New silver, rhodium and iridium complexes with anthracene-functionalized N-heterocyclic carbene ligands: Crystal structures, cytotoxicity and fluorescence studies

{"full_text": " Polyhedron 257 (2024) 117011\n\n\n Contents lists available at ScienceDirect\n\n\n Polyhedron\n journal homepage: www.elsevier.com/locate/poly\n\n\n\n\nNew silver, rhodium and iridium complexes with anthracene-functionalized\nN-heterocyclic carbene ligands: Crystal structures, cytotoxicity and\nfluorescence studies\nHatice Bekci a, Nam\u0131k O\u0308zdemir b, Zeynel S\u0327ahin c, Ak\u0131n Mumcu d, Serkan Dayan e, *, Mert\nOlgun Karatas\u0327 f, *\na\n Develi H\u00fcseyin S\u0327ahin Vocational School, Kayseri University, Kayseri, Turkey\nb\n Department of Mathematics and Science Education, Faculty of Education, 9055139 Samsun, Turkey\nc\n Department of Material Engineering, Faculty of Engineering, Marmara University, 9034722 I\u0307stanbul, Turkey\nd\n Scientific and Technological Research Center, I\u0307no\u0308n\u00fc University, 9044280 Malatya, Turkey\ne\n Drug Application and Research Center, Molecular Synthesis and Industrial Application Laboratory (MSIA-Lab), Erciyes University, Kayseri, Turkey\nf\n Department of Chemistry, Faculty of Science, I\u0307no\u0308n\u00fc University, 9044280 Malatya, Turkey\n\n\n\n\nA R T I C L E I N F O A B S T R A C T\n\nKeywords: In the present study, we have synthesized anthracene-functionalized metal complexes to investigate their\nBenzimidazole cytotoxicity and photophysical properties. In this context, firstly, an Ag\u2013NHC (NHC = N-heterocyclic carbene)\nAnthracene complex (2a) has been synthesized by the interaction of Ag2O and N-(2-methylbenzyl)-N-((anthracen-9-yl)\nN-heterocyclic carbene\n methyl)benzimidazolium chloride (1a). Corresponding Rh\u2013 (3a) and Ir\u2013NHC (4a) complexes have also been\nSilver\nRhodium\n synthesized by the transmetalation reaction between 2a and corresponding metal compounds. Additionally, for\nIridium comparison purposes, an ether-functionalized Ag\u2013NHC complex (2b) with N-(methoxyethyl)-N-((anthracene-9-\nFluorescence yl)methyl)benzimidazole-2-ylidene ligand, and [AgL2]NO3 type complex (2c) with a N-coordinated N-\nCytotoxicity ((anthracen-9-yl)methyl)benzimidazole ligand have been synthesized. All complexes have been characterized by\n the combination of NMR and mass spectroscopic techniques, and elemental analyses. Moreover, solid state\n structures of 2a, 2b and 4a have been determined by the single crystal X-ray diffraction analysis. Cytotoxic\n potentials of all compounds have been tested against human lung adenocarcinoma alveolar basal epithelial cell\n line (A549) using the MTT assay, and all complexes performed strong anti-proliferative activity. Stability studies\n have disclosed that only 1a and 2c are able to retain their structure in the culture medium (DMEM) that bio\u00ad\n logical assays were carried out. Photophysical measurements revealed that all compounds have similar emission\n bands because of the conjugation of anthracene group. Finally, 1a and 2c have been visualized by fluorescence\n confocal microscopy to investigate cellular uptake and subcellular distribution of the complexes, and the findings\n indicated that both compounds dispersed along the cell membranes nuclear regions.\n\n\n\n\n1. Introduction complexes makes it possible to prepare an unlimited number of metal\n complexes. The nature of the ligand is quite decisive on the electronic\n The medical applications of metal compounds trace back to ancient and steric properties of the complex, and N-heterocyclic carbenes\ntimes, but their investigation as modern therapeutic agents began after (NHCs), which are a class of neutral carbon compounds, are one of the\nthe discovery of cisplatin in 1965 [1]. The coordination numbers of mostly used class of ligands in organometallic chemistry. Metal-NHC\nmetal atoms ranging from two to ten allow the metal complexes to have complexes have found wide application in the fields of catalysis and\nvarious geometric structures, and this feature, which is impossible to medicinal chemistry, thanks to their two advantages over other organic\nachieve with organic compounds, paves the way for unique interactions ligands; first, NHCs are strong \u03c3\u2013donor ligands, able to form strong\nwith biomolecules [2]. Moreover, introducing the organic ligands, metal\u2013carbon bond, and therefore produce highly stable metal com\u00ad\nwhose carbon scaffold can be modified, to the structure of metal plexes, second, the carbon scaffold of NHC ligands can be easily\n\n\n * Corresponding authors.\n E-mail addresses: serkandayan@erciyes.edu.tr (S. Dayan), mert.karatas@inonu.edu.tr (M.O. Karatas\u0327).\n\nhttps://doi.org/10.1016/j.poly.2024.117011\nReceived 19 February 2024; Accepted 26 April 2024\nAvailable online 27 April 2024\n0277-5387/\u00a9 2024 Elsevier Ltd. All rights reserved.\n\fH. Bekci et al. Polyhedron 257 (2024) 117011\n\n\nmodified for specific requirements [3].\n Increased stability in aqueous solution and test medium that bio\u00ad\nlogical assay was carried out are highly important for a drug candidate,\nand thanks to their high stability, numerous NHC complexes have been\nreported for biological purposes with both noble and earth-abundant\nmetals [4]. Furthermore, \u201cswitchable\u201d or \u201cmultifunctional\u201d metal-NHC\ncomplexes can be easily prepared by the attaching the responsive\ngroup to NHC scaffold [5]. For example, metal-NHC complexes that are\nresponsive to stimuli such as light [6] or pH [7] can be prepared by the\nattaching the responsive group to NHC scaffold. Also, metal-NHC com\u00ad\nplexes with enhanced biological activity and bio-conjugation can be\nprepared by the attaching biologically-relevant group to NHC scaffold\n[8].