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Article

Silver(I) Complexes Based on Oxadiazole-Functionalized α-Aminophosphonate: Synthesis, Structural Study, and Biological Activities

by
Shaima Hkiri
1,2,
Kübra Açıkalın Coşkun
3,
Elvan Üstün
4,
Ali Samarat
2,
Yusuf Tutar
5,
Neslihan Şahin
6 and
David Sémeril
1,*
1
Synthèse Organométallique et Catalyse, UMR-CNRS 7177, University of Strasbourg, 4 rue Blaise Pascal, 67008 Strasbourg, France
2
Laboratory of Hetero-Organic Compounds and Nanostructured Materials (LR18ES11), Faculty of Sciences of Bizerte, University of Carthage, Bizerte 7021, Tunisia
3
Department of Medical Biology and Genetics, Faculty of Medicine, University of İstanbul Aydın, Istanbul 34295, Turkey
4
Department of Chemistry, Faculty of Art and Science, University of Ordu, Ordu 52200, Turkey
5
Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, University of Health Sciences-Turkey, Istanbul 34668, Turkey
6
Department of Science Education, Faculty of Education, University of Cumhuriyet, Sivas 58140, Turkey
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(23), 8131; https://doi.org/10.3390/molecules27238131
Submission received: 28 October 2022 / Revised: 15 November 2022 / Accepted: 16 November 2022 / Published: 22 November 2022
(This article belongs to the Special Issue Recent Advance in Transition Metal Complexes and Their Applications)
Browse Figures
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Abstract

:
Two silver(I) complexes, bis{diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-κN3:κN4-amino) (4-trifluoromethylphenyl)methyl]phosphonate-(tetrafluoroborato-κF)}-di-silver(I) and tetrakis-{diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-κN3-amino)(4-trifluoromethylphenyl)methyl]phosphonate} silver(I) tetrafluoroborate, were prepared starting from the diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-amino)(4-trifluoromethylphenyl)methyl]phosphonate (1) ligand and AgBF4 salt in Ag/ligand ratios of 1/1 and 1/4, respectively. The structure, stoichiometry, and geometry of the silver complexes were fully characterized by elemental analyses, infrared, single-crystal X-ray diffraction studies, multinuclear NMR, and mass spectroscopies. The binuclear complex ([Ag2(1)2(BF4)2]; 2) crystallizes in the monoclinic asymmetric space group P21/c and contains two silver atoms adopting a {AgN2F} planar trigonal geometry, which are simultaneously bridged by two oxadiazole rings of two ligands, while the mononuclear complex ([Ag(1)4]BF4; 3) crystallizes in the non-usual cubic space group Fd-3c in which the silver atom binds to four distinct electronically enriched nitrogen atoms of the oxadiazole ring, in a slightly distorted {AgN4} tetrahedral geometry. The α-aminophosphonate and the monomeric silver complex were evaluated in vitro against MCF-7 and PANC-1 cell lines. The silver complex is promising as a drug candidate for breast cancer and the pancreatic duct with half-maximal inhibitory concentration (IC50) values of 8.3 ± 1.0 and 14.4 ± 0.6 μM, respectively. Additionally, the interactions of the ligand and the mononuclear complex with Vascular Endothelial Growth Factor Receptor-2 and DNA were evaluated by molecular docking methods.

