transitions can be assigned to MLCT/ILCT, ILCT/M′LCT, and L2LCT/L1LCT, respectively. Despite similarities, the nature of these transitions in 6 differs from that of 2. Therefore, absorptions at 226, 239, and 274 nm can be attributed to MLCT/ILCT, MLCT/M′LCT/ILCT, and L2LCT, respectively. In 3, three important bars at 246, 257, and 262 nm can be assigned to L1LCT, L2LCT, and M′LCT/L2LCT, respectively. Finally, for 7, similar to 3, the three important bars are 237, 243, and 257 nm, and these transitions are attributed to MLCT/M′LCT/ILCT, ILCT/L1LCT, and ILCT. Changing from (S-OiPr)2 to (S-OCy)2 in 3 and 7 has subtle effects on TD-DFT and UV–vis spectra, and all main transitions show a mixture of transitions. Detailed band assignments for high oscillator strength and major contributions for 2, 3, 6, and 7 are provided in Figures S26–S40.

Figure 9.

Figure 9

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Overlaid experimental absorbance spectrum (in dichloromethane) and calculated TD-DFT of 1, 2, 3, 6, and 7 with the PBE0 functional.

Figure 10.

Figure 10

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Assigned fragments of studied complexes.

Antimicrobial Tests

The antibacterial actions of the studied complexes on the gram-positive (Staphylococcus aureus) and gram-negative (Escherichia coli) bacteria were analyzed using the Kirby–Bauer disk-diffusion technique.81,82 The effect of dimethyl sulfoxide (DMSO), as the initial solvent for the preparation of the stock solutions, was also separately determined on the bacterial growth in its highest quantity used. According to the results, while 4 inhibits S. aureus growth at the tested concentration range (with areas of clearance of 6 mm), it has no antibacterial activity against E. coli. None of the other complexes (2, 3, and 7) showed a significant inhibitory effect against either the gram-positive (S. aureus) or gram-negative (E. coli) bacteria at the tested concentrations.

Cytotoxicity Studies

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out on MCF-7 cells to evaluate the toxicity of 2, 3, and 7. As mentioned before (Scheme 1), 3 and 7 contain iron(II) centers other than gold(I) as the central cytotoxic metal ion in their formula. The anticancer effects of several heterometallic complexes containing iron and gold have been previously studied.63,83−87 Cell viability curves of the cells treated with the complexes have been shown in Figure 11. Based on these results, 2 with dppe linker and no iron(II) exhibits its antiproliferative activity at a low concentration of about 10 μM and has an IC50 value of 9.63 μM. Compound 3 containing the dppf linker showed good antiproliferative/cytotoxic activity with an IC50 value of 27 μM, although lower in magnitude than compound 2. Remarkably, 7, with a similar structure to 3 but with dicyclohexylphosphate in place of diisopropylphosphate alkyl groups, showed a very high cytotoxicity effect. These results reveal the influence of both linkers and substituents on cytotoxicity, and both could remarkably increase the antiproliferative activity.

Figure 11.

Figure 11

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Effects of 2 (left), 3 (middle), and 7 (right) on the cell viability of MCF-7 breast cancer cells obtained from the MTT test.

Hemolysis Assay

The possible hemolytic effects of complexes 2, 3, and 7 were also evaluated on the human erythrocytes. The results showed that these compounds did not significantly affect the integrity of the erythrocyte membranes at the tested concentrations, and the highest hemolytic effect is observed for compound 7 (∼14%) at 100 μM (Figure 12). No significant cell aggregation was also observed at the tested concentration range.

Figure 12.

Figure 12

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In vitro hemolytic activity of 2 (left), 3 (middle), and 7 (right). Human erythrocytes were incubated with desired concentrations of the compounds for 3 h. The data are averages from three independent repeats and have been reported as a percentage of the values in the control cells (untreated ones).

