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Asymmetrically Coordinated Heterodimetallic Ir-Ru System: Synthesis, Computational, and Anticancer Aspects.
{"full_text": " pubs.acs.org/IC Article\n\n\n\n Asymmetrically Coordinated Heterodimetallic Ir\u2212Ru System:\n Synthesis, Computational, and Anticancer Aspects\n Saumyaranjan Mishra, Suman Kumar Tripathy, Debasish Paul, Paltan Laha, Manas Kumar Santra,*\n and Srikanta Patra*\n Cite This: Inorg. Chem. 2023, 62, 7003\u22127013 Read Online\n\n\n ACCESS Metrics & More Article Recommendations *\n s\u0131 Supporting Information\nSee https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.\n\n\n\n\n ABSTRACT: Herein, we present an unprecedented formation of a\n heterodinuclear complex [{(ppy)2IrIII}(\u03bc-phpy){RuII(tpy)}](ClO4)2 {[1]-\n Downloaded via MOSCOW STATE UNIV on May 12, 2026 at 11:26:07 (UTC).\n\n\n\n\n (ClO4)2} using terpyridyl/phenylpyridine as ancillary ligands and\n asymmetric phpy as a bridging ligand. The asymmetric binding mode\n (N\u2227N-\u2229-N\u2227N\u2227C\u2212) of the phpy ligand in {[1](ClO4)2} is confirmed by 1H,\n 13\n C, 1H\u22121H correlated spectroscopy (COSY), high-resolution mass\n spectrum (HRMS), single-crystal X-ray crystallography techniques, and\n solution conductivity measurements. Theoretical investigation suggests that\n the highest occupied molecular orbital (HOMO) and the least unoccupied\n molecular orbital (LUMO) of [1]2+ are located on iridium/ppy and phpy,\n respectively. The complex displays a broad low energy charge transfer (CT)\n band within 450\u2212575 nm. The time-dependent density functional theory\n (TDDFT) analysis suggests this as a mixture of metal-to-ligand charge\n transfer (MLCT) and ligand-to-ligand charge transfer (LLCT), where both ruthenium, iridium, and ligands are involved. Complex\n {[1](ClO4)2} exhibits RuIIIrIII/RuIIIIrIII- and RuIIIIrIII/RuIIIIrIV-based oxidative couples at 0.83 and 1.39 V, respectively. The complex\n shows anticancer activity and selectivity toward human breast cancer cells (IC50; MCF-7: 9.3 \u00b1 1.2 \u03bcM, and MDA-MB-231: 8.6 \u00b1\n 1.2 \u03bcM) over normal breast cells (MCF 10A: IC50 \u2248 21 \u00b1 1.3 \u03bcM). The Western blot analysis and fluorescence microscopy images\n suggest that combined apoptosis and autophagy are responsible for cancer cell death.\n\n\n \u25a0 INTRODUCTION\n The development of transition metal-based multimetallic\n Au,46 Re\u2212Au,47,48 Re\u2212Pt,49 Au\u2212Ir,50 Os\u2212Ir,51 Eu\u2212Pt,52 Ti\u2212\n Au\u2212Ti,40 Au\u2212Ti\u2212Au,39,41 Ti\u2212Au\u2212Fe,53 Pt\u2212Ru\u2212Pt,34 Au\u2212\n systems with suitable ligand frameworks is a fascinating area Ru\u2212Au,54 etc. have been developed, and their anticancer\n of contemporary research. Such systems often display new/ activity is studied extensively. In addition to exhibiting better\n improved properties against their monometallic analogues and anticancer activity, multimetallic systems are also found to\n find diverse applications in chemistry and biology.1\u221216 target different intracellular organs other than nucleic acid,\n Recently, the exploration of such systems as anticancer leading to an alternative mode of action.22,28\u221230,37,42,44,55\n Interestingly, a combination of Ru and Ir has rarely been\n agents17\u221221 has gained serious momentum with the success\n explored in this aspect, although their mononuclear analogues\n of their mononuclear analogues. In addition, they have\n are well known for their interesting photophysical and\n demonstrated a significant improvement in anticancer activity\n photochemical properties, stability, efficient DNA intercalating\n and exhibit a different mechanism of cell death compared to\n ability, biological activity, etc.23,56\n cisplatin.17,18\n Nevertheless, polynucleating pyrazine-based ligands have\n Alternatively, an entailed approach of combining different\n been extensively used for the development of multimetallic\n cytotoxic units into a single molecular framework is exciting, as\n assemblies. Most of the ligand frameworks used are either rigid\n they combine the properties of individual therapeutic units,\n or flexible. Ligands having rigid and flexible frameworks with\n which may exhibit improved pharmacological profiles.22,23 In\n variable coordination sites are relatively uncommon.57\u221262 The\n addition, such scaffolds offer synchronous delivery to the target\n site eliminating multiple drug combinations. Although a\n plethora of homometallic di- and multinuclear systems have Received: January 25, 2023\n been developed and studied, the exploration of heterometallic Published: April 25, 2023\n systems is relatively less. A few examples of the combination of\n metals such as Ru\u2212Ti,22 Ru\u2212Co,24\u221226 Ru\u2212Ni,26 Ru\u2212Zn,26\n Ru\u2212Fe,27 Ru\u2212Au,28\u221232 