\n The attachment of a fluorophore group to a drug is a new strategy to\ntrace them in cells [9], and this approach has also successfully been\napplied for metal-NHC complexes [10]. Silver [10a,b,e,f], gold [10b,c,d,\nf], rhodium [10 g,h] and ruthenium [10] complexes with anthracene-\n[10a,e,f,g], pyridine- [10], coumarin- [10] or naphthalimide- Scheme 1. Synthesis and structure of 2a-4a.\nfunctionalized [10d,h] NHC ligands have been used to learn more in\u00ad\nformation on distribution of metal-NHC complexes in human ovarian,\nbreast, colon and neuroblastoma cancer cell lines. Among these fluo\u00ad\nrophores, anthracene comes into prominence because of relatively\neasier preparation of anthracene-functionalized complexes, and there\u00ad\nfore, more anthracene-functionalized metal-NHC complexes have been\nreported with promising biological activity [11]. On the other hand, N-\nflanking anthracenyl moiety in NHC ligands can be classified as \u201cnon-\ninnocent\u201d group. In a recent study, Hartinger and co-workers reported\nthat a incorporation of a N-substituted anthracenyl moiety to [Rh(Cp) Scheme 2. Synthesis and structure of 2b.\n(NHC)Cl2] (Cp = cyclopentadienyl) type complex led to the formation of\nheptadentate and octadentate all-carbon atom ligands [12]. The most\nrecently, Han and co-workers reported the [4 + 4] photodimerization of\nsilver and gold complexes with anthracene-functionalized NHC ligands\nunder irradiation at 365 nm [13].\n Following the promising results obtained with anthracenyl-\nfunctionalized NHC complexes, in the present study, we aimed to\ndevelop anticancer metal complexes that are decorated with anthra\u00ad\ncenyl moiety with good stability in test medium and fluorescence Scheme 3. Synthesis and structure of 2c.\nemission for bio-imaging. For this purpose, in the first step, we prepared\nsilver, rhodium and iridium complexes of N-(2-methylbenzyl)-N-\n We must note that all complexes were synthesized under open-air con\u00ad\n((anthracen-9-yl)methyl)benzimidazol-2-ylidene ligand. Later, we pre\u00ad\n ditions and in the absence of the light. All complexes are highly stable in\npared a silver-NHC complex with N-(2-methoxyethyl)-N-((anthracen-9-\n solid state against oxygen and moisture, and silver complexes, 2a-c,\nyl)methyl)benzimidazol-2-ylidene and a N-coordinated silver complex\n were stored in dark.\nwith N-((anthracen-9-yl)methyl)benzimidazole for comparison\n The complexes were characterized by the combination of NMR and\npurposes.\n mass spectroscopy, and elemental analyses. Additionally, solid state\n crystal structures of 2a, 2b and 4a were determined by single crystal X-\n2. Results and discussion\n ray analysis.\n In the 1H NMR spectrum of 2a, the signal of acidic \u2013NCHN\u2013\n2.1. Synthesis and characterization of the complexes\n hydrogen, which had been observed at 9.25 ppm, disappeared\n completely. The signals of the aromatic hydrogens were observed in the\n In the first step, N-(2-methylbenzyl)-N-((anthracen-9-yl)methyl)\n range of 8.64\u20136.62 ppm, in the expected integral values. The signal of\nbenzimidazolium chloride (1a) was synthesized according to the pro\u00ad\n methylene hydrogens connecting the imidazole and anthracene moieties\ncedure described in our previous study [14]. The Ag\u2013NHC complex (2a)\n was observed as a singlet at 6.57 ppm, while the signal of methylene\nof this ligand was synthesized by the reaction of Ag2O and 1a in\n hydrogens between imidazole and phenyl moieties was observed as a\nmethylene chloride. Rh\u2013NHC (3a) and Ir\u2013NHC (4a) complexes were\n singlet at 5.57 ppm. The signal of methyl hydrogens was observed as a\nsynthesized by the transmetalation reaction between 2a, and [RhCl\n singlet at 2.34 ppm. In the 13C NMR spectrum of 2a, the signal of\n(COD)]2 and [IrCl(COD)]2 (COD = cyclooctadiene), respectively. Later,\n \u2013NCHN\u2013 carbon, which had been observed at 142.5 ppm, disappeared\nin order to synthesize an ether-functionalized Ag\u2013NHC with improved\n completely, but the signal of carbene carbon could not been detected\nsolubility, we synthesized N-(2-methoxyethyl)-N-((anthracen-9-yl)\n due to labile nature of Ag\u2013C bond. The signals of aromatic carbons were\nmethyl)benzimidazolium chloride (1b) according to procedure\n observed in the range of 135.4\u2013112.1 ppm. The methylene carbon\ndescribed in our previous study [14], and deprotonation of 1b by Ag2O\n connecting imidazole and anthracene moieties was observed at 51.9\nin DCM yielded 2b. Lastly, we synthesized a silver complex with N-co\u00ad\n ppm, while the methylene carbon between imidazole and phenyl moi\u00ad\nordinated ligand for comparison purposes. N-(((anthracen-9-yl)methyl)\n eties was observed at 47.1 ppm. The methyl carbon was observed at\nbenzimidazole) (1c) was synthesized according to the procedure\n 19.6 ppm. LC-MS spectrum of 2a in DMSO showed that the complex has\ndescribed in literature [10], and its [AgL2](NO3) type complex (2c) was\n bis-NHC structure with [Ag(NHC)2](AgCl2) formula in solution.\nsynthesized by the interaction of 1c and AgNO3 in ethanol. Structures,\n In the 1H NMR spectrum of 2b, the signal of acidic \u2013NCHN\u2013\nsynthesis and yields of all complexes are outlined in Schemes 1, 2 and 3.