Inhibitory Effects of the Complexes on the Diphenolase Activity of Mushroom Tyrosinase

Tyrosinase overexpression and activation in many hyperpigmentation-related disorders and diseases in humans such as melanoma, chloasma, solar lentigo, freckles, etc. In plants, this enzyme is responsible for the unwanted enzymatic browning of vegetables and fruits, which significantly reduces their appearance, flavor, and economic value.88,89 Tyrosinase is also involved in insect defense, wound healing, molting, and encapsulation of parasites, and it so makes insects resistant to insecticides and damages agriculture and food industries.90 Thus, introducing novel safe and potent compounds with tyrosinase inhibitory effects is highly demanded in various areas such as agriculture, food, pharmaceutical, and cosmetics industries. Although several organic/inorganic synthetic and natural tyrosinase-inhibiting compounds have been found so far, most of them have serious side effects. To find novel tyrosinase inhibitors, we also evaluated the inhibitory potency of complexes 2, 3, 4, and 7 on diphenolase activity of mushroom tyrosinase as the model enzyme for tyrosinase inhibition studies. According to the results, the complexes moderately inhibited the enzyme diphenolase activity, and the highest enzyme inhibition was observed by compound 2 (52% in 20 μM) (Table 4). While the inhibitory potencies of complexes 3 and 4 were close to that of complex 2, complex 7 showed a lower inhibition rate (38%). There are reports on the inhibition of tyrosinase by metal-containing inorganic complexes. Iron-substituted phosphomolybdic acid (PMo11Fe) reversibly inhibited mushroom tyrosinase activity in a noncompetitive manner.91

Table 4. Inhibition of the Diphenolase Activity of Mushroom Tyrosinase by the Complexesa.

complex no. enzyme inhibition (%) concentration (μM)
2 52 20
3 48 40
4 49 60
7 38 80
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a

The right column represents the concentration of each complex that shows the highest inhibitory effect.

Molecular Docking Analysis

Many metal-based complexes have shown anticancer effects through interactions with DNA.31,63,64,92,93 We used the molecular docking approach to model interactions between the target DNA (PDB ID: 1BNA) and complexes (2, 3, and 7) and predict the binding sites and binding energies. The binding energies were −4.75, −3.55, and −4.53 kcal/mol for 2, 3, and 7, respectively, which were the lowest estimated energies. Docking was done on validated structures with the root-mean-square deviation (RMSD) < 1 Å. The results showed that all three complexes interact with DNA through a minor groove and bind to the same site. As shown in Figure 13, the complexes hydrophobically interact with the nucleotides G24, G2, C23, C3, G22, G4, A5, and A6. Complex 2 also forms a hydrogen bond with nucleotide A5.

Figure 13.

Figure 13

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Molecular docking images indicating interactions and binding sites of 2 (A), 3 (B), and 7 (C) with the target DNA (PDB ID: 1BNA).

Conclusions

In conclusion, we have prepared seven novel complexes of gold(I) with dialkyldithiophosphate and borate ligands and we have characterized their structures using a combination of NMR, UV–vis, IR spectroscopy, and single-crystal X-ray crystallography techniques. The X-ray diffraction data of five complexes provided vital information about these complexes’ solid-state parameters, allowing conclusions about the role of bridging phosphine and terminal sulfur donor ligands on the physicochemical properties of these complexes. For example, the short Au–Au interatomic distance in complex 1 is due to attractive bonding interactions between closed-shell d10 Au(I) centers. Based on DFT computational analysis of some of the complexes, they show mostly ILCT- and MLCT-type electronic transitions in their UV–vis spectra and the exact nature of transitions was unequivocally assigned using this computational analysis. Overall, dithiodialkylphosphates and borates proved to be excellent ligands and together with phosphine coligands they form stable gold complexes. The results of the biological activities of these complexes show that their performance depends upon the nature of the bridging and terminal ligands. For example, 7, with a structure similar to 3 but a slightly different terminal ligand, showed a very high cytotoxicity effect. The highest hemolytic effect is also observed for compound 7, while tyrosinase inhibitory potencies of the complexes seem to be less dependent on the nature of the ligands.