Ru\u2212Sn,33 Ru\u2212Pt,34\u221237 Ru\u2212Sm,38 Ti\u2212\n Au,25,39,40 Ti\u2212Pd,41 Fe\u2212Pd,42,43 Fe\u2212Au,42,44 Cu\u2212Au,45 Co\u2212\n\n \u00a9 2023 American Chemical Society https://doi.org/10.1021/acs.inorgchem.3c00272\n 7003 Inorg. Chem. 2023, 62, 7003\u22127013\n\fInorganic Chemistry pubs.acs.org/IC Article\n\npolypyridyl-pyrazine-based 2,3-di(pyridin-2-yl)pyrazino[2,3- reaction between 5,6-diamino-1,10-phenanthroline with com-\nf ][1,10] phenanthroline (phpy) ligand offers a rigid framework mercially available 2,2\u2032-bipyridyl.23,62 The heterodinuclear\nat the phenanthroline end and flexible donors sites at the {[1](ClO4)2} is synthesized first by reacting the phpy ligand\npyrazine end. The flexible pyridine donors at the pyrazine end with dimeric precursor [(ppy)2IrIII(\u03bc-Cl)]2 (1:0.5 mole\ncan potentially coordinate with the same/different metals in ratio),62 followed by its purification and further reaction with\nvarious coordination modes (Chart 1). [RuIII(tpy)Cl3] (1:1 mole ratio) (see Experimental Section)\n (Scheme 1). Complex {[1](ClO4)2} is isolated as its ClO4 salt.\nChart 1. Different Metal Binding Modes of the phpy Ligand The complex is soluble in most of the polar organic solvents\n and is sufficiently stable in the air.\n The diamagnetic {[1](ClO4)2} is 1:2 electrolyte in the\n CH3CN solution. The presence of ClO4\u2212 counteranion is\n evidenced by observing the characteristic \u03bd(ClO4\u2212) infrared\n vibrations at 1100 and 670 cm\u22121. Apparently, from the\n conductivity data, it appears that complex {[1](ClO4)2} is\n formed with binding mode A as shown in Chart 1.\n Accordingly, complex {[1](ClO4)2} should exhibit a molecular\n In general, Ru center coordinates with polypyridyl ligands ion peak centered at 1356.1393 (corresponding {[1]ClO4}+).\nthrough neutral N\u2227N donor sites (Chart 1A).23 Binding of Ru Surprisingly, the high-resolution mass spectrum of {[1]ClO4}+\nthrough anionic N\u2227N\u2227C\u2212/N\u2227C\u2212 donor sites of polypyridyl shows a molecular ion peak centered at 1320.1653 (calculated\nligands are less common (Chart 1B).63\u221265 Bridging ligands 1320.1628), which is \u223c36 units less than the expected\nfunctioning as asymmetric N\u2227N and N\u2227N\u2227C\u2212/N\u2227C\u2212 donors molecular mass (Figure 1). This suggests the alternative\nare rare.66\u221270 Further, the study of heterodinuclear Ru\u2212Ir\ncomplex bridged through asymmetric N\u2227N and N\u2227N\u2227C\u2212\nbridging ligands is not known. Thus, the present study intends\nto highlight the formation of a heterodinuclear (Ir\u2212Ru)\ncomplex, where Ru center forms the cyclometalated complex\n(Ru\u2212C) with the phpy ligand and their cytotoxic activity\nagainst various cancer cells.\n Herein, we report the synthesis of a cyclometalated\nheterodinuclear complex [{(ppy)2IrIII}(\u03bc-phpy){RuII(tpy)}]-\n(ClO4)2 {[1](ClO4)2} incorporating pyridyl-based ligands (tpy\n= 2,2\u2032:6\u2032,2\u2033-terpyridine; ppy= 2-phenylpyridine; phpy = 2,3-\ndi(pyridin-2-yl)pyrazino[2,3-f ][1,10] phenanthroline). The\ncharacterization and physicochemical properties of complex\n{[1](ClO4)2 } are carried out using various analytical\ntechniques. The density functional theory (DFT) study of\n[1]2+ has been conducted to determine the geometric structure\nand vertical excitation energies to verify the origin of the\nexperimentally observed bands in the UV\u2212vis spectrum. The\nanticancer activity of complex {[1](ClO4)2} is studied using\nMCF-7 (p53 wild) and MDA-MB-231 (p53 mutant) cell lines. Figure 1. High-resolution mass spectrum (HRMS) of {[1]ClO4}+ in\nMoreover, the mechanism of cancer cell death has been CH3CN. The inset represents the expanded molecular ion peak (red)\nestablished via fluorescence-activated cell sorting (FACS), and its simulated pattern (blue).\nWestern blot analysis, and confocal microscopy techniques.\n\n\u25a0 RESULTS AND DISCUSSION\nThe dinucleating ligand 2,3-di(pyridin-2-yl)pyrazino[2,3-f ]-\n formulation B, as shown in Chart 1, where complex\n {[1](ClO4)2} loses one Cl\u2212 ligand and an H atom from the\n bridging ligand (phpy). The phpy ligand gets deprotonated\n[1,10] phenanthroline (phpy) is prepared by the condensation and coordinates with [(tpy)Ru] unit through an unusual\n\nScheme 1. Scheme for the Synthesis of Heterodimetallic Complex 1\n\n\n\n\n 7004 https://doi.org/10.1021/acs.inorgchem.3c00272\n Inorg. Chem. 2023, 62, 7003\u22127013\n\fInorganic Chemistry pubs.acs.org/IC Article\n\n\n\n\nFigure 2. 1H\u22121H correlated spectroscopy (COSY) spectrum of complex [1](ClO4)2 in DMSO-d6.\n\n\n\n\nFigure 3. (a) ORTEP and (b) geometry-optimized structure (in the gas phase) of complex [1]2+. Ellipsoids are drawn at a 20% probability level.\nHydrogen atoms and counteranions are eliminated for clarity.