1. Introduction

The coordination chemistry of silver(I), which displays a [Kr] 4d10 5s1 electronic configuration, is particularly rich and can adopt a wide range of geometries [1,2,3]. In addition to linear silver(I) complexes [4,5,6], it is common to find triangular [7,8] or T-shaped [4,9], tetrahedral [10,11], or square plane [4,12] geometries but also compounds in which the silver atom is coordinated to five [13], six [13], seven [14], and even eight [15] ligands, often generating coordination polymers [16,17].
One of the most widely used coordinating atoms to silver has been found to be the nitrogen atom, which is generally incorporated in polydentate heterocyclic structures. Among these aza-heterocyclic ligands, 1,3,4-oxadiazoles have been well studied, leading to a wide coordination diversity of the silver cation [18,19,20,21,22,23,24,25,26,27,28]. For instance, Dong et al. reported the use of the 2,5-di(pyridin-4-yl)-1,3,4-oxadiazole ligand (A; Figure 1) with the AgSO3CF3 metal precursor (metal/ligand ratio: 1/2) in a CH2Cl2/MeOH mixture, to obtain the infinite one-dimensional polymeric compound {[Ag4(A)4](SO3CF3)4}n in a 71% yield. The single-crystal analysis revealed the presence of two different Ag(I) centers: the first one adopted nearly a linear coordination with the two pyridyl N-atoms from two A ligands, while the second one had a distorted trigonal coordination environment made of three N-donor atoms of two pyridyl and the 1,3,4-oxadiazole moieties. The tetramer formed a 40-membered macrocycle, which was further connected to a smaller 14-membered dimeric unit [29]. The same group reported the reaction of 2-(5-(2-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)phenyl isonicotinate (B; Figure 1) with an equimolar amount of AgPF6, which led to the formation of a bimetallic metallocycle of formula [Ag2(B)2·(MeOH)2](PF6)2 in which each Ag(I) center adopted a three-coordination sphere formed by one (N,O)-chelating donor and one pyridyl N-donor from a second B ligand. The two ligands arranged in a head-to-head fashion to form a distorted rectangular binuclear ring [30]. Recently, Qin et al. described the formation of a three-dimensional polymer from the 1,3,5-tris(5-(methylthio)-1,3,4-oxadia-zol-2-yl)benzene ligand (C; Figure 1) and AgSO3CF3 precursor (metal/ligand ratio: 3/1). The single crystal analysis revealed that the asymmetric unit is composed of two crystallographically independent silver cations, one ligand C, one coordinated water molecule, one coordinated triflate anion, a free counter anion, and a molecule of dichloromethane. The first Ag(I) adopts a distorted tetrahedral coordination sphere generated by four N(oxadiazole) atoms from four separate ligands. The second Ag(I) is also four-coordinated by two N(oxadiazole) atoms from two separate ligands and two oxygen atoms from a water molecule and a triflate anion. The polymeric network is generated by ligand C, which acts as a hexa-dentate ligand, binding to six Ag(I) cations. It is worth noting that, in the formed polymer, the sulfur atoms are not involved in the coordination with the metal [31]. An inorganic ribbon, formed by mixing (E)-3-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)acrylic acid (D; Figure 1) and AgNO3 (metal/ligand ratio: 1/1) in the presence of a base, was reported by the group of Kokunov. In this polymer, two bidentate carboxylate groups bind two silver atoms and form dimeric blocks in which the Ag-Ag distance is only 2.854(1) Å. The distorted tetrahedral coordination of the Ag(I) cation is completed with an oxadiazole ring [32].
The possibility to modulate the coordination sphere of the silver(I) cation has allowed, in particular, the development of efficient silver complexes for medicinal applications, notably as antibacterial, antifungal, or anticancer agents [33,34,35,36,37,38,39,40,41]. In recent years, there has been growing interest in organic silver complexes as promising anticancer agents with efficacious activity against various cancer cell lines [42,43,44]. These complexes, which exhibit low toxicity for humans [45] and have long been used as antimicrobial drugs, are potential candidates to replace platinum-based anticancer drugs such as cisplatin (cis-diaminodichloroplatine(II) [Pt(NH3)2Cl2]) [46], which, despite their success, have drug resistance, undesirable side-effects such as gastrointestinal disorders, bleeding, allergic reactions, or a decrease in immunity, and are effective against only a few types of cancer [47].
Angiogenesis is a physiological process of formation and development of new vessels from existing vessels [48]. The growth and spread of solid tumor cells require tumor angiogenesis [49]. There are many growth factors involved in tumor angiogenesis, one of the most notable of these is the vascular endothelial growth factor (VEGF) family [50]. The vascular endothelial growth factor receptors (VEGFRs) in mammalian cells include three members: VEGFR-1, VEGFR-2, and VEGFR-3 [51]. Among these three receptors, VEGFR-2 is considered to be the most important marker for endothelial cell development and directly regulates tumor angiogenesis [52]. Some studies reported that VEGFR-2 has been found in colon cancer, pancreatic cancer, small cell lung cancer, and breast cancer cells [53]. Therefore, managing the action mechanism of VEGFR-2 could be an effective way in the treatment of several types of cancer.
In this context, we now report the coordination of diethyl[(5-phenyl-1,3,4-oxadia-zol-2-ylamino)(4-trifluoromethylphenyl)methyl]phosphonate to the silver cation AgBF4. The cytotoxicities of the α-aminophosphonate and one of its silver complexes were investigated toward the MCF-7 human breast cancer, which is the most frequently diagnosed cancer and the most common cause of death in women, and PANC-1 human pancreatic cancer cell lines. Our interest in this kind of ligand is stimulated by the well-known anticancer properties of 1,3,4-oxadiazoles [54] and α-aminophosphonates [55,56,57,58], which could be beneficial for obtaining novel silver(I) complexes with enhanced anticancer activity. Additionally, the interactions of α-aminophosphonate and one of its silver complexes against VEGFR-2 and DNA crystal structures were analyzed by molecular docking methods.