Experimental Section

General Considerations

Reagents and solvents were used as received from commercial suppliers. Infrared spectra were recorded on a Bruker Vector 22 FT-IR spectrometer (ATR in the range 400–4000 cm–1). UV–vis spectra were recorded on an Ultrospec 3100 Pro, UV–vis spectrophotometer using samples dissolved in acetonitrile. C, H, N, and S analyses were performed with a vario EL CHNS elemental analyzer. NMR spectra in solution were recorded on a Bruker AV-300 spectrometer in CDCl3 with SiMe4 (for 1H and 13C) and H3PO4 (for 31P) as external references. Au(SMe2)Cl, Na(S-Mt)2, (dppm)Au2Cl2, (dppe)Au2Cl2, and (dppf)Au2Cl2 were synthesized using established procedures.94−96

Synthesis of Potassium O,O′-Di(isopropyl)dithiophosphate, KP(S-OiPr)2

O,O′-Dialkyldithiophosphates were prepared through a two-step reaction of phosphorus pentasulfide with the corresponding alcohol in the presence of potassium carbonate.97−100 Potassium carbonate (10 mmol, 1.38 g) was added to a mixture of phosphorus pentasulfide (2.5 mmol, 1.11 g) in the desired alcohol (5 mL, excess) at 60 °C. The reaction mixture was stirred for 2 h at 80 °C. The reaction mixture was filtered while hot to remove unreacted potassium carbonate. The filtrate was allowed to cool and pure potassium O,O′-dialkyldithiophosphate was crystallized as a colorless solid in quantitative yield that could be recrystallized in ethanol. Potassium O,O′-diisopropyldithiophosphate: colorless solid; mp: 205–206 °C; 31P NMR (D2O, 162 MHz): δ = 107.43 ppm; 1H NMR (D2O, 400 MHz): δ = 1.19 (12H, d, J = 6.4 Hz), 4.55–4.65 (2H, m); 13C NMR (D2O, 100 MHz): δ = 23.0 (d, JCP = 4.0 Hz), 72.1 (d, JCP = 7.0 Hz). Potassium O,O′-dicyclohexyldithiophosphate: colorless solid; mp: 262–264 °C; 31P NMR (D2O, 162 MHz): δ = 107.54 ppm; 1H NMR (D2O, 400 MHz): δ = 1.09–1.28 (6H, m), 1.32–1.45 (6H, m), 1.61–1.65 (4H, m), 1.88–1.92 (4H, m), 4.26–4.37 (2H, m); 13C NMR (D2O, 100 MHz): δ = 23.7, 24.8, 33.3 (d, JCP = 4 Hz), 77.4 (d, JCP = 9 Hz).

General Procedure for the Synthesis of Metal Complexes (dppm)Au2(S-OiPr)2, 1

To a flask containing K(S-OiPr)2 (30 mg, 0.118 mmol) was added a suspension of (dppm)Au2Cl2 (50 mg, 0.058 mmol) in THF (5.0 mL). The solution was stirred for 24 h at room temperature, and the resulting potassium chloride precipitate was removed by centrifugation. The solvent was removed under reduced pressure. Light brown crystals were obtained upon dissolving the clean product in dichloromethane, allowing slow evaporation of the solvent in an open vessel (32 mg, 45.1%); 1H NMR (CDCl3, 300 MHz): δ 7.79–7.72 (m, 8H), 7.43–7.31 (m, 12H), 4.93 (sept., 4H), 3.73 (t, 2H), 1.35 (d, 24H); 13C{1H} NMR (75 MHz): δ 133.5, 132.0, 129.3, 72.0, 29.7, 23.9; 31P NMR (121 MHz): δ 99.3, 29.9; IR (cm–1, KBr pellet): 3478 (m), 3409 (m), 3045 (m), 2975 (s), 2923 (m), 2362 (w), 1708 (m), 1432 (s). Anal. calcd for C37H50Au2O4P4S4: C, 36.88; H, 4.18; S, 10.64; found: C, 36.90; H, 4.10; S, 10.55.

