Green Light-Triggered Photocatalytic Anticancer Activity of Terpyridine-Based Ru(II) Photocatalysts.

{"full_text": " pubs.acs.org/IC Article\n\n\n\n Green Light-Triggered Photocatalytic Anticancer Activity of\n Terpyridine-Based Ru(II) Photocatalysts\n Arif Ali Mandal, Virendra Singh, Sukanta Saha, Silda Peters, Tumpa Sadhukhan, Rajesh Kushwaha,\n Ashish Kumar Yadav, Apurba Mandal, Aarti Upadhyay, Arpan Bera,* Arnab Dutta, Biplob Koch,*\n and Samya Banerjee*\n Cite This: Inorg. Chem. 2024, 63, 7493\u22127503 Read Online\nSee https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.\n\n\n\n\n ACCESS Metrics & More Article Recommendations *\n s\u0131 Supporting Information\n\n\n ABSTRACT: The relentless increase in drug resistance of platinum-based\n Downloaded via MOSCOW STATE UNIV on May 12, 2026 at 11:22:31 (UTC).\n\n\n\n\n chemotherapeutics has opened the scope for other new cancer therapies with\n novel mechanisms of action (MoA). Recently, photocatalytic cancer therapy, an\n intrusive catalytic treatment, is receiving significant interest due to its\n multitargeting cell death mechanism with high selectivity. Here, we report\n the synthesis and characterization of three photoresponsive Ru(II) complexes,\n viz., [Ru(ph-tpy)(bpy)Cl]PF6 (Ru1), [Ru(ph-tpy)(phen)Cl]PF6 (Ru2), and\n [Ru(ph-tpy)(aip)Cl]PF6 (Ru3), where, ph-tpy = 4\u2032-phenyl-2,2\u2032:6\u2032,2\u2033-terpyr-\n idine, bpy = 2,2\u2032-bipyridine, phen = 1,10-phenanthroline, and aip = 2-\n (anthracen-9-yl)-1H-imidazo[4,5-f ][1,10] phenanthroline, showing photocata-\n lytic anticancer activity. The X-ray crystal structures of Ru1 and Ru2 revealed a\n distorted octahedral geometry with a RuN5Cl core. The complexes showed an\n intense absorption band in the 440\u2212600 nm range corresponding to the metal-\n to-ligand charge transfer (MLCT) that was further used to achieve the green\n light-induced photocatalytic anticancer effect. The mitochondria-targeting photostable complex Ru3 induced phototoxicity with IC50\n and PI values of ca. 0.7 \u03bcM and 88, respectively, under white light irradiation and ca. 1.9 \u03bcM and 35 under green light irradiation\n against HeLa cells. The complexes (Ru1\u2212Ru3) showed negligible dark cytotoxicity toward normal splenocytes (IC50s > 50 \u03bcM).\n The cell death mechanistic study revealed that Ru3 induced ROS-mediated apoptosis in HeLa cells via mitochondrial depolarization\n under white or green light exposure. Interestingly, Ru3 also acted as a highly potent catalyst for NADH photo-oxidation under green\n light. This NADH photo-oxidation process also contributed to the photocytotoxicity of the complexes. Overall, Ru3 presented\n multitargeting synergistic type I and type II photochemotherapeutic effects.\n\n\n \u25a0 INTRODUCTION\n Cancer is one of the major causes of death worldwide (ca. 10\n cell signaling cascades and/or modify gene expression\n regulation, ultimately causing tumor cell damage.17\u221219 This\n M deaths in 2020) and it is badly affecting the global health novel concept, photocatalytic cancer therapy, has shown\n index.1 Primarily, Pt-based anticancer drugs have been promising results in overcoming cisplatin resistance with high\n employed as chemotherapeutics in combating this disease.2\u22125 tumor selectivity both in vivo and in vitro.20 The advantages of\n However, their low tumor selectivity, adverse side effects, and photocatalytic cancer drug development could be (i) low to\n acquired drug resistance have led to new initiatives toward extremely low drug dose, helpful to avoid the toxicity of metal\n developing better chemotherapeutic agents and advanced (in the case of metal-based photocatalytic anticancer agents),\n cancer therapies with reduced side effects, better tumor (ii) selective activation of the drug at the specified tumor site,\n selectivity, and enhanced cytotoxicity.6,7 Recently, a new type helpful to reduce drug\u2019s side effects, and (iii) overcoming\n of photoactivated cancer therapy termed \u201cphotocatalytic current drug resistance issues by multifunctional and multi-\n cancer therapy\u201d has arisen as a potential non-invasive\n targeting anticancer mechanism.21,22\n alternative to the current cancer therapies.8\u221211 In photo-\n catalytic cancer therapy, a photosensitive drug molecule is\n exposed to a certain wavelength of light to induce cytotoxicity Received: February 14, 2024\n via in-cell catalytic reactions and the production of reactive Revised: March 25, 2024\n oxygen species (ROS).12\u221215 The in-cell catalytic reactions Accepted: March 25, 2024\n (such as NADH/NAD(P)H oxidation) and ROS generation Published: April 5, 2024\n are ultimately reported to perturb energy metabolism and\n redox state in cancer cells selectively.10,16 These further disrupt\n\n \u00a9 2024 American Chemical Society https://doi.org/10.1021/acs.inorgchem.4c00650\n 7493 Inorg. Chem. 2024, 63, 7493\u22127503\n\fInorganic Chemistry pubs.acs.org/IC Article\n\n\n\n\nFigure 1. Chemical structures of the Ru(II) photocatalysts Ru1\u2212Ru3.