2. Results and Discussion

2.1. Silver(I) Complexes Synthesis

The slow diffusion of hexane into a THF solution of diethyl[(5-phenyl-1,3,4-oxadia-zol-2-ylamino)(4-trifluoromethylphenyl)methyl]phosphonate (1) and AgBF4 led to crystals of silver-α-aminophosphonate adducts with various compositions and structures (Scheme 1). Infrared and mass spectrometry analysis carried out on the crystals revealed that the arrangement of the formed complexes depended exclusively on the metal-to-ligand ratio (Ag/1) used for the synthesis. Moreover, the IR spectrum of complex 2, unlike complex 3, displayed two weak bands at 724 and 751 cm−1 and five broad bands in the range of 925–1067 cm−1 consistent with a coordinated BF4 anion to a silver atom (see Supplementary Materials) [59].
Despite partial decomposition of complex 2 during the ESI-TOF analysis, cations with two silver atoms and a BF4 counter anion could be observed at m/z = 1666.18 [M + 1 − BF4]+ and 2121.30 [M + (1)2 − BF4]+. On the other hand, mass spectrum analysis of complex 3 displayed cations corresponding to m/z = 562.03 [M − (1)3 − BF4]+, 1019.15 [M − (1)2 − BF4]+, 1474.27 [M − 1 − BF4]+, and 1929.40 [M − BF4]+ (Figure 2). Indeed, two different silver complexes, 2 ([Ag2(1)2(BF4)2]) and 3 ([Ag(1)4]BF4), were obtained starting from Ag/1 ratios of 1/1 and 1/4, in 42 and 28% yields, respectively (Scheme 1).

2.2. Single-Crystal X-ray Diffraction Studies

The binuclear complex 2 crystallized in the monoclinic asymmetric space group P21/c and contained two silver atoms, two distinct enantiomeric α-aminophosphonate 1 (the two C9 atoms have an (R)- and an (S)-configuration), and two BF4 anions. The CF3 (F1, F2, and F3) moiety was disordered over two positions with a ratio of 0.6/0.4 (Figure 3 and Table 1). The silver atoms, which adopted {AgN2F} planar trigonal geometries, were simultaneously bridged by two oxadiazole rings of two ligands with Ag1-N1 and Ag1-N2 bonds of 2.260(2) and 2.215(2) Å, respectively. The coordination spheres were completed with the coordination of the counter anion BF4 through a fluorine atom [23] (Ag-F4 2.652(2) Å; sum of van der Waals radii 3.27 Å [60]). The counter anion was also maintained by a hydrogen bond with the amine (NH3···F5 2.117 Å). The distance between the two silver ions was 3.417 Å. This distance was slightly smaller than the sum of the van der Waals radii of two silver ions (3.44 Å [60]), suggesting the occurrence of very weak argentophilic interactions [61]. The oxadiazole rings were planar with the phenyl substituents (dihedral angle of 3.03°) and angled with respect to the 4-trifluoromethylphenyl ring (dihedral angle of 44.21°).
The mononuclear complex 3 crystallized in the non-usual cubic space group Fd-3c. The silver atom bound to four distinct enantiomeric α-aminophosphonates (the four C9 atoms had twice (R)- and twice (S)-configuration). The CF3 (F1, F2, and F3) and ethyl (C10 and C11) moieties were disordered over two positions with ratios of 0.5/0.5 and 0.57/0.43, respectively (Figure 4 and Table 1). The silver atoms adopted {AgN4} slightly distorted tetrahedral geometries with Ag1-N1 bonds of 2.289(4) Å and N1-Ag1-N1 angles of 105.56(10) or 117.6(2)°. The dihedral angles between the oxadiazole and the phenyl or the 4-trifluoromethylphenyl rings were 12.43 and 53.89°, respectively.
The study revealed the presence in the solid state, for each silver complex, of eight hydrogen bonds involving their N-H and P=O moieties [62] (H···O 1.877 Å) supramolecularly interlinked to each complex with four neighbors around the three crystallographic axes. In the crystal lattice (118,085(4) Å3), the 48 [Ag(1)4] cations generated a three-dimensional microporous supramolecular network, which contained a void between the inorganic molecules (18,208 Å3). At the end of the crystal structure determination, residual electron density peaks (4825 e-) were found for which no satisfactory disorder model could be obtained. The disordered species were a mixture of counter anion BF4 (1968 e-) and solvent molecules (2857 e-), occupying the space left vacant by the silver complexes [31]. The SQUEEZE program was used to account for the disorder. The contribution of these species was removed from the final structure factor calculations (see Supplementary Materials).
It is interesting to note that in both silver complexes, the potentially coordinating group P(O)(OEt)2 was not involved in a coordination with the metal centers.