\n\nN\u2227N\u2227C\u2212 binding mode (Chart 1B). This type of asymmetric correlation spectroscopy study was conducted (Figure 2) to\nN\u2227N and N\u2227N\u2227C\u2212 coordination mode of the phpy ligand is elucidate further the structural aspect of complex [1](ClO4)2.\nnot observed before. The molecular ion peak of {[1](ClO4)}+ Because of the presence of several aromatic protons of a similar\nnicely matches with the simulated mass pattern, which further chemical environment, the peaks are not well resolved, and\nsupports the formation of the complex with unusual binding some of them are overlapped. Fortunately, complex [1]-\nmode of [(tpy)Ru] with the distal unit of the phpy ligand (ClO4)2 possesses two distinct protons (20 and 21), which\n(Chart 1B). Hence, the molecular structure of complex only correlate with each other due to the absence of\n{[1](ClO4)2} could be formulated as [{(ppy)2IrIII}(\u03bc-phpy)- neighboring protons and should appear as a doublet. Two\n{RuII(tpy)}](ClO4)2 (Chart 1). doublets at 8.13 ppm and 7.79 ppm are detected and correlate\n The solution identity of complex {[1](ClO4)2} is confirmed with each other. This further supports the Ru\u2212C coordination\nby 1H and 13C NMR spectroscopy (Figure S1). The complex in complex [1](ClO4)2.\nhas shown the desired number of protons (40) within 0\u221210 The single-crystal X-ray crystallographic analysis was\nppm in its 1H NMR spectrum, indicating the presence of phpy, conducted to get more insight into the structure and unusual\nppy, and tpy ligands and confirming its unusual binding mode bond formation. The X-ray quality crystals were grown in\n(Chart 1B). The 13C NMR spectrum of [1](ClO4)2 displays dimethyl sulfoxide (DMSO) at room temperature. The oak\nthree distinct signals at 202.6, 167.1, and 166.9 ppm, which ridge thermal ellipsoid plot (ORTEP) diagram of complex\ncorrespond to the binding carbon centers of phpy with [1](ClO4)2 is shown in Figure 3a, and important crystallo-\nruthenium and ppy with iridium, respectively. A similar type of graphic parameters are listed in Tables TS1 and TS2. Complex\nobservation for cyclometalated complexes has also been [1](ClO4)2 was crystallized out in a triclinic crystal system\nreported previously.55,57,62,64,71 This further affirms the Ru\u2212 with the P1\u0305 space group. From the crystal structure, it is\nC coordination in complex [1](ClO 4 ) 2 . The 1 H\u2212 1 H observed that [(ppy)2Ir] is coordinated to the rigid part,\n 7005 https://doi.org/10.1021/acs.inorgchem.3c00272\n Inorg. Chem. 2023, 62, 7003\u22127013\n\fInorganic Chemistry pubs.acs.org/IC Article\n\nwhereas the [Ru(tpy)] unit is coordinated to the flexible part\nof the phpy ligand (Figure 3a). It is interesting to note that the\nphpy ligand offers a tridentate N\u2227N\u2227C\u2212 coordination mode\nwhile coordinating with [Ru(tpy)]. However, it showed a\nneutral N\u2227N-\u2229-N\u2227N binding mode when the [(p-cym)RuCl]\nfragment is used.23 Change in the coordination mode by\nvarying the p-cym ligand to the tpy ligand is a quite remarkable\nobservation. This type of unusual anionic ditopic N\u2227N and\nN\u2227N\u2227C\u2212 coordination mode displayed by the phpy ligand is\nnot seen before. The Ir1\u2212N10/N11 distances (2.148\u22122.133 \u00c5)\nare found to be longer than the Ir1\u2212N1/N2 distances (1.992\u2212\n2.047 \u00c5), which is due to the trans-directing effect of the\nanionic C center of the ppy ligands. The N\u2212Ir1\u2212N and N\u2212\nIr1\u2212C bond angles are in line with the structurally similar\niridium complexes.23,55\u221257,62,64 On the other hand, the Ru1\u2212\nN7/N8/N9(tpy) (1.937\u22122.092 \u00c5) distances are quite shorter\nthan Ru1\u2212N6 (2.65 \u00c5), which is again the trans-directing effect\nof the phenanthroline C(C31) unit of the phpy ligand. This\nfurther confirms the Ru\u2212C coordination of the [Ru(tpy)] unit\nwith the phpy ligand.\n The equilibrium geometry of [1]2+ has been calculated at the\nlevel of density functional theory (DFT) using the B3LYP\nhybrid functional. The optimized geometry and related bond\nparameters of complex [1]2+ are displayed in Figure 3b and\nTables TS3\u2212TS5. From the DFT analysis, it is observed that\nthe pyridine rings of the phpy ligand deviate from planarity.\nHowever, the other ligands such as tpy and ppy are planner, Figure 4. Pictorial representation of the Kohn\u2212Sham orbitals of [1]2+\nwhich is evident from the dihedral angles. The calculated Ru\u2212 in the gas phase.\nN (1.99\u22122.15 \u00c5), Ru\u2212C (2.06 \u00c5), Ir\u2212N (2.06 \u00c5), and Ir\u2212C\n(2.02 \u00c5) bond distances are in agreement with the [1](ClO4)2 also shows the reduction of the phenanthroline\nexperimentally observed (Table TS2) and structurally unit of the phpy ligand at the negative potential of the cyclic\ncharacterized similar complexes.23,55,62,72\u221274 A slight deviation voltammogram.