(dppe)Au2(S-OiPr)2, 2

To a flask containing K(S-OiPr)2 (29.5 mg, 0.116 mmol) was added a suspension of (dppe)Au2Cl2 (50 mg, 0.057 mmol) in THF (5.0 mL). The solution was stirred for 24 h at room temperature, and the resulting potassium chloride precipitate was removed by centrifugation. The solvent was removed under reduced pressure. Green crystals were obtained upon dissolving the clean product in dichloromethane and evaporating the solvent slowly in an open vessel (40 mg, 56.6%); 1H NMR (CDCl3, 300 MHz): δ 7.84–7.77 (m, 6H), 7.53–7.26 (m, 12H), 4.95 (sept., 4H), 2.82 (s, 4H), 1.39 (d, 24H); 13C{1H} NMR (CDCl3, 75 MHz): 133.6, 132.1, 129.5, 72.4, 24.0, 23.09; 31P NMR (CDCl3, 121 MHz): 98.1, 37.1; IR (cm–1, KBr pellet): 3449 (m), 3055 (w), 2972 (m), 2924 (w), 1436 (s). Anal. calcd for C38H52Au2O4P4S4: C, 37.45; H, 4.30; S, 10.52; found: C, 37.50; H, 4.20; S, 10.55.

(dppf)Au2(S-OiPr)2, 3

To a flask containing K(S-OiPr)2 (37.2 mg, 0.147 mmol) was added a suspension of (dppf)Au2Cl2 (75 mg, 0.073 mmol) in THF (5.0 mL). The solution was stirred for 24 h at room temperature, and the resulting potassium chloride precipitate was removed by centrifugation. The solvent was removed under reduced pressure. Small orange crystals were obtained upon dissolving the clean product in dichloromethane and evaporating the solvent slowly in an open vessel (66 mg, 64.5%); 1H NMR (CDCl3, 300 MHz): δ 7.61–7.38 (m, 20H), 4.95 (sept., 4H), 4.84–4.80 (m, 4H), 4.32–4.29 (m, 4H), 1.38 (d, 24H); 13C{1H} NMR (CDCl3, 75 MHz): δ 133.6, 133.4, 131.6, 131.0, 130.2, 129.1, 128.9, 75.7, 75.6, 75.0, 74.8, 72.4, 71.6, 70.7, 23.9; 31P NMR (CDCl3, 121 MHz): 98.7, 32.1; IR (cm–1, KBr pellet): 3423 (m), 3046 (w), 2929 (s), 2851 (m), 2362 (m), 2337 (m), 1435 (s). Anal. calcd for C46H56Au2FeO4P4S4: C, 40.19; H, 4.11; S, 09.33; found: C, 40.1; H, 4.20; S, 09.20.

(dppe)Au2(S-BMt)2, 4

To a flask containing Na(S-Mt)2 (42.5 mg, 0.162 mmol) was added a suspension of (dppe)Au2Cl2 (70 mg, 0.081 mmol) in THF (5.0 mL). The solution was stirred for 24 h at room temperature, and the resulting potassium chloride precipitate was removed by centrifugation. The solvent was removed under reduced pressure. Brown crystals were obtained upon dissolving the clean product in dichloromethane and evaporating the solvent slowly in an open vessel (60 mg, 58.1%); 1H NMR (CDCl3, 300 MHz): δ 7.82–7.67 (m, 8H), 7.46–7.35 (m, 12H), 6.96 (s, 4H), 6.69 (s, 4H), 3.58 (s, 12H), 2.85 (s, 4H); 13C{1H} NMR (CDCl3, 75 MHz): δ 158.0, 133.5, 133.3, 132.2, 131.2, 129.1, 129.0, 128.9, 123.8, 118.4, 66.5, 35.8; 31P NMR (CDCl3, 121 MHz): 33.9; IR (cm–1, KBr pellet): 3426 (m), 3128 (w), 2920 (w), 2361 (m), 1461 (s), 1438 (s).