\n\n 2\n\fH. Bekci et al. Polyhedron 257 (2024) 117011\n\n\nhydrogen, which had been observed at 9.11 ppm, disappeared 54.0, 52.4 ppm. The methylene carbon connecting the imidazole and\ncompletely. The signals of aromatic hydrogens were observed in the anthracene moieties was observed at 50.0, while the methylene carbon\nrange of 8.75\u20137.37 ppm, in the expected integral values. The signal of between imidazole and phenyl moieties was observed at 47.9 ppm. The\nmethylene hydrogens between imidazole and anthracene moieties was signals of remaining aromatic and aliphatic hydrogens were observed in\nobserved as a singlet at 6.49 ppm. Totally four hydrogens of two the expected integral values. LC-MS spectrum of the complex in DMSO\nmethylene carbons belonging to ether group were observed as two showed that the complex has [Ir(NHC)Cl] structure in solution.\nseparate multiplets at 4.35 and 3.58 ppm, while the signal of methyl\nhydrogens were observed as a multiplet at 3.05 ppm. In the 13C NMR 2.2. Crystal structure description\nspectrum of 2b, the signal of \u2013NCHN\u2013 carbon, which had been observed\nat 142.3 ppm, disappeared completely, and the signal of the carbene The molecular structures of 2a, 2b and 4a were determined by\ncarbon was observed at 188.4 ppm. The signals of aromatic carbons single-crystal X-ray diffraction studies and shown in Fig. 1. All the\nwere observed in the range of 134.3\u2013112.5 ppm. The methylene carbon compounds crystallize in the triclinic space group P \u2212 1 with two mol\u00ad\nconnecting the imidazole and anthracene moieties was observed at 49.5 ecules in the unit cell. Important bond lengths and angles of the com\u00ad\nppm. The methylene carbons belonging to ether group were observed at pounds are listed in Table 1.\n71.1 and 58.7 ppm, and the methyl carbon was observed at 45.3 ppm. X-ray studies of 2a and 2b prove the formation of neutral (NHC)Ag-\nLC-MS spectrum of 2b in DMSO showed that the complex has bis-NHC Cl type monomeric complexes without argentophilic Ag\u22c5\u22c5\u22c5Ag in\u00ad\nstructure with [Ag(NHC)2](AgCl2) formula in solution. teractions. The silver atoms are coordinated by the carbenic carbon of\n In the 1H NMR spectrum of 2c, the \u2013NCHN\u2013 hydrogen was observed the NHC ligand and a chloride ion, and deviate significantly from line\u00ad\nat 7.86 ppm, as a singlet. The signals of aromatic hydrogens were arity with C\u2500Ag\u2500Cl angles ranging from 171.61(5) to 173.72(7)\u25e6 . The\nobserved in the range of 8.82\u20137.35 ppm, in the expected integral values Ag\u2500Cl and Ag\u2500C distances changing from 2.3167(8) to 2.3276(6) \u00c5 and\nand coupling patterns. The signal of methylene hydrogens between from 2.0913(18) to 2.092(3) \u00c5, respectively, lie within the range usually\nimidazole and anthracene moieties was observed as a singlet at 6.57 found for (NHC)Ag-Cl complexes [16]. The dihedral angle between the\nppm. In the 13C NMR of 2c, the signal of \u2013NCHN\u2013 carbon was observed mean planes of benzimidazole and anthracene rings is 80.58(11)\u25e6 in 2a\nat 144.9. The number of signals detected in aromatic region and 80.49(6)\u25e6 in 2b. Furthermore, the benzene ring makes dihedral\n(141.6\u2013112.2 ppm) matched the numbers of different carbon atoms angles of 85.91(14) and 66.84(13)\u25e6 with the mean planes of benzimid\u00ad\nexpected from the structure. The methylene carbon connecting the azole and anthracene rings, respectively.\nimidazole and anthracene moieties was observed at 41.9 ppm. In addi\u00ad The asymmetric unit of 4a consists of one complex molecule and a\ntion to elemental analysis, LC-MS spectrum of 2c in DMSO also sup\u00ad half hexane molecule in the asymmetric unit. The coordination of the\nported the N-coordination of ligand that yields [Ag(L)2]NO3 type metal atom is a slightly distorted quasi-square-planar, considering the\ncomplex. Despite our all attempt, we could not obtain suitable crystals mid-points of the 1,2 and 5,6 bonds of the cycloocta-1,5-diene (COD)\nfor single-crystal X-ray analysis for 2c, however, the proposed structure ligand as the donors. The metal center is coordinated to the two alkene\nby the combination of NMR and mass spectroscopy and elemental bonds of COD ligand, to a carbenic carbon atom of the NHC ligand and to\nanalysis techniques are consistent with literature [15]. a chloride atom. For quantitative evaluation of the extent of distortion\n In the 1H NMR spectrum of 3a, the diastereotopic methylene hy\u00ad around the metal centers, the four-coordinate structural indexes \u03c44 [17]\ndrogens between imidazole and anthracene moieties were observed as and \u03c4\u20324 [18] were employed;\noverlapped with aromatic hydrogens around 7.6 and 6.8 ppm. The other\nmethylene hydrogens connecting imidazole and phenyl moieties were\n \u25e6 \u25e6\n 360 \u2212 (\u03b1 + \u03b2) \u2032 \u03b2\u2212 \u03b1 180 \u2212 \u03b2\n \u03c44 = \u03c4 = +\nalso observed as diastereotopic hydrogens around 6.8 and 5.8 ppm with 360\u25e6 \u2212 2\u03b8 4 360\u25e6 \u2212 \u03b8 180\u25e6 \u2212 \u03b8\n16.6 Hz of coupling constant. The four olefinic COD hydrogens were\n where \u03b1 and \u03b2 (\u03b2 > \u03b1) are the two greatest valence angles and \u03b8 is the\nobserved as multiplets at 5.32, 3.64 and 2.65 ppm. The remaining aro\u00ad\nmatic and aliphatic hydrogens were observed in expected integral ideal tetrahedral angle (109.5\u25e6 ). The \u03c44 and \u03c4\u20324 values for ideal square-\nvalues. In the 13C NMR spectrum of 3a, the signal of carbene carbon was planar and tetrahedral coordination spheres are 0 and 1, respectively.