\nfrom the idealized geometries of both ruthenium and iridium Both ruthenium and iridium complexes are known to exhibit\ncenters in [1]2+ is observed from the optimized geometrical excellent anticancer activity toward various cancer\nparameters (Tables TS3\u2212TS5). cells.17,22,81\u221284 Thus, the anticancer activity of [1](ClO4)2 is\n Further, the nature and composition of frontier orbitals are tested using two breast cancer cell lines: non-metastatic MCF-\nanalyzed from the optimized geometry. It is found that the 7 and highly metastatic triple-negative breast cancer cell line\nhighest occupied molecular orbital (HOMO) of the complex MDA-MB-231 by using standard 3-(4,5-dimethylthiazol-2-yl)-\nresides at \u22128.87 eV and is localized on the ppy (63%) unit and 2,5-diphenyltetrazolium bromide (MTT) assay (Figures 6a\niridium center (35%) (Figure 4 and Table TS6). On the other and S3). The IC50 values of [1](ClO4)2 against cancer cells are\nhand, the least unoccupied molecular orbital is situated at gathered in Table 1.\n\u22126.89 eV and localized mainly on the phpy ligand (90%). The Complex [1](ClO4)2 shows a significantly higher anti-\nHOMO\u2212LUMO energy gap is 1.98 eV, which falls in the proliferative activity against both cancer cell lines as compared\nvisible region (vide infra). to the standard cisplatin. Moreover, data reveals that complex\n Experimentally, the heterodinuclear [1](ClO4)2 displays [1](ClO4)2 is more active against MCF-7 cells compared to\nligand-based transitions below 350 nm along with broad low- MDA-MB-231 cells. Interestingly, complex [1](ClO4)2 dis-\nenergy MLCT bands in the visible region (400\u2212600 nm) plays moderately less toxicity toward normal breast cells (MCF\n(Figure 5a).75\u221280 It is difficult to exactly assign the MLCT 10A) (IC50 \u2248 21 \u00b1 1.3 \u03bcM), suggesting its selectivity toward\ntransitions from the ruthenium or iridium center. Cyclo- cancer cells (Table 1).\nmetalated {Ir(ppy)2} centers generally show an MLCT band Next, we studied the stability of the complex in a phosphate\naround or below 400 nm.23,62,76\u221278,80 Thus, the low-energy buffer saline solution. It is found that all of the complexes are\nbands for [1](ClO4)2 could be assigned to the RuN5C \u2192 reasonably stable in buffer solution at least for 48 h (Figure\nphpy/tpy MLCT transition.65 To get more insight into the S2).\nelectronic transitions, TDDFT analysis using the optimized To understand the molecular mechanism of the anticancer\ngeometry was conducted. This reveals that the broad low- activity of complex [1](ClO4)2, fluorescence-activated cell\nenergy band is composed of a mixture of MLCT and LLCT sorting (FACS) analysis was conducted (Figure S4). A\ntransitions [Ru(d\u03c0)/ppy(\u03c0)/tpy(\u03c0) \u2192 phpy(\u03c0*); Ir(d\u03c0)/ppy(\u03c0) \u2192 significant amount (73%) of the cell population is observed\nphpy(\u03c0*); ppy(\u03c0) \u2192 phpy(\u03c0*)/tpy(\u03c0)*], where ruthenium, at the sub-G1 phase after 48 h of treatment of [1](ClO4)2,\niridium, and ligands are involved (Table TS7). indicating the apoptotic mode of cell death. Further, the\n Complex [1](ClO4)2 displays two quasi-reversible redox Western blot analysis for the marker proteins, such as Apaf1,\ncouples, E1/2, at 0.83 and 1.39 V, which may be attributed to cleaved caspase 3, PUMA, etc., responsible for apoptosis, are\nRuIIIrIII/RuIIIIrIII (RuN5C center) and RuIIIIrIII/RuIIIIr IV examined (Figure 6b,c). It is observed that the expression\n(IrN4C2 center) oxidation, respectively (Figure 5b). Complex levels of Apaf1, cleaved caspase 3 in MCF-7 cells, and Apaf1,\n 7006 https://doi.org/10.1021/acs.inorgchem.3c00272\n Inorg. Chem. 2023, 62, 7003\u22127013\n\fInorganic Chemistry pubs.acs.org/IC Article\n\n\n\n\nFigure 5. (a) UV\u2212vis and (b) cyclic voltammogram of complex [1](ClO4)2 in CH3CN.\n\n\n\n\nFigure 6. (a) Dose-dependent suppression of cell viability of complex [1](ClO4)2 in human breast MCF-7 and MDA-MB-231 cancer cell lines.\nThe graph represents the average of three biological replicates. (b, c) Expression levels of marker proteins involved in apoptosis and autophagy were\nanalyzed by immunoblotting assay. (d) Fluorescence microscopic images of MDA-MB-231 cancer cells treated with acridine orange in the absence\n(left) and presence (right) of [1](ClO4)2 (5 \u03bcM). (e) Expression levels of autophagic marker proteins were examined by immunoblotting in the\nabsence and presence of autophagic inhibitor 3-methyladenine (3-MA). (f) Expression levels of kinases were examined following the treatment of\ncomplex [1](ClO4)2 at the indicated concentration.