(dppm)Au2(S-OCy)2, 5

To a flask containing K(S-OCy)2 (39.5 mg, 0.118 mmol) was added a suspension of (dppm)Au2Cl2 (50 mg, 0.058 mmol) in THF (5.0 mL). The solution was stirred for 2 h at room temperature, and the resulting white precipitate (KCl) was removed by centrifugation. The solvent was removed under reduced pressure. Colorless crystals were obtained upon dissolving the clean products in dichloromethane and evaporating the solvent slowly in an open vessel (25 mg, 31.1%); 1H NMR (CDCl3, 300 MHz): δ 7.87–7.80 (m, 8H), 7.43–7.32 (m, 12H), 4.74–4.61 (m, 4H), 3.99 (t, 2H), 2.14–1.10 (m, 44H); 13C{1H} NMR (CDCl3, 75 MHz): δ 133.8, 132.2, 129.3, 128.7, 128.2, 127.8, 69.0, 42.0, 33.5, 25.3, 23.8; 31P NMR (CDCl3, 121 MHz): 98.5, 33.4; IR (cm–1, KBr pellet): 3683 (s), 3295 (m), 3151 (m), 2929 (m), 2854 (m), 1700 (s), 1536 (s). Anal. calcd for C49H66Au2O4P4S4: C, 43.11; H, 4.87; S, 9.39; found: C, 43.10; H, 4.56; S, 9.01.

(dppe)Au2(S-OCy)2, 6

To a flask containing K(S-OCy)2 (38.6 mg, 0.116 mmol) was added a suspension of (dppe)Au2Cl2 (50 mg, 0.057 mmol) in THF (5.0 mL). The solution was stirred for 24 h at room temperature, and the resulting white precipitate (KCl) was removed by centrifugation. The solvent was removed under reduced pressure. Pale brown crystals were obtained upon dissolving the clean product in dichloromethane and evaporating the solvent slowly in an open vessel (31 mg, 38.4%); 1H NMR (CDCl3, 300 MHz): δ 7.83–7.76 (m, 8H), 7.53–7.46 (m, 12H), 4.72–4.57 (m, 4H), 2.81 (m, 4H), 2.19–1.91 (m, 8H), 1.85–1.44 (m, 21H), (1.40–1.1, 14H); 13C{1H} NMR (CDCl3, 75 MHz): δ 133.6, 132.2, 129.6, 129.5, 33.5, 25.3, 23.9; 31P NMR (CDCl3, 121 MHz): 97.7, 36.7; IR (cm–1, KBr pellet): 3693 (s), 3296 (m), 3116 (m), 2927 (m), 1718 (s), 1533 (s). Anal. calcd for C50H68Au2O4P4S4: C, 43.54; H, 4.97; S, 9.30; found: C, 43.32; H, 4.66; S, 9.1.

(dppf)Au2(S-OCy)2, 7

To a flask containing K(S-OCy)2 (66 mg, 0.198 mmol) was added a suspension of (dppf)Au2Cl2 (100 mg, 0.098 mmol) in THF (5.0 mL). The solution was stirred for 24 h at room temperature and the resulting white precipitate (KCl) was removed by centrifugation. The solvent was removed under reduced pressure. Light brown crystals were obtained upon dissolving the clean product in dichloromethane and evaporating the solvent slowly in an open vessel (50 mg, 33.2%); 1H NMR (CDCl3, 300 MHz): δ 7.57–7.38 (m, 20H), 4.79 (m, 4H), 4.72–4.59 (m, 4H), 4.29 (m, 4H), 2.26–1.91 (m, 8H), 1.75–1.42 (m, 16H), 1.13–0.81 (m, 8H); 13C{1H} NMR (CDCl3, 75 MHz): δ 133.6, 133.4, 131.7, 130.9, 129.9, 129.1, 128.9, 77.2, 75.5, 74.9, 74.7, 33.5, 25.3, 23.9; 31P NMR (CDCl3, 121 MHz): 98.2, 30.1; IR (cm–1, KBr pellet): 3415 (m), 3047 (w), 2929 (s), 2852 (m), 2361 (m), 2337 (w), 1435 (s). Anal. calcd for C58H72Au2FeO4P4S4: C, 45.38; H, 4.73; S, 8.35; found: C, 45.42; H, 4.66; S, 8.20.

Computational Details

DFT calculations were carried out with the program suite Gaussian09 using PBE0 functional and Def2-TZVP was used to describe Au and Fe centers and the Def2-SVP basis set was utilized for the other elements (C, H, N, P, O, S) in dichloromethane with a conductor-like polarized model (CPCM).75,76,101 TD-DFT of complexes 1, 2, 3, 6, and 7 were done in solution phase (DCM) with the same level of theory and 45 excited states were studied.