\n\n In metal-based photocatalytic cancer drug development, apoptosis.50 Interestingly, the complex did not inhibit the\nNADH is one of the target molecules for in-cell catalysis, as it growth of tumors in the ectopic tumor models but significantly\nhas been discovered that the NADH coenzyme level in cancer inhibited the growth of tumors in orthotopic tumor models.50\ncells is higher than that of normal cells.23\u221227 NADH is also Recently, Glazer's group developed red light-responsive\nvery crucial for many intracellular biochemical processes such Ru(II)-based photocages with a CYP1B1 (cancer-associated\nas (i) functions of ca. 400 oxidoreductases, (ii) ATP cytochrome P450 enzyme) inhibitor.51 These prodrugs\ngeneration, (iii) maintenance of in-cell redox balance and released cytochrome inhibitors upon exposure to red light\ncellular metabolism, (iv) main electron donor in the (600 nm, 58.7 J/cm2).51 These inhibitors inhibited CYP1B1\nmitochondrial electron transfer chain, etc.26\u221229 Thus, system- with an IC50 of 300 pM.51 Gasser's group reported several\natic oxidation of NADH to NAD+ in cancer cells using a low important Ru(II) polypyridyl complexes as efficient PDT\nnontoxic catalytic amount of the drug can present an agents.52\u221254\nalternative cancer cell death mechanism.8,14 In metal-based Significantly, Ru(II) complexes are being widely used for\nphotocatalytic cancer drug development research, Ir(III) PDT application, but the potential of Ru(II) complexes in in-\nphotocatalysts dominated mostly due to their excited state cell catalysis is not fully realized, such as in the oxidation of\nphotochemistry.30\u221232 In 2019, for the first time, Sadler and co- NADH. Recently, our group and Huang's group showed the\nworkers achieved blue light-triggered in-cell NADH oxidation usefulness of Ru(II) photocatalysts (only 3 reports so far) for\nwith an Ir(III) photocatalyst, which induced immunogenic developing green and red light photocatalytic anticancer\napoptosis in cancer cells by altering the intracellular NAD+/ drugs.13,14 We reported green/red light-responsive Ru(II)\nNADH ratio.21 Subsequently, our group and Huang's group complexes, viz., [Ru(bpy)2(bpy-dph)]Cl2 and [Ru(bnp)(tpy-\nhave reported several other highly efficient green light-active pyren)](PF6)2 (bpy = 2,2\u2032-bipyridine, bpy-dph = 4,4\u2032-\nIr(III)-based photocatalysts for photocatalytic cancer drug diphenyl-2,2\u2032-bipyridine, bnp = 2,6-bis(2-naphthyridyl)-\ndevelopment.10\u221212 Recently, Deng et al. achieved NIR light- pyridine, and tpy-pyren = 4\u2032-(pyren-1-yl)-2,2\u2032:6\u2032,2\u2033-terpyr-\ntriggered anticancer activity in hypoxic tumors with the carbo/ idine), which induced apoptotic cancer cell death through\noxaliplatin derivative of Pt(IV) prodrug by oxidizing NADH.33 NAD(P)H oxidation and diverse ROS generation via\n On the other hand, Ru(II)-based photosensitizers with synergistic type I and type II pathways.13,14 Interestingly,\nattractive photostability, excited state chemistry, and tunable [Ru(bnp)(tpy-pyren)](PF6)2 was found to overcome drug\nphotophysics/photochemistry are widely used in cancer resistance via intracellular glycerophospholipid, lipid, and\nphotodynamic therapy (PDT) research.34\u221247 Ru(II)-based peptide metabolism inhibition as a result of NAD(P)H\nTLD1433 from McFarland's group obtained fast-track photo-oxidation.14 As only three reports are available with\napproval from the FDA as a green light PDT agent for Ru(II) photocatalysts in photocatalytic cancer drug develop-\nbladder cancer.39 Chao et al. developed Ru(II)-based PDT ment research, more investigations with Ru(II) photocatalysts\nagents with biotin as the tumor-targeting group.48 The are needed to decide the fate of photoresponsive Ru(II)\ncomplexes showed excellent phototoxicity (IC50, ca. 3.3 \u03bcM) complexes in photocatalytic cancer therapy. Thus, in this work,\ntoward the cisplatin-resistant A549R cancer cells upon we have developed two green light-responsive Ru(II)\nirradiation of two-photon light (800 nm, 0.27 mW cm\u22122, 80 complexes, viz., [Ru(ph-tpy)(phen)Cl]PF6 (Ru2), [Ru(ph-\nMHz, 100 fs).48 Turro and co-workers showed photoinduced tpy)(aip)Cl]PF6 (Ru3) (Figure 1), as efficient NADH photo-\nphosphine (\u2212PPh3) exchange from Ru(II) polypyridyl oxidation catalysts. The complex [Ru(ph-tpy)(bpy)Cl]PF6\ncomplexes on visible light irradiation, and these complexes (Ru1) was used as a control. The detailed anticancer\nshowed >4\u22126 toxicity against the MDA-MB-231 cells upon investigation with Ru2 and Ru3 revealed that these complexes\nblue light irradiation than dark.49 Bonnet et al. developed a tris- are remarkably phototoxic in green and visible light, which was\nheteroleptic Ru(II) prodrug with 2-methylthiomethylpyridine also supported by the DFT calculation data. The anticancer\n(mtmp).50 This complex cleaved off mtmp after green light activities of these complexes originated from their intracellular\nirradiation (520 nm, 19 J/cm2) and bound to DNA to promote production of ROS and photo-oxidation of NADH.\n 7494 https://doi.org/10.1021/acs.inorgchem.4c00650\n Inorg. Chem. 2024, 63, 7493\u22127503\n\fInorganic Chemistry pubs.acs.org/IC Article\n\n\n\n\nFigure 2. (a) Absorption spectra of complexes (Ru1\u2212Ru3) in DMSO. (b) Emission spectrum of Ru3 in DMSO (\u03bbex: 425 nm). ORTEP diagram of\nthe cationic complex of (c) Ru1 and (d) Ru2 with thermal ellipsoids at a 50% probability level, along with the atom numbering of the heteroatoms\nin [RuN5Cl]PF6. The counter-anion (PF6) and hydrogens are omitted for clarity.