\nobserved as a doublet at 197.8 ppm with 51.0 Hz of JRh-C coupling The calculated \u03c44 and \u03c4\u20324 geometry indices are both 0.03, indicating a\nconstant. The olefinic carbons of COD that are coordinated to Rh center slightly distorted square-planar geometry. The coordination plane is\nwere also observed as doublets, at 100.5, 100.4, 70.3 and 68.7 ppm with almost pseudo-perpendicular to the carbene heterocycle plane with a\n6.6 and 14.3 Hz of JRh-C coupling constants. The methylene carbon dihedral angle of 81.49(9)\u25e6 . Besides, the benzimidazole ring makes\nconnecting imidazole and anthracene moieties were observed at 50.4, dihedral angles of 77.35(16) and 79.91(9)\u25e6 with the mean planes of\nwhile the methylene carbon between imidazole and phenyl moieties benzene and anthracene rings, respectively.\nwere observed at 48.2 ppm. The number of signals detected in aromatic The COD ring exhibits a boat conformation with the Ir\u2500CCOD dis\u00ad\nand aliphatic regions exactly matched the numbers of the remaining tances ranging from 2.101(3) to 2.180(3) \u00c5. The C\u2550C bond of the COD in\naromatic and aliphatic carbons expected from the structure. LC-MS a trans-position to the NHC ligand [1.385(6) \u00c5] is significantly shorter\nspectrum of the complex in DMSO showed that the complex has [Rh and displays longer Ir\u2500CCOD distances than the C\u2550C bond trans to\n(NHC)Cl] structure in solution. chloride [1.407(5) \u00c5]. This indicates a strong trans-influence of the NHC\n In the 1H NMR spectrum of 4a, one of the diastereotopic methylene ligands and considerably weaker coordinative bond of C\u2550C trans to the\nhydrogens between imidazole and anthracene moieties was observed as NHC ligand than trans to chloride. The Ir\u2500Cl bond distance is 2.3574(9)\na doublet at 6.61 ppm with 15.1 Hz of coupling constant, while the other \u00c5, and the coordination bond lengths and angles are in line with those of\nwas observed as overlapped with aromatic hydrogens around 7.4 ppm. other [IrCl(COD)(NHC)] complexes [19].\nThe other methylene hydrogens that are between imidazole and phenyl In all compounds, the fact that N1\u2500C1 and N2\u2500C1 bonds are notably\nmoieties were observed similarly, one was observed as overlapped with shorter than N1\u2500C2 and N2\u2500C7 bonds is an indicator of delocalization\naromatic hydrogens around 6.4 ppm, while the other was observed as a within the benzimidazole rings. The internal N\u2013C\u2013N ring angle at the\ndoublet at 5.69 ppm with 16.5 Hz of coupling constant. The four olefinic carbene centers falls in the range 105.6(2)-106.2(2)\u25e6 .\nCOD hydrogens were observed as multiplets at 4.75, 3.24 and 2.89 ppm.\nThe remaining aromatic and aliphatic hydrogens were observed in ex\u00ad 2.3. Photophysical properties\npected integral values. In the 13C NMR spectrum of 4a, the signal of\ncarbene carbon was observed at 193.1 ppm. The four olefinic COD Photophysical properties of 1a and all metal complexes were inves\u00ad\ncarbons that are coordinated to Ir center were observed at 87.5, 87.4, tigated in the DMSO solution at the same concentrations Fig. 2. The\n\n 3\n\fH. Bekci et al. Polyhedron 257 (2024) 117011\n\n\n\n\n Fig. 1. Crystral structures of 2a, 2b and 4a.\n\n\n times of complex 3a. Excitation spectra were measured for complexes\nTable 1\n by fixing the emission wavelength at 420 nm. The excitation spectrum of\nSelected geometric parameters for 2a, 2b and 4a.\n each complex is identical to its corresponding absorption spectrum\n Parameters 2a 2b 4a Fig. 2C. However, the excitation spectrum of 2c shows inconsiderable\n Bond lengths (\u00c5) blue-shifting as in absorption spectra. The combined emission, absorp\u00ad\n M\u2500Cl1 2.3167(8) 2.3276(6) 2.3574(9) tion, and excitation spectra at the 300\u2013500 nm region of the electro\u00ad\n M\u2500C1 2.092(3) 2.0913(18) 2.028(3) magnetic spectrum of complex 2c (as an example) are shown in Fig. 2D.\n M\u2500C31 \u2212 \u2212 2.113(3)\n M\u2500C32 \u2212 \u2212 2.101(3)\n The emission spectrum is a typical mirror image of the absorption\n M\u2500C35 \u2212 \u2212 2.180(3) spectrum. In addition, the complex showed Stokes shift of 49 nm at the\n M\u2500C36 \u2212 \u2212 2.177(3) UV\u2013visible spectrum.\n M\u2500ct1 \u2212 \u2212 1.986(3)\n M\u2500ct2 \u2212 \u2212 2.066(3)\n N1\u2500C1 1.349(3) 1.361(2) 1.361(3) 2.4. Cytotoxicity studies\n N1\u2500C2 1.391(3) 1.385(2) 1.394(4)\n N2\u2500C1 1.346(3) 1.347(2) 1.360(3) The cytotoxicity of six compounds (1a, 2a, 3a, 4a, 2b, 2c) were\n N2\u2500C7 1.392(3) 1.399(2) 1.385(3)\n Bond angles (\u25e6 )\n assessed against the human lung adenocarcinoma alveolar basal\n Cl1\u2500M\u2500C1 173.72(7) 171.61(5) 90.58(8) epithelial cell line A549 using the MTT assay. After a 24-hour exposure\n M\u2500C1\u2500N1 123.68(19) 123.65(13) 126.27(18) to the compound solutions, the cellular morphology changes were\n M\u2500C1\u2500N2 130.09(19) 130.16(13) 128.13(19) observed using an inverted microscope, and cell viability was deter\u00ad\n Cl1\u2500M\u2500ct1 177.38(6)\n \u2212 \u2212\n mined spectrophotometrically following a predefined protocol. The\n Cl1\u2500M\u2500ct2 \u2212 \u2212 90.19(10)\n Cl1\u2500M\u2500C31 \u2212 \u2212 160.32(10) cytotoxicity results have been depicted graphically as cell viability\n Cl1\u2500M\u2500C32 \u2212 \u2212 160.35(10) (Fig. 3). The half-maximal inhibitory concentration (IC50) values for the\n Cl1\u2500M\u2500C35 \u2212 \u2212 91.05(12) compounds (1a, 2a, 3a, 4a, 2b, 2c) at 24 