2.3. In Vitro Effects Assessment on MCF-7 and PANC-1 Cell Lines

Preliminary in vivo toxicity studies carried out on brain of mice demonstrated that the monomeric silver complex 3 is not neurotoxic contrary to the dimeric complex 2 [63]. Consequently, the antitumor potential of the α-aminophosphonate 1 and the tetrahedral silver complex 3 were evaluated against MCF-7 and PANC-1 cells by a one-dose assay. The 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays were performed to investigate the dose-dependent silver compounds’ effect on cell viability. For this purpose, compounds were added on cells at an increasing concentration (3.125–200 μM) during 24 and 48 h and IC50 values were calculated (Table 2). After 24 h of incubation, the results indicated that α-aminophosphonate 1 was about twice less cytotoxic than the silver complex 3, and IC50 values of 22.8 ± 0.8 and 11.2 ± 0.4 μM were obtained when the MCF-7 cell line was treated with 1 and 3, respectively (Figure 5). Both compounds had a dose-dependent effect and, when exposed to the PANC-1 cell line, they showed lower cytotoxicity with IC50 values of 35.0 ± 1.0 and 18.3 ± 1.2 μM for 1 and 3, respectively (Figure 6).
The two drugs 1 and 3 had a time-dependent effect; the cytotoxicities could be improved by extending the incubation time to 48 h. Thus, with the silver complex 3, IC50 values of 8.3 ± 1.0 and 14.4 ± 0.6 μM were observed on MCF-7 and PANC-1 cell lines, respectively. The IC50 values are slightly higher than those previously reported in the literature for cisplatin, 5.7 ± 0.1 (incubation for 24 h) and 14.4 ± 1.1 (incubation for 48 h) for MCF-7 [64] and PANC-1 [65] cell lines, respectively.
Comparison with other organometallic silver complexes tested on MCF-7 and PANC-1 cell lines, such as silver(I) complexes in which the metal is coordinated to carbon [6,66], phosphorus [67,68], or nitrogen [69] atoms, showed that α-aminophosphonate 1 and complex 3 exhibited comparable effects (Figure 7).

2.4. Molecular Docking Studies

Molecular docking is a frequently used method in detailed bioactivity analysis of molecules [70]. It is possible to make qualitative and quantitative evaluations of the interactions between target macromolecule crystals and candidate bioactive molecules [71]. While the interaction areas qualitatively indicate how the ligand and the biological macromolecule will interact, the relative value of the binding can be considered as a quantitative measurement of the affinity. High ligand binding affinity means both stronger interaction between the ligand and target molecule and measurement of the ligand concentration required for inhibition [72].
Boda et al. synthesized some new isatin-1,2,4-oxadiazole derivative molecules and analyzed the activity of these molecules against some cancer cell lines including MCF-7. The authors analyzed the interactions between these molecules and the VGEFR-2 crystal structure and recorded a binding energy of −10.85 kcal/mol [73]. Serdaroğlu et al. reported the in vitro cytotoxic activities of silver complexes coordinated to N-heterocyclic carbene ligands. The study showed that the organometallic molecules could be efficient anti-cancer agents with a binding affinity of −7.59 kcal/mol [74]. Although there are many studies of molecular docking, which analyzed the anticancer activities of aminophosphonate derivatives and their metal complexes, a finite number of them have focused on the interactions with VGEFR-2 for a detailed analysis of anticancer activity [75,76,77,78,79].
In our work, the α-aminophosphonate 1 was optimized with the ORCA package program [80,81] and the most stable structure interacted with the VEGFR-2 crystal structure [82]. Some interactions for the ligand were detected: (i) four H-bonds between the ligand and Asp1044, Cys1043, Glu883, and Lys866 with lengths of 2.19, 3.66, 2.91, and 3.00 Å, respectively; (ii) π-alkyl interactions with Ala864, Val897, Val914, Cys917, and Leu1033; (iii) van der Waals interactions; (iv) halogenic interaction of the CF3 with Arg 1030. The total energy of all these interactions was −7.58 kcal/mol. The binding sites of the ligand and the silver complex 3 were different due to the larger steric hindrance of the complex. Complex 3 carried out fewer interactions but they were stronger than 1, and the most important interactions were H-bonds with Asp1044, Arg1078, and Arg1025 with lengths of 2.75, 3.20, and 3.07 Å, respectively. Additional van der Waals and alkyl interactions contributed to the total binding between the silver complex and the target molecule. The total value of these interactions was calculated at −7.82 kcal/mol (Figure 8). The results show that the silver complex 3 will bind more effectively than the α-aminophos-phonate 1, and will, therefore, be a more effective inhibitor. These results are also in agreement with the experimental anticancer results vide supra.
Molecular docking is also a frequently used method for analyzing the interaction of molecular pharmaceuticals with DNA [83]. The B-DNA dodecamer (1bna) crystal structure was used to determine the interaction modes of molecules with DNA [84]. Both molecules (1 and 3) interact with approximately the same regions of DNA. While the α-aminophosphonate 1 interacted with the region consisting of Thy8, Cyt9, Gua10, Cyt11, and Gua12, the silver complex 3 additionally interacted with Ade6 and Thy7. The final interaction energies were determined as −6.9 and −7.86 kcal/mol for 1 and 3, respectively (Figure 9).

3. Materials and Methods

All manipulations were carried out under dry argon. Solvents were dried by conventional methods and were distilled immediately before use. Routine 1H, 31P{1H}, and 19F{1H} spectra were recorded with Bruker FT instruments (AC 300 and 500). 1H NMR spectra were referenced to residual protonated solvents (δ = 7.26 ppm for CDCl3). 31P and 19F NMR spectroscopic data are given relative to external H3PO4 and CCl3F, respectively. Chemical shifts and coupling constants are reported in ppm and Hz, respectively. Infrared spectra were recorded with a Bruker FT-IR Alpha-P spectrometer. The optical density was measured at 570 nm with an ELISA Microplate Reader spectrophotometer. Elemental analyses were carried out by the Service de Microanalyse, Institut de Chimie, Université de Strasbourg. Diethyl[(5-phenyl-1,3,4-oxadiazol-2-ylamino)(4-trifluoro-methylphenyl)methyl]phosphonate (1) was prepared by a literature procedure [85].