X-ray Crystal Structure Determination and Refinement

Crystals of 1 were grown by layering the dichloromethane solution with n-hexane. Crystals of 2, 3, 6, and 7 were grown by the layering of its acetonitrile solution with ether.

The X-ray diffraction data of samples 1 and 3 were collected with a Rigaku OD Gemini diffractometer using an Atlas S2 CCD detector and mirror-collimated Cu Kα (λ = 1.54184 Å) radiation from a sealed X-ray tube in the case of 1 and graphite monochromated Mo Kα (λ = 0.71073 Å) radiation from a sealed X-ray tube in the case of 3. Sample 1 was cooled to 180 K, and sample 3 was cooled to 150 K during the measurement. The X-ray diffraction data of samples 2, 6, and 7 were collected with Rigaku OD Supernova using an Atlas S2 CCD detector, and mirror-collimated Cu Kα (λ = 1.54184 Å) from a microfocused sealed X-ray tube in the case of 2 and 7 and mirror-collimated Mo Kα (λ = 0.71073 Å) from a microfocused sealed X-ray tube in the case of 6. The samples were cooled to 95 K during the measurement. Integration of the CCD images, absorption correction, and scaling were done by the program CrysAlisPro 1.171.41.123a (Rigaku Oxford Diffraction, 2022). Crystal structures were solved by charge flipping with the program SUPERFLIP102 and refined with the Jana2020 program package (not yet published successor of Jana2006103) by the full-matrix least-squares technique on F2. The molecular structure plots were prepared by Mercury 2020.1.103 All hydrogen atoms were visible in difference Fourier maps and were kept in the geometrically correct positions with a C–H distance of 0.96 Å. The positions of hydrogen atoms connected to boron atoms were refined freely. The isotropic atomic displacement parameters of hydrogen atoms were evaluated as 1.2Ueq of the parent atom. The disordered functional groups were refined with restrained geometry and the sum of occupancies constrained to 1 for each position. Crystallographic data, details of the data collection, structure solution, and refinements, are listed in Tables 1 and 2.

Antibacterial Tests

The antibacterial effects of the complexes were investigated against the gram-negative (Escherichia coli PTCC 1330) and gram-positive (Staphylococcus aureus PTCC 1112) bacteria using the Kirby–Bauer disk-diffusion method.82,83 At first, the complexes were dissolved in DMSO and then diluted to different extents (0–800 μM) with the sterile phosphate-buffered saline (PBS). To investigate the antibacterial effects of the complexes, a single colony of each gram-negative/positive bacteria was overnight cultured in a sterile Luria-Bertani (LB) medium at 37 °C. 30 μL of the culture was then evenly spread on a sterile LB-agar medium, and Whatman paper discs (6 mm diameter) impregnated with different concentrations of each complex were evenly placed on each plate. The plates were then placed in an incubator (37 °C) for 18 h. Tetracycline and sterile water were used as the positive and negative controls, respectively, during the experiments. The plates were removed at the end of the incubation and the clearance area was measured (in mm) for each sample, which is the distance between the beginning of the bacterial growth and the edge of the filter paper disc.

Cytotoxicity Analysis

The cytotoxicity of the complexes was in vitro analyzed on the human breast cancer cell line (MCF-7). The cells were purchased from the National Cell Bank of Iran (NCBI, Pasteur Institute, Tehran, Iran) and maintained in the Roswell Park Memorial Institute (RPMI) medium 1640 (Gibco, USA) containing 10% fetal bovine serum (FBS; Gibco, USA) and 1% penicillin–streptomycin in a humidified CO2 incubator at 37 °C. The MTT method was used to evaluate cell viability in the presence of different concentrations of the complexes. At first, a density of 12 × 103 cells per well was seeded in 96-well plates (in 100 μL of the complete RPMI 1640 medium), and incubation continued for 24 h (at 37 °C) to obtain the exponential growth phase. The complexes prepared in DMSO were then diluted with the same medium to obtain the stock solutions. Treatment of the cells with different concentrations of each complex was carried out for 48 h at 37 °C in a humidified CO2 incubator. The final concentration of DMSO was below 1% (v/v) in all assays. The cells treated with the medium and also the medium containing 1% DMSO were used as the controls. Following the incubation, the medium was completely removed from the wells, and the cells were washed with PBS. A fresh medium containing MTT was then added to each well, and the cells were incubated at 37 °C for 4 h. The supernatant containing the MTT solution was then removed, and 100 μL of DMSO was added to each well to solubilize the formazan crystals. Finally, the absorbance values were recorded at 570 nm using an ELISA reader, and the cell viability percentage was calculated according to the following formula: % cell viability = [OD (treated cells)/OD (control cells)] × 100. The represented data are the averages from at least three independent MTT assays for each complex. Statistical analyses were performed using Graphpad Prism 6.01 software (GraphPad Software Inc., San Diego, California) by one-way analysis of variance (ANOVA) followed by Tukey’s test. A p-value less than 0.05 was statistically significant.