h were calculated as 3.71 \u00b5M,\n Cl1\u2500M\u2500C36 \u2212 \u2212 89.30(12) 5.51 \u00b5M, 5.34 \u00b5M, 5.65 \u00b5M, 5.27 \u00b5M, and 5.83 \u00b5M, respectively. To\n C1\u2500M\u2500ct1 92.05(10)\n estimate the IC50 values, a common approach involves fitting the\n \u2212 \u2212\n C1\u2500M\u2500ct2 \u2212 \u2212 178.25(13)\n C1\u2500M\u2500C31 \u2212 \u2212 92.37(11) experimental data to a dose\u2013response curve using linear regression. For\n C1\u2500M\u2500C32 \u2212 \u2212 91.47(12) this purpose, the x-y data representing compound concentrations and\n C1\u2500M\u2500C35 \u2212 \u2212 162.96(13) corresponding cell viability percentages are plotted, and a straight line is\n C1\u2500M\u2500C36 159.94(14)\n \u2212 \u2212\n fitted to the data. The equation of the fitted line is expressed as Y = a * X\n ct1\u2500M\u2500ct2 \u2212 \u2212 87.19(11)\n N1\u2500C1\u2500N2 106.2(2) 106.14(15) 105.6(2) + b, where Y represents the response (cell viability), X represents the\n concentration of the compound, and \u2019a\u2019 and \u2019b\u2019 are coefficients. The\n IC50 value can then be calculated from the equation as (0.5 \u2212 b)/a.\nUV\u2013visible spectra were recorded in the range between 250 nm to 450 Both cell viability results and IC50 calculations revealed that 1a,\nnm wavelength, and absorption bands are shown in Fig. 2A. The com\u00ad only organic compound tested, has stronger cytotoxic effect compared to\nplexes exhibit a similar absorption spectrum, with a strong band around all complexes. In particular, only 1a performed remarkable cytotoxicity\n260 nm and a weak band around 370 nm. Because of the conjugation the at 7.812 \u00b5M, and this outcome can be attributed to better solubility\nanthracene groups, the complexes have four additional peaks are gained by the ionic structure. When the results of the complexes are\nobserved between 330 and 400 nm in the UV\u2013visible spectrum as compared, it is possible to say that all complexes have approximately the\nmentioned in the literature [10]. Emission spectra for the complexes same level of cytotoxicity.\nwere obtained by exciting them at 370 nm. Complexes display similar\nthree emission bands that two main and one weak peak at around 398,\n 2.5. Stability studies\n421, and 445 nm, respectively Fig. 2B. There is no significant shifting\nbetween 1a and all metal complexes in the emission spectrum. When we\n In order for drug candidates to perform their own activity in the\ncompare the emission intensities of the complexes with the highest 2c\n biological assays, they must be soluble and stable in the test medium in\nand lowest 3a intensity, complex 2c is intense more than twenty-three\n which the assay was carried out. In this context, we tested the stability of\n\n 4\n\fH. Bekci et al. Polyhedron 257 (2024) 117011\n\n\n\n\nFig. 2. Measurement for the complexes were obtained in DMSO solution at 2x10-6 M concentration under the same conditions. (A) The UV\u2013visible spectra, (B) the\nemission spectra, (C) the excitation spectra, (D) overlapped absorption (\u03bbmax 370 nm), emission (\u03bbem 419 nm) and excitation (\u03bbex 370 nm) spectra of complex 2c.\n\n\n\n\nFig. 3. Cell viability of A549 cells after 24 h incubation in the presence of 1a \u2013\n4a, 2b, 2c compounds at different dilution values (I: 62.500 \u00b5M, II: 31.250 \u00b5M,\nIII: 7.812 \u00b5M, IV: 3.906 \u00b5M, V: 1.953 \u00b5M).\n\n\nall compounds whose cytotoxicity was examined in this study for 24 h in\nthe culture medium (DMEM). The results disclosed that only 1a and 2c\ncan save their stability for 24 h and remain intact (Fig. 4). While partial\ndegradation products were observed in complexes 2b, 3a and 4a, Fig. 4. (A) 1H NMR spectra of 1a in 400 mL DMSO\u2011d6 at different time in\u00ad\n tervals in the presence of 100 mL of culture medium (DMEM). (B) 1H NMR\ncomplex 2a was observed to be completely degraded.\n spectra of 2c in 400 mL DMSO\u2011d6 at different time intervals in the presence of\n 100 mL of culture medium (DMEM).\n\n\n\n\n 5\n\fH. Bekci et al. Polyhedron 257 (2024) 117011\n\n\n2.6. Fluorescence microscopy BM3.5. C, H and N analyses were carried out using LECO CHNS-932\n elemental analyser. 1H and 13C NMR spectra were recorded on Bruker\n The gaining deeper mechanistic insights requires understanding the AscendTM 400 Avance III HD. Chemical shifts are expressed in parts per\ncellular uptake and distribution of the tested drug candidate. Therefore, million (ppm) and referenced to residual solvent peaks. Coupling con\u00ad\nwe used fluorescence confocal microscopy to investigate subcellular stants, J, are given as Hz. Absorption spectra were measured on a Shi\u00ad\ndistribution of the compounds tested in this study. For this purpose, we madzu UV-2600 spectrophotometer, and fluorescence excitation and\nchose the ligand precursor 1a and complex 2c, considering their higher emission spectra were recorded on the Hitachi F-7000 spectrofluorom\u00ad\nemission intensity and excellent stability in test medium, and relatively eter using a 10 mm path length cuvette at room temperature. LC-MS/MS\nhigher cytotoxicity of 1a. Compound 1a and complex 2c, each at a spectra were recorded using a Shimadzu 8040 LC-MS\nconcentration of 15.625 \u00b5M, were incubated with the A549 cell line at spectrophotometer.