3.1. General Procedure for the Synthesis of the Silver(I) Complexes

A solution of Ag(BF4) (0.019 g, 0.10 mmol) in THF (2 mL) was added to a solution of diethyl[(5-phenyl-1,3,4-oxadiazol-2-ylamino)(4-trifluoromethylphenyl)methyl]phosphonate (1, 0.10 or 0.4 mmol for the synthesis of 2 and 3, respectively) in THF (10 mL). The reaction mixture was stirred in the dark for 16 h at room temperature. The solvent was removed under reduced pressure. Crystals were grown from a slow diffusion of hexane into a solution of the crude product, dissolved into the minimal amount of THF. The colorless crystals of the silver complex were collected and dried under vacuum.

3.1.1. Bis{diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-κN3:κN4-amino)(4-trifluoromethyl-phenyl)methyl]phosphonate-(tetrafluoroborato-κF)}-di-silver(I) (2)

Yield 42%. 1H NMR (300 MHz, CDCl3): δ = 7.85 (dd, 4H, arom. CH of CF3C6H4, 3JHH = 6.9 Hz, 4JHH = 1.8 Hz), 7.71–7.62 (m, 8H, arom. CH), 7.49–7.42 (m, 6H, arom. CH), 5.28 (d, 2H, CHP, 2JPH = 22.5 Hz), 4.24–4.11 (m, 4H, OCH2CH3), 4.03–3.81 (m, 4H, OCH2CH3), 1.32 (t, 6H, OCH2CH3, 3JHH = 7.2 Hz), 1.15 (t, 6H, OCH2CH3, 3JHH = 7.1 Hz) ppm, in the spectrum, the two NH protons are not observed; 31P{1H} NMR (121 MHz, CDCl3): δ = 19.1 (q, P(O), 7JPF = 2.0 Hz) ppm. 19F{1H} NMR (282 MHz, CDCl3): δ = −62.72 (d, CF3, 7JPF = 2.2 Hz), −147.92 (brs, BF4) ppm. IR: ν = 724, 751, 925, 954, 1017, 1031, 1067 (F3BF-Ag), 1658 cm−1 (C=N). MS (ESI-TOF): decomposition of the complex occurred during the analysis, although some cations containing two silver complex could be observed at m/z = 1666.18 [M + 1 − BF4]+ and 2121.30 [M + (1)2 − BF4]+ (expected isotopic profile). Elemental analysis calcd. (%) for C40H42Ag2B2F14N6O8P2 (1300.08): C 36.95, H 3.26, N 6.46; found C 35.85, H 3.14, N 6.27.

3.1.2. Tetrakis-{diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-κN3-amino)(4-trifluoromethyl-phenyl)methyl]phosphonate}silver(I) Tetrafluoroborate (3)

Yield 28%. 1H NMR (300 MHz, CDCl3): δ = 7.86 (dd, 8H, arom. CH of CF3C6H4, 3JHH = 7.8 Hz, 4JHH = 1.2 Hz), 7.74–7.62 (m, 16H, arom. CH), 7.54–7.44 (m, 12H, arom. CH), 5.34 (d, 4H, CHP, 2JPH = 21.9 Hz), 4.24–4.14 (m, 8H, OCH2CH3), 4.08–3.90 (m, 8H, OCH2CH3), 1.32 (t, 12H, OCH2CH3, 3JHH = 7.0 Hz), 1.20 (t, 12H, OCH2CH3, 3JHH = 7.0 Hz) ppm; in the spectrum, the four NH protons are not observed; 31P{1H} NMR (121 MHz, CDCl3): δ = 17.9 (q, P(O), 7JPF = 2.2 Hz) ppm. 19F{1H} NMR (282 MHz, CDCl3): δ = −62.77 (d, CF3, 7JPF = 2.2 Hz), −148.47 (s, BF4) ppm. IR: ν = 1633 cm−1 (C=N). MS (ESI-TOF): m/z = 562.03 [M − (1)3 − BF4]+, 1019.15 [M − (1)2 − BF4]+, 1474.27 [M − 1 − BF4]+ and 1929.40 [M − BF4]+ (expected isotopic profile). Elemental analysis calcd. (%) for C80H84AgBF16N12O16P4 (2016.14): C 47.66, H 4.20, N 8.34; found C 47.54, H 4.33, N 8.21.