In Vitro Hemolytic Effects

The hemolytic effects of the complexes were examined as a previously reported procedure.88 Briefly, the red blood cell (RBC) suspensions (with 1% hematocrit) were treated with different concentrations of each complex for 3 h at 37 °C under gentle stirring. At the end of the incubation time, the suspensions were centrifuged at 12 000g for 10 min, and the absorbance values of supernatants at 540 nm were then recorded. The RBCs treated with PBS and Triton X-100 (10 v/v) were considered as negative and positive controls, respectively. The hemolysis percentage values were finally calculated using the corresponding formula.88

Tyrosinase Activity Assay

Diphenolase activity of the mushroom tyrosinase was determined by the dopachrome method in the absence and presence of different concentrations of 2, 3, 4, and 7. 3, 4-Dihydroxyphenylalanine (l-DOPA) was used as the substrate (final concentration 2 mM) and dopachrome formation was kinetically monitored at 475 nm. The enzyme and substrate were prepared in NaH2PO4–Na2HPO4 buffer (pH 6.8), and the complexes were first dissolved in DMSO and then diluted with the same buffer to various concentrations (500 nM to 50 μM). The final concentration of DMSO in the test solutions never exceeded 1% (v/v). To investigate the possible inhibitory effect of complexes on diphenolase activity of the enzyme, the enzyme was incubated for 30 min with different concentrations of the complexes, and the assay was then carried out as previously described88 at room temperature. The absorbance curve over time was monitored at 475 nm, and tyrosinase activity was finally calculated according to the linear slope against the untreated control sample.

Molecular Docking Simulations

To obtain detailed information on the binding of 2, 3, and 7 to DNA, the Autodock 4.0 software was used. Lamarckian genetic algorithm (LGA) was applied as the most efficient search method for docking. The pdb files of the complexes were created using the ChemOffice software (ChemDRAW Professional Version 15), and the three-dimensional (3D) crystal structure of DNA (PDB ID: 1BNA) was obtained from the protein data bank (www.rcsb.org/pdb). The prepared pdb files of the DNA and complexes were then introduced to the Visual Molecular Dynamics (VMD) program, and molecular docking was finally run on the Autodock program. For the complexes, a grid box of 66 × 76 × 126 points was centered on the ligand in the complex with a spacing of 0.375 Å for 1BNA in the x, y, and z directions, respectively. The point numbers for 1BNA in x, y, and z were 14.779, 20.976, and 8.804. The metal ion parameters were added to the docking parameters. The docked poses were visualized using the AutoDock Tools 1.5.6 and PyMOL molecular graphics program. The output structures were then converted to the PDBQT using the MGL tools 1.5.6, and the best conformations of the complexes were selected for further analysis.

Acknowledgments

Funding for this work by the Institute for Advanced Studies in Basic Sciences (IASBS) Research Council is acknowledged. Crystallography of 1, 2, 3, 6, and 7 used the infrastructure supported by the Operational Programme Research, Development, and Education financed by the European Structural and Investment Funds and the Czech Ministry of Education, Youth and Sports (Project No. SOLID21 CZ.02.1.01/0.0/0.0/16_019/0000760).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c00645.

  • TD-DFT data, figures, tables providing spectroscopic data, and NMR line shape analysis (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao3c00645_si_007.pdf (3.3MB, pdf)

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