\n37 \u25e6 C for 2 h, followed by the analysis of cellular images. Through this Chloro[1-((2-methyl)benzyl)-3-((anthracen-9-yl)methyl)benzi\u00ad\nexamination, it was distinctly observed that both compounds dispersed midazol-2-ylidene]silver(I), 2a. The ligand precursor (1-((2-methyl)\nalong the cell membranes and accumulated within the nuclear regions benzyl)-3-((anthracen-9-yl)methyl)benzimidazolium chloride (1a) was\nbeyond the cell membrane (Fig. 5). Importantly, such fluorescence sig\u00ad synthesized according to procedure described in our previous study\nnals were not detected in the control cells. These findings indicate that [14]. A methylene chloride (50 mL) mixture of 1a (0.86 mmol, 387 mg)\nthe effects of the compounds occur not only at the cytoplasmic level but and silver(I) oxide (0.43 mmol, 100 mg) was stirred at room tempera\u00ad\nalso at the nuclear level. ture for 72 h. After this period, the solution was filtered through Celite.\n The solvent was removed under vacuo, the crude product was washed\n3. Conclusion with n-hexane (3 x 5 mL) and dried under reduced pressure. All ma\u00ad\n nipulations during the synthesis, and storage of the solid was done in the\n In summary, we have reported the synthesis and characterization of absence of the light. Yellow solid, 445 mg (93 %). Melting point:\nAg\u2013, Rh\u2013 and Ir\u2013NHC complexes of a N-(2-methylbenzyl)-N-((anthra\u00ad 271\u2013272 \u25e6 C. Anal. Calcd. for C30H24AgClN2: C, 64.82; H, 4.35; N, 5.04\ncen-9-yl)methyl)benzimidazole-2-ylidene ligand, an Ag\u2013NHC complex %. Found: C, 64.27; H, 4.48; N, 4.97 %. 1H NMR (400 MHz, CDCl3): \u03b4\nof N-(methoxyethyl)-N-((anthracen-9-yl)methyl)benzimidazole-ylidene 8.64 (m, 1H, ArH), 8.29 (d, 2H, ArH, J = 8.7), 8.12 (d, 2H, ArH, J = 8.6),\nligand, and a N-coordinated [AgL2]NO\u20133 type silver complex with N- 7.60\u2013\u20137.51 (m, 4H, ArH), 7.20\u2013\u20137.02 (m, 7H, ArH), 6.62 (d, 1H, ArH, J\n((anthracen-9-yl)methyl)benzimidazole ligand. The anti-proliferative = 7.7), 6.57 (s, 2H, \u2013NCH2C14H9), 5.57 (s, 2H, \u2013NCH2C6H4\u20132\u2013CH3),\nassays revealed that all compounds have remarkable activity against 2.34 (s, 3H, Ph\u20132\u2013CH3). 13C NMR (100 MHz, CDCl3): \u03b4 Carbene carbon\nA549 cells at the 62.50 and 31.25 \u00b5M concentration levels, however we was not detected, 135.4, 134.3, 134.1, 132.7, 131.5, 131.2, 130.9,\nmust emphasize that the cytotoxicity of the complexes are lower 130.5, 130.1, 128.3, 127.8, 126.5, 126.2, 125.4, 124.4, 124.3, 123.2,\ncompared to standard drug cisplatin [20]. Stability studies disclosed that 122.9, 112.2, 112.1, 51.9 (\u2013NCH2C14H9), 47.1 (\u2013NCH2C6H4\u20132\u2013CH3),\nonly 1a and N-coordinated silver complex, 2c, are able to retain their 19.6 (Ph\u20132\u2013CH3). LC-MS (m/z): Anal. Calcd. for C60H48AgN4 (Ag\nstability in the test medium, among the tested compounds. Furthermore, (NHC)2) is 931.3; found is 932.0.\nit is possible to trace 1a and 2c in the cell by fluorescence microscopy Chloro[1-((2-methoxy)ethyl)-3-((anthracen-9-yl)methyl)benzi\u00ad\nowing to their high fluorescence emission intensity. Although, strong midazol-2-ylidene]silver(I), 2b. The ligand precursor (1-((2-methoxy)\ncytotoxicity, excellent stability in test medium and utilization in fluo\u00ad ethyl)-3-((anthracen-9-yl)methyl)benzimidazolium chloride (1b) was\nrescence microscopy render 1a and 2c as promising anticancer agents, synthesized according to procedure described in our previous study\nand we think that all compounds reported in this study deserve further [14]. A methylene chloride (50 mL) mixture of 1b (0.86 mmol, 347 mg)\nmechanistic investigations owing to their promising and useful and silver(I) oxide (0.43 mmol, 100 mg) was stirred at room tempera\u00ad\nproperties. ture for 72 h. After this period, the solution was filtered through Celite.\n The solvent was removed under vacuo, the crude product was washed\n4. Experimental section with n-hexane (3 x 5 mL) and dried under reduced pressure. All ma\u00ad\n nipulations during the synthesis, and storage of the solid was done in the\n4.1. Synthesis and spectroscopic measurements absence of the light. Yellow solid, 312 mg (71 %). Melting point:\n 213\u2013214 \u25e6 C. Anal. Calcd. for C25H22AgClN2O: C, 58.90; H, 4.35; N, 5.50\n4.1.1. General remarks %. Found: C, 58.77; H, 4.59; N, 5.60 %. 1H NMR (400 MHz, DMSO\u2011d6): \u03b4\n The complexes were synthesized under open-air conditions. The re\u00ad 8.75 (s, 1H, ArH), 8.31 (d, 2H, ArH, J = 8.5), 8.14 (d, 2H, ArH, J = 8.2),\nagents and solvents were purchased from commercial sources and used 7.80 (d, 1H, ArH, J = 7.9), 7.70 (d, 1H, ArH, J = 7.8), 7.56\u20137.37 (m, 6H,\nwithout further purification. Melting points were determined in open ArH), 6.49 (s, 2H, \u2013NCH2C14H9), 4.35 (m, 2H, \u2013CH2CH2OCH3), 3.58 (m,\ncapillary tubes and were uncorrected, using Gallenkamp MPD350. 2H, \u2013NCH2CH2OCH3), 3.05 (m, 3H, \u2013NCH2CH2OCH3). 13C NMR (100\n\n\n\n\nFig. 5. Compounds 1a and 2c, and control were visualized using confocal microscopy. A549 cells were incubated with a concentration of 15.625 \u00b5M at 37 \u25e6 C for 2 h.\n\n 6\n\fH. Bekci et al. Polyhedron 257 (2024) 117011\n\n\nMHz, DMSO\u2011d6): \u03b4 188.4 (Ag\u2013Ccarbene), 134.3, 134.1, 131.5, 131.2, ArH, J = 8.5), 5.69 (d, 1H, \u2013NCH2C6H4-2-CH3 as a gemina hydrogen, J\n130.01, 129.97, 127.8, 125.8, 125.4, 124.6, 124.4, 124.0, 112.9, 112.5, = 16.5), 4.75 (m, 2H, CHcod), 3.24 (m, 1H, CHcod), 2.89 (m, 1H, CHcod),\n71.1 (\u2013NCH2CH2OCH3), 58.7 (\u2013NCH2CH2OCH3), 49.5 (\u2013NCH2C14H9), 2.24\u20132.01 (m, 3H, CH2cod), 1.74\u20131.55 (m, 4H, CH2cod), 1.42 (m, 1H,\n45.3 (\u2013NCH2CH2OCH3). LC-MS (m/z): Anal. Calcd. for C50H44AgN4O2 CH2cod), 2.51 (s, 3H, Ph-2-CH3). 