\n\ncleaved caspase 3, and PUMA in MDA-MB-231 cells are In addition to apoptotic cell death, previous studies showed\n that organometallic compounds also induce autophagic cell\nincreased (Figure 6b,c), indicating that cells undergo apoptotic\n death.18,21 We, therefore, examined whether complex [1]-\ncell death following the treatment with [1](ClO4)2. (ClO4)2 has a role in autophagic cell death. A significant\n 7007 https://doi.org/10.1021/acs.inorgchem.3c00272\n Inorg. Chem. 2023, 62, 7003\u22127013\n\fInorganic Chemistry pubs.acs.org/IC Article\n\nTable 1. In Vitro Growth Inhibition against Human Breast and 2-phenylpyridine as ancillary ligands and asymmetric phpy\nCancer (MCF-7 and MDA-MB-231) and Normal Breast as the bridging ligand. The complex is characterized by various\n(MCF 10A) Cell Lines and the Hydrophobicity of Complex analytical techniques. The unusual Ru\u2212C binding mode is\n[1](ClO4)2 confirmed by single-crystal X-ray crystallography, HRMS, 13C\n NMR, and COSY techniques. The iridium center is\n complexes MCF-7a MDA-MB-231a MCF 10A coordinated through normal N\u2227N binding mode at the\n [1](ClO4)2 9.3 \u00b1 1.2 8.6 \u00b1 1.2 21.2 \u00b1 1.3 1.22 phenanthroline end, whereas the ruthenium is coordinated\n [Ir] 17.8 \u00b1 4.8 ND ND ND through the unusual N\u2227N\u2227C\u2212 coordination mode at the\n [Ru] 89.0 \u00b1 9.8 ND ND ND pyrazine end. Theoretical investigation suggests that the\n [Ir] + [Ru] 19.1 \u00b1 3.1 ND ND ND HOMO is mainly localized on the Ir and ppy, whereas the\n Phpy >100 ND ND ND LUMO resides on the phpy ligand. Complex [1](ClO4)2\n Cisplatin 35.5 \u00b1 7.2 ND ND ND displays better anticancer activity against human breast cancer\na cell lines MCF-7 and MDA-MB-231 as compared to cisplatin.\n IC50 values are in \u03bcM; ND: not determined. [Ir] \u2248 [(ppy)2Ir-\n(phpy)](ClO4); [Ru] \u2248 [(tpy)Ru(phpy)Cl](ClO4). The FACS and Western blot analyses reveal that the complex\n induces both apoptosis and autophagy. Complex [1](ClO4)2\n has moderate selectivity toward human breast cancer cells than\nincrease in LC3B II is observed in both cell lines, indicating toward normal breast cells (IC50 = 9.3 \u00b1 1.2 \u03bcM for MCF-7\nthat the autophagy mode of action is also functioning (Figure and IC50 \u223c 21.2 \u00b1 1.3 \u03bcM for MCF 10A).\n6b,c). Moreover, the microscopic analysis of MDA-MB-231 Most of the cancer cells are cell death resistant due to the\ncells treated with [1](ClO4)2 reveals the formation of acidic aberrant activation of kinases like AKT and MAP kinase. Of\nvacuoles (Figure 6d). note, AKT is aberrantly activated in the majority of breast\n To further confirm the autophagy mode of cell death, the cancers.89 Our finding reveals that [1](ClO4)2 inactivates cell\ncells were treated with autophagy inhibitor 3-methyladenine death resistance kinases but activates cell-death-promoting\n(3-MA). It is observed that [1](ClO4)2 treatment increases the kinase JNK to induce cell death. Metal complex inducing\nlevel of LC3B II, which is significantly reduced upon the 3-MA cancer cell death through the nonapoptotic mode is very\ntreatment, suggesting that [1](ClO4)2 induces autophagic cells important for the treatment of resistant cancer. Our earlier\nalso (Figure 6e). Thus, collectively the data suggests that observation shows that the use of p-cymene [(ppy)2IrIII(\u03bc-\ncomplex [1](ClO4)2 induces both apoptosis and autophagy phpy)(p-cym)RuIICl]2+ leads to autophagy,23 whereas in the\nmodes of cell death in both MCF-7 and MDA-MB-231 cancer present work, the heterodimetallic complex with the\ncell lines. terpyridine ligand displays combined apoptosis and autophagy.\n It should be noted that both mononuclear cyclometalated Moreover, the mononuclear iridium complex\niridium complex [(ppy)2IrIII(phpy)]+ and heterodimetallic [(ppy)2IrIII(phpy)]+ shows paraptosis.62 Further, mere varia-\niridium\u2212ruthenium complex [(ppy)2IrIII(\u03bc-phpy)(p-cym)- tion of ancillary ligand and selection of metal can modulate the\nRuIICl]2+ with the same phpy ligand display a similar mode of action to a great extent. Thus, the present\nanticancer activity (IC50 values 0.86 and 0.91 \u03bcM, respectively) contribution provides a unique example that would be useful\nand exhibit paraptotic and autophagic modes of cell death, for the development of anticancer agents for the treatment of\nrespectively.23,62 However, in the present study, replacing p- resistant cancer.\ncymene with terpyridine (tpy) ligand and keeping other metals\nand ligands the same cause the mechanism of action to change\nfrom autophagy to a combination of apoptosis and autophagy.