3.2. X-Crystal Structure Analysis

Single crystals suitable for X-ray analysis were obtained by the slow diffusion of hexane into a THF solution of the complex. The samples were studied on a Bruker PHOTON-III CPAD and Bruker APEX-II CD for complexes 2 and 3, respectively, using Mo-Kα radiation (λ = 0.71073 Å) at T = 120(2) K. The structures were solved with SHELXT-2014/5 [86] (complex 2) or SHELXS-97 [87] (complex 3), which revealed the non-hydrogen atoms of the molecule. After anisotropic refinement, all of the hydrogen atoms were found with a Fourier difference map. The structure was refined with SHELXL-2014/7 [88] by the full-matrix least-square techniques (use of F square magnitude; x, y, z, βij for C, Ag, B, F, N, O, and P atoms; x, y, z in riding mode for H atoms).

3.3. Cell Culture and Cell Viability Assay

The experiments were performed on MCF-7 (human breast cancer, HTB-22) and PANC-1 (human pancreatic cancer, CRL-1469) cell lines. The cell lines obtained from the American Type Culture Collection and were cultivated on 10% fetal bovine serum (FBS), 1% L-glutamine, and 100 IU/mL of penicillin and 10 mg/mL of streptomycin containing high-glucose Dulbecco’s modified Eagle’s medium (DMEM) (Gibco™, Sigma). Cells were cultivated in a humidified atmosphere with 5% CO2 at 37 °C.
The cytotoxic activity of compound 1 and silver complex 3 on cells was evaluated using the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method as previously described by Mosmann [89] with slight modifications. Cells (7000 per 200 μL) in medium were seeded into 96-well microplates. Compound 1 or 3 was added to the wells by serial dilution (200 μM, 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, and 3.125 μM) and the cells were incubated at 37 °C in a 5% CO2 incubator for 24 h and 48 h. At the end of the incubation time, the MTT reagent (20 μL) was added and the cells were incubated for a further 4 h. The formed formazan crystals were dissolved in 100 μL of DMSO and the absorptions were measured at 570 nm with an ELISA Microplate Reader. Experiments were performed five times and the IC50 values, which corresponds to the concentration required for 50% inhibition of cell viability, were calculated by Graphpad prism software (version 8.2.1, San Diego, CA, USA). Results were expressed as percentage of viable cells relative to the negative control (untreated cells).

3.4. Molecular Docking Calculation Methods

The molecular docking procedures were performed with AutoDock 4.2 [90] against VGEFR-2 and B-DNA dodecamer crystal structures [82,84]. All the structures were downloaded from the RCSB protein data bank (https://www.rcsb.org/, accessed on 20 October 2022) (PDB ID: 1ywn for VGEFR-2; 1bna for B-DNA dodecamer, accessed on 16 August 2022). The maximum torsion number with the fewest atoms was set for the ligand molecules. Kollman charges were regarded, and only polar hydrogens were employed in all target crystal structures. Water molecules in the targets were extracted as well as Gasteiger charges, and randomized starting positions were utilized during the processes. Lamarckian genetic algorithms were employed with 150 genetic algorithm populations for 10 runs [91]. The standard program defaults were used during the running. All the illustrations were performed with Discovery Studio 4.1.0. (BIOVIA Corp, San Diego, CA, USA).

4. Conclusions

A simple modification of the silver salt to ligand, bearing an oxadiazole ring, to silver salt ratio drastically modified the coordination sphere of silver(I) cations, leading either to a trigonal dimeric or to a tetrahedral monomeric silver complex. The α-aminophosphonate and the monomeric silver complex were evaluated in vitro against MCF-7 and PANC-1 cell lines by a one-dose assay. The presence of a silver atom had a beneficial effect on the cytotoxic activities, and approximately twofold lower half-maximal inhibitory concentration (IC50) values were observed when the organometallic complex was employed compared to the organic drug. The silver complex is promising as a drug candidate for breast cancer and the pancreatic duct and future studies will be devoted to investigate its mode of action along with its in vivo effectiveness and safety for clinical application. The anticancer activities of the molecules were also confirmed and detailed by molecular docking methods. The results show that the silver complex could be a more effective anticancer agent than the ligand and this in silico result is in accordance with the experimental ones.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27238131/s1, FT-IR spectra of silver complexes 2 and 3; X-ray structure of complexes 2 and 3.

Author Contributions

Conceptualization, N.Ş., A.S. and D.S.; methodology, S.H., E.Ü., K.A.C. and Y.T.; software, E.Ü., K.A.C. and Y.T.; validation, N.Ş. and D.S.; formal analysis, N.Ş. and D.S.; investigation, S.H., E.Ü., K.A.C. and Y.T.; writing—original draft preparation, S.H., N.Ş. and D.S.; writing—review and editing, D.S.; supervision, D.S. All authors have read and agreed to the published version of the manuscript.