\n\n\u25a0 RESULTS AND DISCUSSION\n Synthesis and Characterization. Ru(II) complexes\n and one Cl. Four molecules are present in the one-unit cell of\n both Ru1 and Ru2 (Figure S13 in the Supporting\n(Ru1\u2212Ru3) were synthesized by reacting 1 equiv. of RuCl3\u00b7 Information). The obtained crystal structures of Ru1 and\nxH2O with 1.0 equiv. of phenyl-terpyridine followed by the Ru2 were similar to previously reported Ru(II) complexes with\naddition of 1.0 equiv. of bpy (Ru1)/phen (Ru2)/aip (Ru3) in the same coordination sphere.60,61 The selected bond distances\nethanol. The complexes were isolated as PF6\u2212 salt after adding and bond angles are listed in Table 1. The Ru\u2212Cl bonds\nexcess NH4PF6 (Figure S1). All three Ru(II)-based complexes (2.4008 \u00c5 for Ru1 and 2.4078 \u00c5 for Ru2) were the longest\nwere characterized by elemental analysis, HRMS, 1H NMR, among all of the coordinating bonds, indicating their presence\nUV\u2212vis and fluorescence spectroscopy, FT-IR, and SC-XRD at the axial position. However, the observed Ru\u2212Cl bond\n(for complexes Ru1 and Ru2) (Figures S2\u2212S12). The most\nabundant peak in HRMS corresponded to [M]+ in acetonitrile, Table 1. Selected Bond Distances (\u00c5) and Bond Angles\nconfirming the formation of Ru1\u2212Ru3. In the 1H NMR of (deg) of Complexes Ru1 and Ru2\ncomplexes Ru1\u2212Ru3, the characteristic peaks were obtained in\nthe aromatic region. Interestingly, the N\u2212H peak of the Ru1 Ru2\nimidazole ring of aip (\u03b4 = 14.20 ppm) disappeared upon Ru\u2212Cl 2.4008 (7) 2.4078 (8)\ncoordinating with the Ru(II) center, in line with previous Ru\u2212N1 1.954 (2) 1.950 (2)\nstudies.55,56 An intense metal-to-ligand charge transfer Ru\u2212N2 2.069 (2) 2.064 (2)\n(MLCT) band of Ru1\u2212Ru3 was observed at ca. 440\u2212600 Ru\u2212N3 2.083 (2) 2.092 (2)\nnm in DMSO (Figure 2a).57\u221259 Ru3 showed an additional Ru\u2212N4 2.036 (2) 2.042 (2)\npeak near 380 nm corresponding to aip (anthracene)-based Ru\u2212N5 2.066 (2) 2.065 (2)\n\u03c0\u2212\u03c0* transition.55 The absorption of green light might be Cl\u2212Ru\u2212N1 89.07 (6) 92.02 (7)\nuseful for achieving green light-activated cancer therapy via in- Cl\u2212Ru\u2212N2 91.17 (6) 92.53 (7)\ncell NADH oxidation.10,13 In DMSO solution, Ru3 showed an Cl\u2212Ru\u2212N3 94.99 (6) 92.85 (7)\nemission band near ca. 500 nm upon 425 nm excitation due to Cl\u2212Ru\u2212N4 170.48 (6) 170.97 (7)\nthe presence of the anthracene moiety (Figure 2b). Cl\u2212Ru\u2212N5 88.47 (6) 87.90 (7)\n X-ray Crystallography. The structures of Ru1 and Ru2 N1\u2212Ru\u2212N2 79.75 (9) 80.0 (1)\nwere determined by SC-XRD. Slow evaporation of an N1\u2212Ru\u2212N3 174.65 (9) 173.5 (1)\nacetonitrile\u2212toluene (1:1 (v/v)) solution of the complexes N1\u2212Ru\u2212N4 98.01 (9) 95.8 (1)\nproduced reddish-brown crystals for diffraction. Both com- N1\u2212Ru\u2212N5 79.43 (9) 79.20 (9)\nplexes (Ru1 and Ru2) crystallized in a monoclinic system with N2\u2212Ru\u2212N3 96.64 (8) 95.5 (1)\nthe P121/c space group (Table S1). The ORTEP view of the N2\u2212Ru\u2212N4 96.33 (9) 93.2 (1)\ncomplexes is given in Figure 2c,d. The unit cell packing N2\u2212Ru\u2212N5 159.19 (8) 159.1 (1)\ndiagram of Ru1 and Ru2 is given in Figure S13. The crystal N3\u2212Ru\u2212N4 78.37 (8) 79.7 (1)\nstructures of Ru1 and Ru2 revealed their distorted octahedral N3\u2212Ru\u2212N5 104.12 (8) 105.3 (9)\ngeometry, in which the Ru center was surrounded by five N N4\u2212Ru\u2212N5 86.59 (8) 89.2 (1)\n\n 7495 https://doi.org/10.1021/acs.inorgchem.4c00650\n Inorg. Chem. 2024, 63, 7493\u22127503\n\fInorganic Chemistry pubs.acs.org/IC Article\n\nlengths were slightly less than the previously reported\ncomplexes with similar structures.60,61 The shortest bond\nlength between Ru and the central nitrogen atom of the\nterpyridine ligand (Ru\u2212N1) in both complexes Ru1 (1.954 \u00c5)\nand Ru2 (1.950 \u00c5) is comparable to the previously reported\ncomplexes.60,61 Interestingly, in both complexes, the bond\nlength Ru\u2212N4, i.e., trans to Cl\u2212, is relatively shorter than those\nof other Ru\u2212N bonds (Table 1). The trans bond angles Cl\u2212\nRu\u2212N4 and N1\u2212Ru\u2212N3 in Ru1 and Ru2 are about 10\u00b0\ndistorted from the ideal angle. For the N2\u2212Ru\u2212N5 angle, the\nhighest distortion of around 21\u00b0 was found (159.19\u00b0 and\n159.1\u00b0 for Ru1 and Ru2, respectively), in line with previous\nstudies.60,61\n Solubility, Stability, and Lipophilicity. The solubility of\nthe complexes (Ru1\u2212Ru3) was measured in different solvents.\nComplexes were soluble in nonchlorinated polar solvents like Figure 3. Top, center, and bottom of each image, respectively, display\nacetone, DMF, DMSO, and acetonitrile and partially soluble in the virtual natural transition orbital (NTOv), occupied natural\nmethanol, ethanol, and H2O. The photostability of the transition orbital (NTOo) for S0 \u2192 S1 transition, and optimized\ncomplexes (Ru1\u2212Ru3) was monitored via time-dependent structures of Ru1\u2212Ru3.\nUV\u2212vis studies under white light. Ru1\u2212Ru3 in PBS-DMSO\n(99:1 v/v) showed no marked changes in spectra and Ru1 and Ru2, SOMO and SOMO-1 are predominantly\nabsorbance (Figure S14), revealing that these complexes localized on the metal center and the N,N,N-donor ligand,\nmight be used as stable photocatalysts. To assess the whereas for Ru3, SOMO is located on Ru and N,N,N-donor\nlipophilicities of the complexes, their partition coefficients ligand and SOMO-1 on anthracene (Figure S17). The spin\n(log Po/w) were determined in octanol and water. The log Po/w density plots also reveal that spin is localized on Ru and the\nparameter reflects the distribution of the complex between N,N,N-donor ligand (Figure S18). The calculated lowest triplet\nwater and octanol, providing insights into the potential cellular energies for Ru1, Ru2, and Ru3 are 2.23, 1.91, and 1.96 eV\nuptake through passive diffusion.62\u221264 A positive log Po/w value respectively, which are higher than that for 3O2 (0.98 eV),\nindicates a preference for the octanol layer, while a negative suggesting that these complexes can generate singlet oxygen\nvalue suggests a preference for water.62\u221265 The log Po/w values (Table S3).