\nThus, mere variation of ligand can modulate the mode of\n \u25a0 EXPERIMENTAL SECTION\n Materials. The precursor complexes [Ru(tpy)Cl3],74,91 [(ppy)2Ir-\n (\u03bc-Cl)]2,92 and 5,6-diamino-1,10-phenanthroline93 were prepared by\naction. following the reported procedures. The bridging ligand 2,3-di(pyridin-\n Previous studies showed that AKT, MAPK, and JNK 2-yl)pyrazino[2,3-f ][1,10] phenanthroline (phpy) ligand was synthe-\nsignaling pathways play a critical role in apoptotic as well as sized by following the reported procedure.23,60,62 The mononuclear\nautophagic cell death.85\u221289 We found that [1](ClO4)2 also [(ppy)2Ir(phpy)](ClO4) was prepared by following the procedure\ninduces apoptotic as well as autophagic cells. We then reported earlier.23,62 All chemicals were purchased from commercial\ninvestigated whether [1](ClO4)2 induces cell death by altering sources and used as received. The solvents were dried by conventional\nthe activity of these kinases. Immunoblotting results methods and distilled prior to use. All culture media and supplements\ndemonstrate that complex [1](ClO4)2 suppresses the activity for cell work were purchased from Gibco Invitrogen Corporation\n (CA).\nof cell death inhibitory AKT and MAPK kinases (Figure 6f). In\n Instrumentation. The conductivity measurement was done using\naddition, we observe that complex [1](ClO4)2 has a more the OAKton PC2700 conductivity bridge. The UV\u2212vis spectrum was\npotent suppressive effect on AKT as compared to MAPK. For obtained by using a Perkin Elmer Lambda 35 spectrophotometer. The\nexample, as compared to phosphorylated MEK-ERK, phos- FTIR spectrum was recorded using a Bruker \u03b1 FTIR spectropho-\nphorylation of AKT is significantly suppressed upon treatment tometer with the sample prepared as the KBr pellet. Mass spectra\nof 1 \u03bcM of complex [1](ClO4)2 (Figure 6f). It is well known were acquired on a Thermo Fisher Scientific Q Exactive Plus Orbitrap\nthat the inhibition of AKT or activation of JNK leads to the mass spectrometer. 1H NMR spectrum was acquired on a Bruker\ninduction of apoptosis.89,90 Thus, our data revealed that Avance III 400 spectrometer using the DMSO-d6 solvent. Electro-\ncomplex [1](ClO4)2 induces cell death in part by inhibiting chemical measurement was carried out in a dinitrogen atmosphere\ngrowth-promoting kinases. using a CHI 6205 electrochemical analyzer with Et4NClO4 as the\n supporting electrolyte (0.1 M), and the solute concentration was 10\u22123\n\n\u25a0 CONCLUSIONS\nIn conclusion, cyclometalated heterodinuclear complex [1]-\n M. For electrochemical measurements, a glassy carbon working\n electrode, Pt wire counter electrode, and Ag/AgCl as the reference\n electrode were used. The half-wave potential E298 K was set equal to\n(ClO4)2 of Ru and Ir has been developed by using terpyridyl 0.5(Epa + Epc), where Epa and Epc are anodic and cathodic cyclic\n\n 7008 https://doi.org/10.1021/acs.inorgchem.3c00272\n Inorg. Chem. 2023, 62, 7003\u22127013\n\fInorganic Chemistry pubs.acs.org/IC Article\n\nvoltammetric peak potentials, respectively. In this cell, Fc/Fc+ couple cells were treated with 10 \u03bcM of [1](ClO4)2. The cells treated with\nhad an E1/2 value of 0.22 V. 0.01% DMSO were considered as control. At the end of the\n Synthesis of [(ppy)2Ir(\u03bc-phpy)Ru(tpy)](ClO4)2 ([1](ClO4)2). treatment, the cells were washed with ice-cold PBS, fixed with 95%\nThe mononuclear iridium complex [(ppy)2Ir(phpy)](ClO4) (51.5 chilled ethanol, and kept at 4 \u00b0C for 24 h. Then, the fixed cells were\nmg, 0.05 mmol) and [(tpy)RuIIICl3] (22.0 mg, 0.05 mmol) precursor washed again with ice-cold PBS to remove the trace amount of\nwere taken in 1:1 ratio in dry ethanol, followed by 34 \u03bcL of NEt3, and ethanol and stained with the staining solution comprising 50 \u03bcg/mL\nrefluxed for 12 h under dinitrogen atmosphere. The volume of the propidium iodide and 50 \u03bcg/mL RNAse in PBS. The cells were\nsolution was reduced under vacuum and a saturated solution of acquired on a BD FACS Calibur instrument, and the data was\naqueous NaClO4 was added to it, which gave a reddish-brown analyzed using Cell QuestPro software. All of the experiments were\nprecipitate. It was further filtered, washed with enough cold distilled carried out in triplicate.\nwater, and dried in air. Pure [1](ClO4)2 was obtained by column Western Blotting. Exponentially growing MCF-7 and MDA-MB-\nchromatography using neutral alumina as a support and a mixture of 231 cells were treated with 20 and 10 \u03bcM of [1](ClO4)2, respectively,\nsolvent CH2Cl2: CH3CN (2:1). Yield: 47 mg (66%). Molar for 48 h. After 48 h of treatment, the cells were harvested and lysed\nconductivity [\u039bM/(\u03a9\u22121 cm2 M\u22121)] in CH3CN: 198. HRMS with whole cell lysis buffer (50 mM Tris pH 7.4, 200 mM NaCl, 50\n((+)-ESI): m/z 1320.1653 corresponding to {[1]ClO4}+ (calculated mM NaF, 1 mM Na3VO4, 0.5% Triton X-100, and protease inhibitor\nmolecular mass for 1320.1628). 