Funding

We gratefully acknowledge the Tunisian Ministry of Higher Education and Scientific Research for the financial support (grant for S.H.).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

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Molecules 27 08131 g001 550
Figure 1. Examples of 1,3,4-oxadiazole-containing ligands A–D used in silver(I) complexes.
Figure 1. Examples of 1,3,4-oxadiazole-containing ligands A–D used in silver(I) complexes.
Molecules 27 08131 g001
Molecules 27 08131 g002 550
Figure 2. Mass spectrum (ESI-TOF) of silver complexes; observed spectrum (Top) and simulated spectrum (Bottom) for: (C20H21O4N3PF3)3Ag2BF4 (Left) and (C20H21O4N3PF3)4Ag (Right).
Figure 2. Mass spectrum (ESI-TOF) of silver complexes; observed spectrum (Top) and simulated spectrum (Bottom) for: (C20H21O4N3PF3)3Ag2BF4 (Left) and (C20H21O4N3PF3)4Ag (Right).
Molecules 27 08131 g002
Molecules 27 08131 sch001 550
Scheme 1. Synthesis of silver(I) complexes 2 and 3.
Scheme 1. Synthesis of silver(I) complexes 2 and 3.
Molecules 27 08131 sch001
Molecules 27 08131 g003 550
Figure 3. ORTEP drawing of complex 2, 50% probability thermal ellipsoids. Important bond lengths (Å) and angles (°): Ag1-N1 2.260(2), Ag1-N2 2.215(2), Ag1-F4 2.652(2), N1-N2 1.406(3), N2-C8 1.311(4), C8-O1 1.353(3), O1-C7 1.372(3), C7-N1 1.293(4), N1-Ag1-F4 112.85(8), F4-Ag1-N2 123.02(7), N2-Ag1-N1 123.75(8), C7-N1-N2 107.4(2), N1-N2-C8 105.4(2), N2-C8-O1 112.3(2), C8-O1-C7 103.6(2), and O1-C7-N1 111.3(2).
Figure 3. ORTEP drawing of complex 2, 50% probability thermal ellipsoids. Important bond lengths (Å) and angles (°): Ag1-N1 2.260(2), Ag1-N2 2.215(2), Ag1-F4 2.652(2), N1-N2 1.406(3), N2-C8 1.311(4), C8-O1 1.353(3), O1-C7 1.372(3), C7-N1 1.293(4), N1-Ag1-F4 112.85(8), F4-Ag1-N2 123.02(7), N2-Ag1-N1 123.75(8), C7-N1-N2 107.4(2), N1-N2-C8 105.4(2), N2-C8-O1 112.3(2), C8-O1-C7 103.6(2), and O1-C7-N1 111.3(2).
Molecules 27 08131 g003
Molecules 27 08131 g004 550
Figure 4. ORTEP drawing of complex 3, 50% probability thermal ellipsoids (BF4 and solvent molecules are not visible). Important bond lengths (Å) and angles (°): Ag1-N1 2.289(4), Ag1-N1 2.289(4), Ag1-N1 2.289(4), Ag1-N1 2.289(4), N1-N2 1.412(6), N2-C1 1.250(9), C1-O1 1.356(9), O1-C2 1.372(7), C2-N1 1.283(7), N1-Ag1-N1 105.56(10), N1-Ag1-N1 117.6(2), N1-Ag1-N1 105.56(10), N1-Ag1-N1 105.56(10), N1-Ag1-N1 117.6(2), N1-Ag1-N1 105.56(10), C2-N1-N2 105.7(5), N1-N2-C1 107.3(6), N2-C1-O1 112.7(6), C1-O1-C2 102.8(5), and O1-C2-N1 111.5(5).
Figure 4. ORTEP drawing of complex 3, 50% probability thermal ellipsoids (BF4 and solvent molecules are not visible). Important bond lengths (Å) and angles (°): Ag1-N1 2.289(4), Ag1-N1 2.289(4), Ag1-N1 2.289(4), Ag1-N1 2.289(4), N1-N2 1.412(6), N2-C1 1.250(9), C1-O1 1.356(9), O1-C2 1.372(7), C2-N1 1.283(7), N1-Ag1-N1 105.56(10), N1-Ag1-N1 117.6(2), N1-Ag1-N1 105.56(10), N1-Ag1-N1 105.56(10), N1-Ag1-N1 117.6(2), N1-Ag1-N1 105.56(10), C2-N1-N2 105.7(5), N1-N2-C1 107.3(6), N2-C1-O1 112.7(6), C1-O1-C2 102.8(5), and O1-C2-N1 111.5(5).
Molecules 27 08131 g004
Molecules 27 08131 g005 550
Figure 5. MCF-7 cells were treated with increasing concentrations of α-aminophosphonate 1 (a) and silver complex 3 (b) for 24 and 48 h. The viability was determined by metabolic rate using the MTT assay. Absorbance values were measured at 570 nm and normalized against untreated cells.
Figure 5. MCF-7 cells were treated with increasing concentrations of α-aminophosphonate 1 (a) and silver complex 3 (b) for 24 and 48 h. The viability was determined by metabolic rate using the MTT assay. Absorbance values were measured at 570 nm and normalized against untreated cells.
Molecules 27 08131 g005
Molecules 27 08131 g006 550