\nfor the complexes Ru1, Ru2, and Ru3 were 1.25, 1.47, and Green Light-Induced Photocatalytic Oxidation of\n2.31, respectively (Figure S15). The log Po/w values increased NADH. NADH, a crucial molecule for cellular redox balance\nfrom Ru1 to Ru3, aligning with the enlargement of the maintenance, serves as an electron carrier and coenzyme in\nlipophilic moiety in the bidentate N,N-ligand. Considering the several metabolic pathways.23\u221227 Its pivotal involvement in\nestablished correlation between cellular uptake, lipophilicity, electron transfer, energy production, and enzyme regulation\nand cytotoxicity,65,66 it is plausible to anticipate that Ru3 could makes it necessary for the normal functioning of cells and\nshow the highest cellular uptake and phototoxicity within the overall cellular health.23\u221227 Any unnatural alteration in the\nseries. intracellular NADH concentration can disrupt the mitochon-\n DFT Calculation. The DFT calculations were performed drial ETC, intracellular redox harmony, and energy production,\nfor Ru1\u2212Ru3 to understand their electronic structure and ultimately leading to cell death.23\u221227 This concept has been\nphotophysical properties. To optimize the structure, the used by Sadler and co-workers to achieve light-triggered\n\u03c9B97X-D function was applied with the def2-SVP basis set anticancer activity with an Ir(III) complex.21 Further, Huang's\nfor all atoms in water using the CPCM implicit solvation group and our group generalized this concept with both Ir(III)\nmodel.67 The optimized structures of Ru1\u2212Ru3 indicated that and Ru(II) complexes to produce synergistic oxygen-based\nthe Ru(II) center is coordinated with N,N,N-donor and N,N- ROS generation and NADH oxidation to obtain light-triggered\ndonor ligands and one Cl atom in a distorted octahedral anticancer effects against different cancer cell lines.10\u221214\nmanner with a RuIIN5Cl coordination core, similar to the Henceforth, the NADH photo-oxidation ability of Ru1\u2212Ru3\ncrystal structure of the complexes (Figure 3). The frontier was investigated using UV\u2212vis spectroscopy by monitoring the\nmolecular orbitals (FMOs) of Ru1\u2212Ru3 revealed that the intensity of the NADH characteristic band at 339 nm and the\nhighest occupied molecular orbital (HOMO) is distributed NAD+ characteristic band at 259 nm in a PBS-DMSO (99:1 v/\npartially on the Ru center and, to some extent, the N,N-donor v) solution.13,14,68 Ru1\u2212Ru3 (10 \u03bcM) did not show any\nmoiety (Figure S16). The lowest unoccupied molecular orbital changes in the absorption spectra of NADH (240 \u03bcM) in the\n(LUMO) resides on the N,N,N-donor phenyl terpyridine dark (Figure S19b\u2212d in the Supporting Information). Upon\nmoiety for all complexes. Further, we have calculated the green light (525 nm, 50.2 J cm\u22122) irradiation, Ru2 and Ru3\nabsorption and emission energies at the TD-\u03c9B97X-D/ decreased the characteristic absorbance of NADH significantly\ndef2TZVP level of theory in water. The lowest S0 \u2192 S1 and simultaneously increased the absorbance of the NAD+\ntransition energy is \u223c2.5 eV (Table S2) for these complexes, characteristic band (Figure 4a,b). Ru1 on green light exposure\nand natural transition orbital (NTO) plots (Figure 3) show caused NADH oxidation but with low turnover frequency\n1\n MLCT from Ru to the N,N,N-donor ligand. Next, we have (TOF) (ca. 10.9 h\u22121) (Figure S19a in the Supporting\noptimized the triplet states of these complexes using the Information). This result indicated the photo-oxidation of\nU\u03c9B97X-D/def2-SVP level of theory and determined the NADH by Ru2 and Ru3 upon green light exposure. Ru2\nsinglet\u2212triplet energy gap (\u0394ES\u2011T), spin density plots, and oxidized NADH with a turnover frequency (TOF) of ca. 55.5\nSOMO plots at the U\u03c9B97X-D/def2-SVP level of theory. For h\u22121. The TOF of Ru3 was ca. 118.2 h\u22121, the most potent\n 7496 https://doi.org/10.1021/acs.inorgchem.4c00650\n Inorg. Chem. 2024, 63, 7493\u22127503\n\fInorganic Chemistry pubs.acs.org/IC Article\n\n\n\n\nFigure 4. Photocatalytic oxidation of NADH (240 \u03bcM) by Ru2 (10 \u03bcM) (a) and Ru3 (6 \u03bcM) (b) in a PBS-DMSO (99:1 v/v) (pH = 7.4) solution\n(light source: 525 nm, 50.2 J cm\u22122). (c) Detection of H2O2 generation by Ru3 (6 \u03bcM) during NADH (240 \u03bcM) oxidation under dark (D) and\nlight irradiation (L) in a DMSO-PBS (99:1 v/v) solution (light source: 525 nm, 50.2 J cm\u22122).\n\nNADH photocatalyst among these complexes. The better (IC50 > 50 \u03bcM) (Table 3 and Figure S21). In the dark, Ru1\u2212\nNADH photo-oxidation ability of Ru3 might be due to its low Ru3 did not show any significant cytotoxicity (IC50 > 60 \u03bcM)\n\u0394Eg value. Importantly, Ru3 was a better photocatalyst than toward HeLa cells (Table 3 and Figure S22). However, upon\nthe first reported Ir(III)-based NADH oxidation photo- white light (400\u2212700 nm, 5.0 J cm\u22122) exposure, the\ncatalyst.21 Ru3 also showed equivalent or better NADH cytotoxicity of Ru1\u2212Ru3 was enhanced significantly (Table\noxidation TOF than other reported Ru(II)/Ir(III)-based 3 and Figure S23). Among the complexes, Ru3 (IC50 = 0.75 \u00b1\nphotocatalysts (Table S4). Overall, the observed excellent 0.12 \u03bcM) showed better activity as compared to Ru1 (IC50 =\nNADH photo-oxidation ability of Ru3 might contribute to its 6.84 \u00b1 0.21 \u03bcM) and Ru2 (IC50 > 10 \u03bcM) against HeLa cells.