13C NMR (100 MHz, CDCl3): \u03b4 193.1\n(Ag(NHC)2) is 839.3; found is 840.0. (Ir\u2013Ccarbene), 135.5, 135.1, 134.8, 134.5, 131.6, 131.3, 130.4, 129.5,\n Bis(N-(((anthracen-9-yl)methyl)benzimidazole))silver(I) ni\u00ad 129.3, 127.4, 126.3, 125.9, 125.4, 124.9, 124.7, 124.6, 122.4, 122.2,\ntrate, 2c. N-(((anthracen-9-yl)methyl)benzimidazole) (1c) was synthe\u00ad 111.4, 110.6, 87.5, 87.4, 54.0 and 52.4 (four CHcod), 50.0\nsized according to procedure descirbed in literature [10]. 1.18 mmol of (\u2013NCH2C14H9), 47.9 (\u2013NCH2C6H4-2-CH3), 33.5, 33.4, 29.5 and 28.9\n1c was added into the suspension of silver nitrate (0.59 mmol, 100 mg) (four CH2cod), 19.8 (Ph\u20132\u2013CH3). LC-MS (m/z): Anal. Calcd. for\nin ethanol (20 mL). The mixture was stirred for 4 h at 50 \u25e6 C. After this C38H36ClIrN2 ([Ir(NHC)Cl]) is 713.3; found is 713.0.\nperiod, the mixture was allowed to cool to ambient temperature. The\nprecipitate formed was collected by filtration, washed with diethyl ether 4.2. X-ray crystallography\n(3 x 10 mL) and dried under reduced pressure. All manipulations during\nthe synthesis, and storage of the solid was done in the absence of the Single crystal X-ray diffraction data of the compounds were obtained\nlight. Yellow solid, 248 mg (54 %). Melting point: 236\u2013238 \u25e6 C. Anal. at room temperature using a Bruker D8 QUEST diffractometer equipped\nCalcd. for C44H31AgN5O3: C, 67.18; H, 4.10; N, 8.90 %. Found: C, 66.75; with Mo K\u03b1 radiation and a PHOTON III C14 detector. The data were\nH, 4.41; N, 8.74 %. 1H NMR (400 MHz, DMSO\u2011d6): \u03b4 8.82 (s, 1H, ArH), collected, edited and parameterized by the APEX2 and SAINT [21]. The\n8.41 (d, 2H, ArH, J = 8.2), 8.22 (d, 2H, ArH, J = 7.9), 7.93 (d, 1H, ArH, J structures were solved by a dual-space algorithm using SHELXT-2018\n= 8.1), 7.86 (s, 1H, \u2013NCHN\u2013), 7.76 (d, 1H, ArH, J = 8.0), 7.62\u20137.57 (m, [22] and refined with full-matrix least-squares calculations on F2 using\n4H, ArH), 7.43 (t, 1H, ArH, J = 7.6), 7.35 (t, 1H, ArH, J = 7.6), 6.57 (s, SHELXL-2019 [23]. All H atoms were located in difference maps and\n2H, \u2013NCH2C14H9). 13C NMR (100 MHz, DMSO\u2011d6): \u03b4 144.9, 141.6, then treated as riding atoms. Crystal data, data collection and structure\n133.6, 131.6, 131.1, 130.0, 129.9, 128.0, 126.0, 125.1, 124.4, 124.0, refinement details are given in Table S1. Molecular graphics were\n123.7, 119.7, 112.2, 41.9 (\u2013NCH2C14H9). LC-MS (m/z): Anal. Calcd. for created by using OLEX2 [24].\nC44H32AgN4 (Ag(L)2) is 723.2; found is 723.0.\n Chloro[(cyclooctadiene)(1-((2-methyl)benzyl)-3-((anthracen- 4.3. Cytotoxicity studies\n9-yl)methyl))benzimidazol-2-ylidine]rhodium(I), 3a. A methylene\nchloride solution (20 mL) of 2a (0.22 mmol, 120 mg) and [RhCl(COD)]2 Cell Freezing Process: Cells grown in a monolayer are detached using\ndimer (0.11 mmol, 54 mg) was stirred at room temperature for 24 h in trypsin and collected via centrifugation. Cryotubes are prepared, and a\nthe absence of light. After this period, the cleas solution was seperated medium-DMSO mixture is added to protect cells from freezing damage.\nfrom silver chloride precipitate by filtration through Celite. The solvent The tubes are frozen at \u2212 80 \u25e6 C for long-term storage.\nwas removed under vacuo, the crude product was washed with n-hexane Dissolution and Recovery: Frozen cells in cryotubes are transferred to a\n(3 x 5 mL) and dried under reduced pressure. Yellow solid, 95 mg (67 37 \u25e6 C environment to thaw. Medium is quickly added to mitigate the\n%). Melting point: 154\u2013155 \u25e6 C. Anal. Calcd. for C38H36ClN2Rh: C, 69.25; impact of DMSO. Thawed cells are transferred to a centrifuge tube,\nH, 5.51; N, 4.25 %. Found: C, 68.82; H, 5.90; N, 4.27 %. 1H NMR (400 additional medium is added, and centrifugation separates DMSO and\nMHz, CDCl3): \u03b4 8.72 (d, 2H, ArH, J = 8.6), 8.59 (s, 1H, ArH), 8.07 (d, 2H, residual components. The resulting pellet is cultivated in flasks with\nArH, J = 8.4), 7.62\u20137.49 (m, 5H, 4H are ArH and 1H is \u2013NCH2C14H9 as a fresh medium.\ngeminal hydrogen), 7.30\u20137.18 (m, 2H, ArH), 7.04 (t, 1H, ArH, J = 7.5), Propagation and Passage of A549 Cells: A549 cells are cultured in\n6.85\u20136.80 (m, 4H, 2H are ArH, 1H is \u2013NCH2C14H9 as a geminal flasks using Dulbecco\u2019s modified Eagle\u2019s medium (DMEM) medium. The\nhydrogen and 1H is \u2013NCH2C6H4-2-CH3 as a geminal hydrogen), 6.71 (d, cells are maintained by changing the medium every two days under\n1H, ArH, J = 7.5), 6.51 (t, 1H, ArH, J = 7.5), 6.03 (d, 1H, ArH, J = 8.3), controlled conditions. For passage, cells are detached using trypsin,\n5.80 (d, 1H, \u2013CH2C6H4-2-CH3 as a geminal hydrogen, J = 16.6), 5.22 (m, suspended, centrifuged, resuspended, and then inoculated into fresh\n2H, CHcod), 3.64 (m, 1.H, CHcod), 3.35 (m, 1H, CHcod), 2.65 (s, 3H, medium in flasks.\nPh\u20132\u2013CH3), 2.40\u20132.21 (m, 3H, CH2cod), 1.91 (m, 4H, CH2cod), 1.78 (m, Cell Count and MTT Assay: Cell counts are performed using the\n1H, CH2cod). 13C NMR (100 MHz, CDCl3): \u03b4 197.8 (Rh\u2013Ccarbene, JRh-C = CedexXs instrument with trypan blue before seeding cells into plates.\n51.0), 135.5, 135.1, 134.8, 134.7, 131.6, 131.4, 130.5, 129.5, 129.3, The MTT assay assesses cell viability by measuring mitochondrial ac\u00ad\n127.4, 126.3, 125.7, 125.4, 125.1, 124.7, 122.3, 122.1, 111.2, 110.5, tivity through conversion of a tetrazolium salt into a colored formazan\n100.5 and 100.4 (two CHcod, JRh-C = 6.6), 70.3 and 68.7, CHcod, JRh-C = crystal. These processes are crucial for maintaining cell viability, proper\n14.3), 50.4 (\u2013NCH2C14H9), 48.2 (\u2013NCH2C6H4-2-CH3), 32.9, 32.7, 28.9 growth, and accurate experimental results in laboratory settings.