1H NMR (400 MHz,) \u03b4/ppm: 9.72 cocktail) in ice for 30 min.85 Lysates were cleared by centrifuging at\n(dd, J = 8.3, 1.4 Hz, 1H), 8.98 (d, J = 8.1 Hz, 1H), 8.94 (d, J = 4.2 Hz, high speed (16,000g) for 20 min and the supernatants were\n1H), 8.88\u22128.84 (m, 1H), 8.76 (d, J = 8.2 Hz, 1H), 8.69 (d, J = 8.2 transferred to new tubes. Protein concentration was measured by\nHz, 1H), 8.41\u22128.29 (m, 3H), 8.25 (dd, J = 5.2, 1.4 Hz, 1H), 8.20\u2212 the Bradford method.90 The samples were prepared and run in\n8.13 (m, 2H), 8.10 (d, J = 8.3 Hz, 1H), 7.97\u22127.90 (m, 1H), 7.91\u2212 sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-\n7.85 (m, 2H), 7.84\u22127.78 (m, 3H), 7.78\u22127.72 (m, 3H), 7.66\u22127.61 PAGE) with Tris-glycine (25 mM Tris, 192 mM glycine) running\n(m, 1H), 7.39\u22127.35 (m, 2H), 7.33\u22127.26 (m, 2H), 7.11 (ddd, J = 7.2, buffer containing 0.1% SDS. The separated proteins were transferred\n5.9, 1.1 Hz, 1H), 7.05\u22126.97 (m, 4H), 6.91 (ddd, J = 8.2, 5.4, 4.9 Hz, onto the PVDF membrane with a transfer buffer (Tris-glycine\n3H), 6.81\u22126.72 (m, 3H), 6.24 (d, J = 7.4 Hz, 1H), 6.07 (d, J = 7.4 containing 20% methanol). The antibodies specific for BAX, PUMA,\nHz, 1H). 13C NMR (101 MHz,) \u03b4/ppm: 203.07, 167.67, 167.37, cleaved caspase 3, LC3B, pAKT (S473), pERK, pMEK, MEK, and\n156.87, 156.82, 156.39, 154.75, 153.56, 152.96, 152.92, 152.30, AKT were obtained from the cell signaling technology. Antibodies for\n152.24, 152.03, 151.07, 151.03, 150.11, 149.73, 149.39, 149.23, p53, APAF, pJNK, JNK, and ERK were purchased from Santacruz\n148.85, 147.18, 146.52, 144.72, 144.38, 144.34, 143.72, 139.12, Biotechnology. Tubulin and \u03b2-actin were purchased from Sigma-\n139.07, 138.10, 137.62, 137.60, 136.24, 135.82, 135.55, 134.25, Aldrich. p62 was purchased from Abcam. HRP-conjugated secondary\n134.24, 131.79, 131.78, 131.49, 130.75, 130.45, 129.66, 128.15, antibodies were purchased from GE Health Care, and the signals were\n127.84, 127.28, 127.27, 126.26, 126.25, 125.97, 125.59, 125.29, detected using a supersignal chemiluminescence substrate (Pierce,\n124.47, 124.13, 124.02, 123.65, 123.62, 122.83, 122.58, 120.47, Thermo Scientific).\n120.36. Theoretical Calculation. All DFT calculations were performed\n Stability Study of [1](ClO4)2. The stability of complex [1]2+ was using Gaussian 09 suite of quantum chemical programs.94 The\ntested by dissolving it (0.1 mM) DMSO and diluted with 10 mM ground-state geometry of complex [1]2+ was optimized in the gas\nphosphate-buffered saline (PBS). The stability of [1]2+ in PBS was phase with a hybrid exchange-correlation functional B3LYP.95\u221298 The\nstudied by measuring its absorbance with time using a UV\u2212vis LANL2DZ basis set with an effective core potential was employed for\nspectrometer. Ir and Ru atoms,99\u2212102 while the 6-31G(D) basis set was used for\n Preparation of a Stock Solution of [1](ClO4)2. Complex other atoms.103,104 Gaussian\u2019s pruned grid ultrafine was used for\n[1](ClO4)2 was dissolved in DMSO (Hybri-Max, sterile-filtered) to numerical calculation. SCF convergence criteria of 10\u22128 au were\nprepare 100 mM stock concentration. Then, the stock concentration employed throughout the calculation. Vertical electronic singlet state\nof compounds was diluted (1000 times) directly in cell culture media excitation of optimized geometry of complex [1]2+ was computed\nto prepare a 100 \u03bcM working concentration. All other working using the TDDFT formalism in the gas phase.105\u2212107 Gauss-Sum 3.0\nconcentrations were prepared by dilution of 100 \u03bcM working software was used to evaluate the percentage contribution of different\nconcentration. Stock solutions were stored at \u221220 \u00b0C, and working groups to each molecular orbital.108\ndilutions were always freshly prepared. Crystallography. The X-ray-quality crystals of [1](ClO4)2 were\n Cell Culture. Breast cancer cell line MCF-7 was grown in obtained by the slow evaporation of (CH3)2SO solution at room\nDulbecco\u2019s modified Eagle\u2019s medium (DMEM) medium and MBA- temperature. The crystallographic studies were performed using a\nMB-231 in RPMI as monolayer supplemented with 10% fetal bovine Bruker D8 venture instrument using Mo K\u03b1 radiation (\u03bb\u03b1 = 0.71073\nserum (FBS), 100 U/mL penicillin, and 100 \u03bcg/mL streptomycin at \u00c5) at 273 (2) K. APEX 10 software was used for the data collection\n37 \u00b0C in humid, 5% CO2 atmosphere. by using standard phi-omega scan techniques. The data were scaled\n Growth Inhibition. The cytotoxic effect of [1](ClO4)2 was and reduced using SAINT and XPREP software. The structures were\nevaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium solved by direct methods using XSHELL software, and full-matrix\nbromide (MTT) assay. The cells (3 \u00d7 103 per well of 96-well plate) least-squares with XSHELL software was used for refinement by\nwere seeded 24 h prior to the drug treatment. The cells were treated refining on F2.109 The positions of all of the atoms were obtained by\nwith different concentrations of the compounds (0\u2212100 \u03bcM) for 48 h direct methods. All nonhydrogen atoms were refined anisotropically.