\nphototoxicity via in-cell NADH oxidation.13,14 Furthermore, A similar trend of photocytotoxicity was observed under green\nupon green light irradiation (light source: 525 nm, 50.2 J light (IC50: Ru3 = 1.9 \u00b1 0.2 \u03bcM; Ru1 = 8.4 \u00b1 5.0 \u03bcM; Ru2 \u2265\ncm\u22122), Ru3 generates H2O2 in the presence of NADH (Figure 10 \u03bcM) (Figure S24). The high anticancer effect of Ru3 might\n4c). This indicates that molecular O2 is involved in the be due to its higher cellular uptake and the presence of\ncatalytic process, like the Ir(III) photocatalysts reported in the photoresponsive aip ligand with much higher \u03c0-conjugation.\nliterature.10\u221212,21 O2 is probably involved in the regeneration Previous reports have shown that the presence of an imidazole\nof the Ru(II) active catalyst.13\u221215 ring in aip causes cell cycle arrest and subsequently induces\n Cellular Uptake. The adequate internalization of any drug apoptosis against cancer cells.74,75 Also, Chao et al. reported\ncandidate is a crucial factor for high therapeutic value.69\u221271 the dark toxicity of [Ru(ph-tpy)(bpy)Cl]ClO4 on 48 h of\nHigh in-cell uptake of cancer therapeutic agents is reported to incubation against HeLa cells.76 It showed an IC50 of ca. 51.4\nenhance their anticancer potential.69\u221271 Uptake studies were \u03bcM under those conditions.76 With respect to our previous\nconducted by quantifying the cellular ruthenium content using work, Ru3 showed better activity than [Ru(bpy)2(bpy-\ninductively coupled plasma mass spectrometry (ICP-MS) in dph)]Cl2 (IC50 = 0.3 \u03bcM).13 Ru3 showed similar or better\nHeLa cells (Figure S20 in the Supporting Information). anticancer responses than some of the previously reported\nFollowing 6 h of incubation with the Ru1\u2212Ru3 complexes (10 Ru(II)-based phototherapeutic agents with similar structures in\n\u03bcM) in the dark, the cells were lysed and processed in a 2% HeLa cells (Table 2).10,46,77\u221280 For example, [Ru(bpy)(dppn)-\nHNO3 solution. Table 2 reveals that Ru3 exhibited the highest (phpy)]PF6 gave an IC50 value of 7 \u03bcM in HeLa cells, but in\n the dark.77 [Ru(dppz-X2)3](PF6)2 (X = H and F) showed no\nTable 2. Intracellular Ru Content for Ru1\u2212Ru3 after 6 h of toxicity in the dark, but upon light irradiation (light source:\nIncubation with HeLa Cells 9.27 J cm\u22122), it showed IC50 values of ca. 2 and 5.5 \u03bcM,\n complex Ru content in whole cell lysate (ng/106 cells) respectively.78 [Ru(bipy)2dppz-7-acetoxy](PF6)2 showed no\n Ru1 52.4 \u00b1 2.2\n dark toxicity (>100 \u03bcM) but showed IC50 of ca. 9.0 and 5.5\n Ru2 58.7 \u00b1 3.1\n \u03bcM on changing light dose from 2.58 to 9.27 J cm\u22122,\n Ru3 80.2 \u00b1 4.7\n respectively.46 [Ru(dqpCO2Me)(ptpy)](PF6)2 showed no\n dark toxicity (>100 \u03bcM) toward HeLa cells even after 48 h\n of incubation, but on treatment of light (6.95 J cm\u22122), it\ninternalization, with a Ru content of 80.2 \u00b1 4.7 ng/106 cells, showed moderate toxicity (IC50 = 25.3 \u00b1 4.7 \u03bcM).).79 Besides\nfollowed by Ru2 (58.7 \u00b1 3.1 ng/106 cells) and Ru1 (52.4 \u00b1 that, IC50 values of Ru1\u2212Ru3 are much better than those of\n2.2 ng/106 cells). These results align with the log Po/w values of the clinically used photosensitizer 5-ALA (151.1 \u03bcM) and\nthe complexes. The highest intracellular uptake of Ru3 is cisplatin (25.3 \u03bcM) upon green light irradiation (29.56 J\ncertainly due to its higher lipophilicity.62,72,73 Thus, Ru3 might cm\u22122). The choice of light in PACT plays a vital role in\nact as a much better photocytotoxic agent. achieving anticancer activity.10\n Cytotoxicity Studies. The sufficient cellular uptake of ROS Generation. ROS are naturally formed as byproducts\nRu1\u2212Ru3 encouraged us to evaluate their cytotoxicity against of cellular metabolism in various physiological processes in the\nthe HeLa cancer cell line and normal splenocyte in both the human body.80,81 However, increased ROS levels can cause\ndark and white/green light by MTT assay.69 Ru1\u2212Ru3 oxidative stress or inflammation and damage cells and cellular\nshowed no notable dark toxicity toward the normal cells components.80 Therefore, in photoactivated cancer therapy,\n 7497 https://doi.org/10.1021/acs.inorgchem.4c00650\n Inorg. Chem. 2024, 63, 7493\u22127503\n\fInorganic Chemistry pubs.acs.org/IC Article\n\nTable 3. IC50 (\u03bcM) Values of Ru1\u2212Ru3 and Some Ru(II)-Based Complexes against HeLa Cells in the Dark and upon Light\nIrradiation\n HeLa splenocytes\n light (wavelength) (nm)\n complex dark 400\u2212700 525 350 420 PI (400\u2212700 nm) PI (525 nm) dark\n a\n Ru1 94.2 \u00b1 2.8 6.8 \u00b1 0.2 8.5 \u00b1 5.0 13.77 11.11 55.6 \u00b1 1.3\n Ru2a 95.5 \u00b1 2 >10 >10 NA NA 79 \u00b1 3\n Ru3a 66.2 \u00b1 2 0.75 \u00b1 0.12 1.9 \u00b1 0.2 88.37 34.52 75.7 \u00b1 2.2\n [Ru(ph-tpy)(bpy)Cl]ClO4b 51.4\n [Ru(bpy)2(bpy-dph)]Cl2c 140.7 0.3 469\n [Ru(bpy)(dppn)(phpy)]PF6d 7\n [Ru(dppz-H2)3](PF6)2e >100 2\n [Ru(dppz-F2)3](PF6)2e >100 5.5\n [Ru(bipy)2dppz-7-acetoxy](PF6)2f >100 9 5.5\n [Ru(dqpCO2Me)(ptpy)](PF6)2g >100 25.3 \u00b1 4.7\n cisplatinh 16.5 25.3\n 5-ALAh >10000 151.1 6.6\na\n White light irradiation; light treatment: incubation time of 6 h, total irradiation = 5.0 J cm\u22122 over 30 min. Recovery time of 18 h. Green light\nirradiation; light treatment: incubation time of 6 h, total irradiation = 50.2 J cm\u22122 over 30 min. Recovery time of 18 h. Dark treatment: incubation\ntime of 6 h, recovery time of 18 h. bDark treatment: incubation time of 48 h (from ref 76). cGreen light irradiation (525 nm, 29.56 J cm\u22122). Light\ntreatment: incubation time of 8 h, total irradiation = 29.56 J cm\u22122. Recovery time of 40 h. Dark treatment: incubation time of 8 h, recovery time of\n40 h (from ref 13). dDark treatment: incubation time of 2 h, recovery time of 24 h (from ref 77). eDark treatment: incubation time of 48 h, light\nirradiation (420 nm, 9.27 J cm\u22122). Light treatment: incubation time of 4 h, total irradiation = 9.26 J cm\u22122 over 20 min. Recovery time of 44 h (from\nref 78). fDark treatment: incubation time of 48 h, light irradiation (350 nm, 2.58 J cm\u22122). Light treatment: incubation time of 4 h, total irradiation =\n2.58 J cm\u22122 over 10 min. Recovery time of 44 h. Light irradiation (420 nm, 9.27 J cm\u22122). Light treatment: incubation time of 4 h, total irradiation =\n9.27 J cm\u22122 over 20 min. Recovery time of 44 h (from ref 46). gLight irradiation (420 nm, 6.95 J cm\u22122). Light treatment: incubation time of 4 h,\ntotal irradiation = 6.95 J cm\u22122 over 30 min. Recovery time of 44 h. Dark treatment: incubation time of 4, 48 h, recovery time of 44 h (from ref 79).