\nand 28.3 (four CH2cod), 19.8 (Ph\u20132\u2013CH3). LC-MS (m/z): Anal. Calcd. for The cell line used in this study, human lung adenocarcinomic alve\u00ad\nC38H36ClN2Rh ([Rh(NHC)Cl]) is 623.2; found is 623.0. olar basal epithelial cell line A549, was obtained from the American\n Chloro[(cyclooctadiene)(1-((2-methyl)benzyl)-3-((anthracen- Type Culture Collection (ATCC). A549 cell were seeded in a 96-well\n9-yl)methyl))benzimidazol-2-ylidine]iridium(I), 4a. A methylene plate at 12.500 cell/well density. A549 cells were maintained in\nchloride solution (20 mL) of 2a (0.22 mmol, 120 mg) and [IrCl(COD)]2 DMEM. Cell cultures were supplemented with 10 % fetal bovine serum\ndimer (0.11 mmol, 73 mg) was stirred at room temperature for 24 h in (FBS), 2 mM L-glutamine, 10.000 units/mL penicillin and 10 mg/mL\nthe absence of light. After this period, the cleas solution was seperated streptomycin and maintained at 37 \u25e6 C in an atmosphere of 5 % CO2 with\nfrom silver chloride precipitate by filtration through Celite. The solvent 90 % relative humidity according to standard protocols [25]. The anti-\nwas removed under vacuo, the crude product was washed with n-hexane proliferative effect of the compounds (1a, 2a, 3a, 4a, 2b, 2c) was\n(3 x 5 mL) and dried under reduced pressure. Orange solid, 68 mg (42 evaluated using the MTT reduction assay. Cells were treated with con\u00ad\n%). Melting point: 159\u2013162 \u25e6 C. Anal. Calcd. for C38H36ClIrN2: C, 60.99; centrations ranging from 0 to 62.5 \u00b5M of the compounds, which were\nH, 4.85; N, 3.74 %. Found: C, 60.78; H, 5.33; N, 3.97 %. 1H NMR (400 dissolved in 5 % DMSO. The final concentration of DMSO in wells during\nMHz, CDCl3): \u03b4 8.63 (d, 2H, ArH, J = 8.8), 8.49 (s, 1H, ArH), 7.98 (d, 2H, compound treatment was 0.1 %. The treatment was conducted in me\u00ad\nArH, J = 8.4), 7.55\u20137.51 (m, 2H, ArH), 7.44\u20137.41 (m, 3H, 2H are ArH diums without phenol red, supplemented with 10 % FBS, for a duration\nand 1H is \u2013NCH2C14H9 as a geminal hydrogen), 7.19\u20137.10 (m, 2H, ArH), of 24 h. Afterward, cells were rinsed three times with ice-cold PBS. MTT\n6.97 (t, 1H, ArH, J = 7.5), 6.77\u20136.71 (m, 3H, ArH), 6.61 (d, 1H, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was\n\u2013CH2C14H9 as a gemian hydrogen, J = 15.1), 6.45\u20136.41 (m, 2H, 1H is then added to a final concentration of 0.5 mg/mL. Following a 4-hour\nArH and 1H is \u2013CH2C6H4-2-CH3 as a geminal hydrogen), 5.95 (d, 1H, incubation with MTT, a solubilization buffer (10 % sodium dodecyl\n\n 7\n\fH. Bekci et al. Polyhedron 257 (2024) 117011\n\n\nsulfate in 0.01 mol/L HCl) was added, and the colored formazan crystals [10] (a) A. Citta, E. Schuh, F. Mohr, A. Folda, M.L. Massimino, A. Bindoli, A. Casini, M.\n P. Rigobello, Metallomics 5 (2013) 1006\u20131015;\nwere gently re-suspended. The absorbance data at 570 nm were recor\u00ad\n (b) T. Zou, C.T. Lum, S.-S.-Y. Chui, C.-M. Che, Angew. Chem. Int. Ed. 52 (2013)\nded using a microplate reader (Bio-Tek ELX800, BioTek Instruments 2930\u20132933;\nInc., Winooski, VT). (c) B. Bertrand, A. de Almeida, E.P.M. van der Burgt, M. Picquet, A. Citta,\n A. Folda, M.B. Rigobello, P. Le Gendre, E. Bodio, A. Casini, Eur. J. Inorg. Chem.\n (2014) 4532\u20134536;\nCRediT authorship contribution statement (d) K.M. Groves, C.F. Williams, A.J. Hayes, B.D. Ward, M.D. Isaacs, M.O. Symonds,\n D. Lloyd, P.N. Horton, S.J. Coles, S.J.A. Pope, Dalton Trans. 48 (2019) 1599\u20131612;\n (e) M.G. Fabbrini, D. Cirri, A. Pratesi, L. Ciofi, T. Marzo, A. Guerri, S. Nistri,\n Hatice Bekci: Resources, Investigation. Nam\u0131k O\u0308zdemir: Software, A. Dell\u2019Accio, T. Gamberi, M. Severi, A. Bencini, L. Messori, ChemMedChem 14\nInvestigation, Data curation. Zeynel S\u0327ahin: Investigation, Data cura\u00ad (2019) 182\u2013188;\ntion. Ak\u0131n Mumcu: Investigation, Data curation. Serkan Dayan: (f) F. Guarra, N. Busto, A. Guerri, L. Marchetti, T. Marzo, B. Garcia, T. Biver,\n C. Gabbiani, J. Inorg. Biochem. 205 (2020) 110998;\nWriting \u2013 original draft, Methodology, Investigation, Conceptualization. (g) F. Rong, B. Mienli, H. Lihong, W. Liu, Eur. J. Med. Chem. 183 (2019) 111721;\nMert Olgun Karatas\u0327: Writing \u2013 original draft, Methodology, Investi\u00ad (h) W. Streciwilk, A. Terenzi, X. Cheng, L. Hager, Y. Dabiri, P. Prochnow, J.\ngation, Conceptualization. E. Bandow, S. Wo\u0308lfl, B.K. Keppler, I. Ott, Eur. J. Med. Chem. 156 (2018) 148\u2013161.\n [11] (a) S. Harlepp, E. Chardon, M. Bounche, G. Dahm, M. Maaloum, S. Bellemin-\n Laponnaz, Int. J. Mol. Sci. 20 (2019) 4198;\nDeclaration of competing interest (b) C.H.G. Jakob, B. Dominelli, J.F. Schlagintweit, P.J. Fischer, F. Schuderer, R.\n M. Reich, F. Marques, J.D.G. Correira, F.E. K\u00fchn, Chem. Asia J. 15 (2020)\n 4275\u20134279;\n The authors declare that they have no known competing financial (c) F. Binacchi, F. Guarro, D. Cirri, T. Marzo, A. Pratesi, L. Messori, C. Gabbiani,\ninterests or personal relationships that could have appeared to influence T. Biver, Molecules 25 (2020) 5446;\n (d) B.Y.T. Lee, M.P. Sullivan, E. Yano, K.K.H. Tong, M. Hanif, T. Kawakubo-\nthe work reported in this paper.\n Yasukochi, S.M.F. Jamieson, T. Soehnel, D.C. Goldstone, C.G. Hartinger, Inorg.\n Chem. 60 (2021) 14636\u201314644.\nData availability [12] B.Y.T. Lee, A.D. Phillips, M. Hanif, K.K.H. 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