Figure 6. PANC-1 cells were treated with increasing concentrations of α-aminophosphonate 1 (a) and silver complex 3 (b) for 24 and 48 h. The viability was determined by metabolic rate using the MTT assay. Absorbance values were measured at 570 nm and normalized against untreated cells.
Figure 6. PANC-1 cells were treated with increasing concentrations of α-aminophosphonate 1 (a) and silver complex 3 (b) for 24 and 48 h. The viability was determined by metabolic rate using the MTT assay. Absorbance values were measured at 570 nm and normalized against untreated cells.
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Molecules 27 08131 g007 550
Figure 7. Examples of reported silver(I) complexes with anticancer activities.
Figure 7. Examples of reported silver(I) complexes with anticancer activities.
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Molecules 27 08131 g008 550
Figure 8. Interaction residue and interaction type of the molecules (1 and 3) with VGEFR-2 crystal structure.
Figure 8. Interaction residue and interaction type of the molecules (1 and 3) with VGEFR-2 crystal structure.
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Molecules 27 08131 g009 550
Figure 9. Interaction residue and amino acids of DNA crystal structures with 1 and 3.
Figure 9. Interaction residue and amino acids of DNA crystal structures with 1 and 3.
Molecules 27 08131 g009
Table
Table 1. Crystal data and structure refinement parameters for complexes 2 and 3.
Table 1. Crystal data and structure refinement parameters for complexes 2 and 3.
Complex23
CCDC Depository21223612122362
Color/Shapecolorless/needlecolorless/prism
Chemical FormulaC40H42Ag2B2F14N6O8P2C80H84AgBF16N12O16P4
Formula Weight (g mol−1)1300.082016.15
Crystal Systemmonocliniccubic
Space GroupP21/c (number 14)Fd-3c (number 228)
Unit Cell
Parameters		a (Å)21.2741 (8)49.0604 (6)
b (Å)5.3745 (2)49.0604 (6)
c (Å)21.0826 (9)49.0604 (6)
α (°)9090
β (°)96.259 (2)90
γ (°)9090
Volume (Å3)2396.17 (16)118,085 (4)
Z248
D (g cm−3)1.8021.3361
μ (mm−1)0.9960.364
Tmin, Tmax0.811, 0.9070.951, 0.996
F(000)129649,536
Crystal Size (mm)0.220 × 0.120 × 0.1000.140 × 0.120 × 0.012
Index Ranges−27 ≤ h ≤ 27−55 ≤ h ≤ 64
−7 ≤ k ≤ 7−64 ≤ k ≤ 41
−27 ≤ l ≤ 27−64 ≤ l ≤ 23
θ Range for Data Collection (°)2.073 ≤ θ ≤ 27.9072.034 ≤ θ ≤ 27.895
Reflections Collected63,906110,628
Independent/Observed5699/49355899/3088
Rint0.04720.0762
Data/Restraints/Parameters5699/0/3375899/19/254
Goodness-of-Fit on F21.0701.186
Final R Indices (I > 2.0 σ(I))R1 = 0.0371, wR2 = 0.0823R1 = 0.0903, wR2 = 0.2651
R Indices (All Data)R1 = 0.0458, wR2 = 0.880R1 = 0.1435, wR2 = 0.3072
Δρmax, Δρmin (eÅ−3)1.471, −1.0660.689, −0.553
Table
Table 2. Calculated IC50 values (μM).
Table 2. Calculated IC50 values (μM).
Tested Compound24 h48 h
MCF-7 Cell LinePANC-1 Cell LineMCF-7 Cell LinePANC-1 Cell Line
122.8 ± 0.835.0 ± 1.014.9 ± 0.527.6 ± 0.7
311.2 ± 0.418.3 ± 1.28.3 ± 1.014.4 ± 0.6
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Hkiri, S.; Coşkun, K.A.; Üstün, E.; Samarat, A.; Tutar, Y.; Şahin, N.; Sémeril, D. Silver(I) Complexes Based on Oxadiazole-Functionalized α-Aminophosphonate: Synthesis, Structural Study, and Biological Activities. Molecules 2022, 27, 8131. https://doi.org/10.3390/molecules27238131

AMA Style

Hkiri S, Coşkun KA, Üstün E, Samarat A, Tutar Y, Şahin N, Sémeril D. Silver(I) Complexes Based on Oxadiazole-Functionalized α-Aminophosphonate: Synthesis, Structural Study, and Biological Activities. Molecules. 2022; 27(23):8131. https://doi.org/10.3390/molecules27238131

Chicago/Turabian Style

Hkiri, Shaima, Kübra Açıkalın Coşkun, Elvan Üstün, Ali Samarat, Yusuf Tutar, Neslihan Şahin, and David Sémeril. 2022. "Silver(I) Complexes Based on Oxadiazole-Functionalized α-Aminophosphonate: Synthesis, Structural Study, and Biological Activities" Molecules 27, no. 23: 8131. https://doi.org/10.3390/molecules27238131

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