\nh\n Green light irradiation (525 nm, 29.56 J cm\u22122). Light treatment: incubation time of 8 h, light irradiation = 29.56 J cm\u22122. Recovery time of 40 h.\nDark treatment: incubation time of 8 h, recovery time of 40 h (from ref 10).\n\n\n\n\nFigure 5. (a) Time-dependent decrease in the absorbance of DPA, indicating 1O2 generation by Ru3 (10 \u03bcM) in a PBS-DMSO (99:1 v/v) solution\nupon green light irradiation. (b) Time-dependent degradation of MB, indicating OH\u2022 generation by Ru3 (10 \u03bcM) in a PBS-DMSO (99:1 v/v)\nsolution on green light irradiation (light source: 525 nm, 50.2 J cm\u22122). (c) In-cell ROS generation by Ru3 + dark, Ru3 + white light (400\u2212700 nm,\n5.0 J cm\u22122), and Ru3 + green light (light source: 525 nm, 50.2 J cm\u22122) in HeLa cells after 30 min of incubation. Scale bar: 400 \u03bcm.\n\ncontrolled ROS generation has been used to selectively destroy proteins, and cell membranes, ultimately triggering apoptosis\ncancer cells while sparing healthy ones.81 ROS are reported to or necrosis.80\u221282 In photocatalytic cancer therapy, the\ndamage cancer cells by primarily damaging their DNA, photoresponsive metal complexes are reported to produce\n 7498 https://doi.org/10.1021/acs.inorgchem.4c00650\n Inorg. Chem. 2024, 63, 7493\u22127503\n\fInorganic Chemistry pubs.acs.org/IC Article\n\n\n\n\nFigure 6. Confocal images of HeLa cells incubated with Ru3 (15 \u03bcM), the nucleus-specific blue-emitting dye Hoechst, and MitoTracker Red\n(MTR). Panel (i) shows blue emission of nucleus staining dye Hoechst (\u03bbex \u223c 405 nm and \u03bbem \u223c 460 nm), panel (ii) shows red emission of MTR\n(\u03bbex \u223c 630 nm and \u03bbem \u223c 650 nm), panel (iii) shows green emission of Ru3 (\u03bbex \u223c 488 nm and \u03bbem \u223c 500 nm), panel (iv) shows a bright field\nimage, and panel (v) shows a merged image. Scale bars, 10 \u03bcm.\n\nH2O2, OH\u2022, and O2\u2022\u2212 (as the byproducts of NADH oxidation) for cellular imaging (Figure 6). The merged image, combining\nin addition to 1O2 (via a type II energy transfer pathway).8\u221214 nuclear staining with Hoechst dye (blue fluorescent) and\nThe encouraging photophysical properties, DFT calculation complex-based green emission, indicated cytosolic localization.\ndata, and enhanced light-triggered cytotoxicity indicated that Furthermore, the merged image with MitoTracker Red (MTR,\nRu1\u2212Ru3 could have a notable ROS generation tendency. To red fluorescent) suggested the localization of Ru3 in\nexamine the 1O2 production efficiency of Ru1\u2212Ru3, 9,10- mitochondria, with a Pearson correlation coefficient (PCC)\ndiphenyl anthracene (DPA) has been used. In the dark, Ru1\u2212 of 0.74 (Figure 6).\nRu3 (10 \u03bcM) did not cause any notable change in DPA-based For the adenosine triphosphate (ATP) biosynthesis,\nabsorbance, indicating inefficiency in 1O2 generation without required for cell survival and growth, mitochondria are\nlight. However, Ru1\u2212Ru3 efficiently generated 1O2 upon essential. 85 Overload of ROS is reported to damage\ngreen light exposure (Figure 5a and Figure S25a,b in the mitochondria via oxidative stress.86 The alteration of\nSupporting Information). Ru3 emerged as a more potent 1O2 mitochondrial membrane potential (\u0394\u03a8m) indicates mito-\ngenerator than Ru1 and Ru2, as demonstrated by a notable chondrial dysfunction and damage.86 As Ru3 produced in-cell\ndecrease in the DPA-based absorption bands. This observation ROS on light activation, here, the alteration of \u0394\u03a8m was\nindicates that the high photocytotoxicity of Ru3 partially can visualized by JC-1 assay using fluorescence microscopy.86 JC-1\nbe due to light-induced high amounts of 1O2 generation. dye produces red fluorescence when internalized within the\nFurthermore, the OH\u2022 generation tendency of Ru1\u2212Ru3 was mitochondria at high membrane potential (\u0394\u03a8m), whereas at\ndetermined with methylene blue (MB), an OH\u2022 probe. A low membrane potential, JC-1 becomes green fluorescent.87 As\nsimilar trend of activity was obtained for OH\u2022 generation by shown in Figure 7, in the dark, Ru3 could not change the\nRu1\u2212Ru3 (Figure 5b and Figure S25c in the Supporting\nInformation) in the presence of NADH. The OH\u2022 generated\ndue to the homolysis of H2O2 formed during the photo-\noxidation of NADH (as discussed above). All of these data\nindicated that Ru3 is an efficient type-I and type-II PS.