\nin triplicate. After 48 h of drug treatment, the MTT solution (20 \u03bcL The remaining hydrogen atoms were placed in geometrically\nof 5 mg/mL stock for each well) was added to the media and the cells constrained positions and refined with isotropic temperature factors,\nwere further allowed to be incubated for 3.5 h in a humid 5% CO2 generally 1.2Ueq of their parent atoms.\nincubator. Then, the media containing the MTT solution was The CCDC number for [1](ClO4)2 is 2237997.\nreplaced by the MTT solvent (iso-propanol, 4 mM HCl, and 0.01%\nTriton X-100) and incubated for 15 min at room temperature,\nfollowed by gentle shaking to ensure the complete dissolution of\nFormazan. Finally, absorbance was measured at 590 nm using a\n \u25a0\n *\n ASSOCIATED CONTENT\n s\u0131 Supporting Information\nThermo Pierce Elisa plate reader. All experiments were carried out for\nat least three biological triplicates. The percentage of viable cells was The Supporting Information is available free of charge at\ncalculated in comparison with the growth of vehicle-treated cells, and https://pubs.acs.org/doi/10.1021/acs.inorgchem.3c00272.\nit was taken as 100%. 1\n H and 13C NMR spectra, computational data, frontier\n Cell Cycle Analysis. Exponentially growing MCF-7 cells were\ntreated with 20 \u03bcM [1](ClO4)2 for 48 h. Similarly, the MDA-MB-231 orbitals energy tables, and FACS data (PDF)\n\n 7009 https://doi.org/10.1021/acs.inorgchem.3c00272\n Inorg. Chem. 2023, 62, 7003\u22127013\n\fInorganic Chemistry pubs.acs.org/IC Article\n\nAccession Codes (7) Edder, C.; Piguet, C.; Bu\u0308nzli, J. C.; Hopfgartner, G. High-Spin\nCCDC 2237997 contains the supplementary crystallographic Iron(II) as a Semitransparent Partner for Tuning Europium(III)\ndata for this paper. These data can be obtained free of charge Luminescence in Heterodimetallic d-f Complexes. Chem. - Eur. J.\nvia www.ccdc.cam.ac.uk/data_request/cif, or by emailing 2001, 7, 3014\u22123024.\ndata_request@ccdc.cam.ac.uk, or by contacting The Cam- (8) Wu, S.-H.; Shao, J.-Y.; Kang, H.-W.; Yao, J.; Zhong, Y.-W.\nbridge Crystallographic Data Centre, 12 Union Road, Substituent and Solvent Effects on the Electrochemical Properties and\n Intervalence Transfer in Asymmetric Mixed-Valent Complexes\nCambridge CB2 1EZ, UK; fax: +44 1223 336033.\n Consisting of Cyclometalated Ruthenium and Ferrocene. Chem. -\n\n\u25a0 AUTHOR INFORMATION\nCorresponding Authors\n Asian J. 2013, 8, 2843\u22122850.\n (9) Sabater, S.; Mata, J. A.; Peris, E. Hydrodefluorination of\n Carbon\u2212Fluorine Bonds by the Synergistic Action of a Ruthenium\u2212\n Manas Kumar Santra \u2212 National Centre for Cell Science, Palladium Catalyst. Nat. Commun. 2013, 4, No. 2553.\n NCCS Complex, Pune University Campus Ganeshkhind, (10) Swindell, E. P.; Hankins, P. L.; Chen, H.; Miodragovic\u0301, \u0110. U.;\n Pune 411007 Maharashtra, India; Email: manas@ O\u2019Halloran, T. V. Anticancer Activity of Small Molecule and\n nccs.res.in Nanoparticulate Arsenic(III) Complexes. Inorg. Chem. 2013, 52,\n Srikanta Patra \u2212 School of Basic Sciences, Indian Institute of 12292\u221212304.\n Technology Bhubaneswar, Jatni 752050 Odisha, India; (11) Ackerman, L. K. G.; Lovell, M. M.; Weix, D. J. Multimetallic\n orcid.org/0000-0002-0611-4047; Email: srikanta@ Catalysed Cross-Coupling of Aryl Bromides with Aryl Triflates.\n iitbbs.ac.in Nature 2015, 524, 454\u2212457.\n (12) Zanardi, A.; Mata, J. A.; Peris, E. Well-Defined Ir/Pd\nAuthors Complexes with a Triazolyl-Diylidene Bridge as Catalysts for Multiple\n Saumyaranjan Mishra \u2212 School of Basic Sciences, Indian Tandem Reactions. J. Am. Chem. Soc. 2009, 131, 14531\u221214537.\n Institute of Technology Bhubaneswar, Jatni 752050 Odisha, (13) Shibasaki, M.; Yamamoto, Y. Multimetallic Catalysts in Organic\n Synthesis; John Wiley & Sons, Wiley-VCH, 2004.\n India\n (14) Buchwalter, P.; Ros\u00e9, J.; Braunstein, P.; Ros\u00e9, J.; Braunstein, P.\n Suman Kumar Tripathy \u2212 School of Basic Sciences, Indian Multimetallic Catalysis Based on Heterometallic Complexes and\n Institute of Technology Bhubaneswar, Jatni 752050 Odisha, Clusters. Chem. Rev. 2015, 115, 28\u2212126.\n India (15) Dehury, N.; Mishra, S. R.; Laha, P.; Patra, S. Tandem \u03b1/\u03b2-\n Debasish Paul \u2212 National Centre for Cell Science, NCCS Alkylation and Transfer Hydrogenation by Heterodimetallic Ruthe-\n Complex, Pune University Campus Ganeshkhind, Pune nium-Iridium Complex. Inorg. Chim. Acta 2020, 511, 119796\u2212\n 411007 Maharashtra, India 119802.\n Paltan Laha \u2212 School of Basic Sciences, Indian Institute of (16) Patra, S.; Maity, N. Recent Advances in (Hetero)Dimetallic\n Technology Bhubaneswar, Jatni 752050 Odisha, India Systems towards Tandem Catalysis. Coord. Chem. 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