\n Furthermore, the in-cell ROS generation by Ru3 was\nvisualized by DCFDA assay in HeLa cells using fluorescence\nmicroscopy.80\u221282 The nonfluorescent ROS marker 2\u2032,7\u2032-\ndichlorofluorescin diacetate (DCFH-DA) converts to highly\ngreen fluorescent 2\u2032,7\u2032-dichlorofluorescin (DCF) by the\nintracellular ROS.80\u221282 As shown in Figure 5c, Ru3 generated\nsignificant ROS at its IC50 concentrations only after light Figure 7. Visualization of the mitochondrial membrane potential\n change by Ru3 + light via the JC-1 assay. Incubation of Ru3 with\n(white or green) exposure, being inactive under dark HeLa cells for 4 h at IC50 concentration was followed by 20 min white\nconditions, revealing that the remarkable phototoxicity of light (400\u2212700 nm, 5.0 J cm\u22122) or green light (525 nm, 50.2 J cm\u22122)\nRu3 is also due to its highly efficient in-cell ROS generation irradiation. Scale bars, 100 \u03bcm.\n(in addition to NADH oxidation). A similar ROS-mediated\nanticancer mechanism was also observed with the other\nRu(II)-based photosensitizers like [Ru(tpy)(N,N)(py)](PF6)2 \u0394\u03a8m, as indicated by the red fluorescence from JC-1, the same\n(where, N,N = 2,2\u2032-bipyridine, 6,6\u2032-dimethyl-2,2\u2032-bipyridine, as the control. In contrast, in the cells with Ru3 + light\nbenzo[i]-dipyrido[3,2-a:2\u2032,3\u2032-c]phenazine, and 3,6-dimethyl- treatment, J-monomer-based green fluorescence was observed\nbenzo [i]dipyrido [3,2-a:2\u2032,3\u2032-c]phenazine) and chiral [Ru- (Figure 7), indicating a change in \u0394\u03a8m. Overall, the above\n(Ph2phen)2(\u03baS,\u03baN-(Ac-RGDH-NH2))]Cl2 (where Ph2phen = results indicate that Ru3 selectively changes the \u0394\u03a8m only\n4,7-diphenyl-1,10-phenanthroline).34\u221247,83,84 after light activation. This change in \u0394\u03a8m could be a signature\n Cellular Localization, Mitochondrial Dysfunction, and of cellular apoptosis through mitochondrial pathways.85\u221287\nCellular Apoptosis. The luminescence characteristics of the The excellent light-activated cytotoxic effects of Ru3 and the\ncomplexes serve as an important tool for monitoring their change in \u0394\u03a8m by Ru3 + light pushed us to study the\nintracellular distribution.13,47,66 The green emission from Ru3 underlying cell death mechanism induced by Ru3 in the\n(on 488 nm laser excitation), in HeLa cells, affirms its potential presence of light in HeLa cells. The changes in nuclear\n 7499 https://doi.org/10.1021/acs.inorgchem.4c00650\n Inorg. Chem. 2024, 63, 7493\u22127503\n\fInorganic Chemistry pubs.acs.org/IC Article\n\nmorphology were examined using Hoechst/PI dual staining at outcome of the synergism between its NADH oxidation\nthe IC50 concentration of Ru3 to determine the mode of cell capacity and ROS generation ability. The apoptotic cell death\ndeath. Nuclei of both live and apoptotic cells can be stained was initially started from the depolarization of mitochondria\nwith Hoechst 33342 dye. When Hoechst 33342 binds to the upon light irradiation. Overall, this study is a timely\nnuclei of living cells, it is reported to emit a light blue contribution to the progress of photocatalytic cancer drug\nfluorescence, whereas on binding to the apoptotic cells\u2019 nuclei, development research. Moreover, this study also indicates that\nit is known to produce bright blue fluorescence. PI can only Ru(II)-based photocatalysts have a future as multifunctional\nstain the nuclei of cells with compromised nuclear membranes photocatalytic anticancer agents.\nand emits red fluorescence.85\u221287 The result shown in Figure\nS26 revealed that Ru3 did not show any cell death in the dark\ncondition but produced apoptotic cell death responses\n \u25a0\n *\n ASSOCIATED CONTENT\n s\u0131 Supporting Information\n(evident from round stressed cells, loss of cellular networks,\nbright condensed nuclei, and staining of the nuclei by PI) in The Supporting Information is available free of charge at\nthe presence of both green light and white light (Figure 8 and https://pubs.acs.org/doi/10.1021/acs.inorgchem.4c00650.\n Tables for crystallographic data, FMO energies, singlet\u2212\n singlet transition energies, and adiabatic singlet\u2212triplet\n splitting energies; figures for characterization data (1H\n and 13C NMR, FT-IR, and HRMS), unit cell packing,\n photostability, partition coefficients, FMOs, SOMOs,\n isosurfaces of the spin density at triplet, NADH\n oxidation, ICP-MS standard calibration, cell viability\n from MTT assay, 1O2 and OH\u2022 generation, and confocal\n images for the cell death mechanism (PDF)\n\nFigure 8. Green light-triggered apoptosis of HeLa cells induced by Accession Codes\nRu3 (750 nM) costained with Hoechst and PI. Scale bars, 100 \u03bcm. CCDC 2300105 and 2300106 contain the supplementary\n crystallographic data for this paper. These data can be obtained\nFigure S27). Henceforth, from the above observations, it can free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by\nbe concluded that Ru3 + light treatment promotes apoptosis in emailing data_request@ccdc.cam.ac.uk, or by contacting The\nHeLa cells via ROS production and NADH photo-oxidation Cambridge Crystallographic Data Centre, 12 Union Road,\nthrough a change in the \u0394\u03a8m. Cambridge CB2 1EZ, UK; fax: +44 1223 336033.\n\n\u25a0 CONCLUSIONS\nIn this work, we have synthesized, characterized, and evaluated\n \u25a0 AUTHOR INFORMATION\n Corresponding Authors\nthe visible and green light-activated detailed anticancer Arpan Bera \u2212 Department of Inorganic and Physical\nactivities of three terpyridine-based Ru(II) photocatalysts Chemistry, Indian Institute of Science, Bangalore 560012,\n(Ru1\u2212Ru3). The distorted octahedral geometry with a India; Email: arpanbera@iisc.ac.in\nRuN5Cl core of the complexes was evident from the single- Biplob Koch \u2212 Department of Zoology, Institute of Science,\ncrystal structures of complexes Ru1 and Ru2. The photostable Banaras Hindu University, Varanasi, Uttar Pradesh 221005,\ncomplexes showed an MLCT band at ca. 440\u2212600 nm, which India; Email: biplob@bhu.ac.in\nwas very useful for the green-light NADH oxidation photo- Samya Banerjee \u2212 Department of Chemistry, Indian Institute\ncatalytic and photosensitizing activities (for ROS generation) of Technology (BHU), Varanasi, Uttar Pradesh 221005,\nof the complexes in an aqueous solution. Ru2 and Ru3 worked India; orcid.org/0000-0003-4393-4447;\nas efficient photocatalysts for NADH oxidation in an aqueous Email: samya.chy@itbhu.ac.in\nmedium under green light exposure. The TOF of Ru3 was\nmuch higher than [Ir(ttpy)(pq)Cl]PF6.21 Moreover, the Authors\nefficiency of Ru3 for the photocatalytic NADH oxidation Arif Ali Mandal \u2212 Department of Chemistry, Indian Institute\nwas in the range of the most potent Ru(II)-based catalysts of Technology (BHU), Varanasi, Uttar Pradesh 221005,\nreported so far.13\u221215 In the process of catalysis, molecular O2 India\nwas converted to H2O2 via a type-I pathway. Ru2 and Ru3 also Virendra Singh \u2212 Department of Zoology, Institute of Science,\nbehaved as good green light photosensitizers to produce 1O2 Banaras Hindu University, Varanasi, Uttar Pradesh 221005,\nvia the type-II pathway. Ru3 also showed a higher intracellular India\nuptake than Ru1 and Ru2. The efficient intracellular uptake, Sukanta Saha \u2212 Department of Chemistry, Indian Institute of\ngood NADH oxidation, and ROS generation power of Ru3 Technology Bombay, Mumbai, Maharashtra 400076, India\nwithin mitochondria made it an excellent green light anticancer Silda Peters \u2212 Departmentof Chemistry, SRM Institute of\nagent. Ru1\u2212Ru3 did not show any significant toxic effect Science and Technology, Kattankulathur, Tamil Nadu\ntoward normal splenocytes and HeLa cancer cells under dark 603203, India\nconditions but showed remarkable nanomolar apoptotic Tumpa Sadhukhan \u2212 Departmentof Chemistry, SRM Institute\ntoxicity upon irradiation of visible light or green light. Ru3 of Science and Technology, Kattankulathur, Tamil Nadu\nhas good PI values of ca. 88 and 34, respectively, upon white 603203, India; orcid.org/0000-0003-1995-7286\nlight or green light irradiation, which clearly indicates its Rajesh Kushwaha \u2212 Department of Chemistry, Indian\nselective anticancer activity upon light exposure. The green Institute of Technology (BHU), Varanasi, Uttar Pradesh\nlight-activated apoptotic antitumor activity of Ru3 was the 221005, India\n 7500 https://doi.org/10.1021/acs.inorgchem.4c00650\n Inorg. Chem. 2024, 63, 7493\u22127503\n\fInorganic Chemistry pubs.acs.org/IC Article\n\n Ashish Kumar Yadav \u2212 Department of Chemistry, Indian (7) Wang, X.; Wang, X.; Jin, S.; Muhammad, N.; Guo, Z. Stimuli-\n Institute of Technology (BHU), Varanasi, Uttar Pradesh Responsive Therapeutic Metallodrugs. Chem. Rev. 2019, 119, 1138\u2212\n 221005, India 1192.\n Apurba Mandal \u2212 Department of Chemistry, Indian Institute (8) Liu, Z.; Sadler, P. J. Organoiridium Complexes: Anticancer\n Agents and Catalysts. Acc. Chem. Res. 2014, 47, 1174\u22121185.\n of Technology (BHU), Varanasi, Uttar Pradesh 221005,\n (9) Zhu, Z.; Wei, L.; Yadav, A. K.; Fan, Z.; Kumar, A.; Miao, M.;\n India Banerjee, S.; Huang, H. Cyanine-Functionalized 2,2\u2032-Bipyridine\n Aarti Upadhyay \u2212 Department of Inorganic and Physical Compounds for Photocatalytic Cancer Therapy. J. Org. Chem. 2023,\n Chemistry, Indian Institute of Science, Bangalore 560012, 88, 626\u2212631.\n India (10) Fan, Z.; Rong, Y.; Sadhukhan, T.; Liang, S.; Li, W.; Yuan, Z.;\n Arnab Dutta \u2212 Department of Chemistry, Indian Institute of Zhu, Z.; Guo, S.; Ji, S.; Wang, J.; Kushwaha, R.; Banerjee, S.;\n Technology Bombay, Mumbai, Maharashtra 400076, India; Raghavachari, K.; Huang, H. Single-Cell Quantification of a Highly\n orcid.org/0000-0002-9998-6329 Biocompatible Dinuclear Iridium(III) Complex for Photocatalytic\n Cancer Therapy. Angew. Chem., Int. Ed. 2022, 134, No. e202202098.\nComplete contact information is available at: (11) Zhu, Z.; Wei, L.; Lai, Y.; Carter, O. W. L.; Banerjee, S.; Sadler,\nhttps://pubs.acs.org/10.1021/acs.inorgchem.4c00650 P. J.; Huang, H. Photocatalytic glucose-appended bio-compatible\n Ir(III) anticancer complexes. Dalton Trans. 2022, 51, 10875\u221210879.\nAuthor Contributions (12) Wei, L.; Kushwaha, R.; Dao, A.; Fan, Z.; Banerjee, S.; Huang,\nS.B. and A.A.M. designed the studies and formulated the H. Axisymmetric bis-tridentate Ir(III) photoredox catalysts for\nconcept and overall project. A.A.M., A.K.Y., and A.M. anticancer phototherapy under hypoxia. Chem. Commun. 2023, 59,\nsynthesized, characterized, and crystallized the complexes. 3083\u22123086.\n (13) Fan, Z.; Xie, J.; Kushwaha, R.; Liang, S.; Li, W.; Mandal, A. A.;\nA.A.M. did all the in-solution chemistry. R.K., S.P., and T.S. Wei, L.; Banerjee, S.; Huang, H. Anticancer Screening of Ru(II)\nperformed the DFT calculation. S.S. and A.D. performed the Photoredox Catalysts at Single Cancer Cell Level. Chem.\ufffdAsian J.\nSC-XRD measurements. V.S., B.K., A.B., and A.U. performed 2023, 18, No. e202300047.\nall the biological studies. The manuscript was written through (14) Wei, S.; Liang, H.; Dao, A.; Xie, Y.; Cao, F.; Ren, Q.; Yadav, A.\nthe contributions of all authors. All authors have approved for K.; Kushwaha, R.; Mandal, A. A.; Banerjee, S.; Zhang, P.; Ji, S.;\nthe final version of the manuscript. Huang, H. Perturbing tumor cell metabolism with a Ru(II) photo-\n redox catalyst to reverse the multidrug resistance of lung cancer. Sci.\nNotes China Chem. 2023, 66, 1482\u22121488.\nThe authors declare no competing financial interest. (15) Dao, A.; Wu, H.; Wei, S.; Huang, H. Novel Ru(II) complexes\n with multiple anticancer photoreactivity: ligand exchange, photoredox\n\u25a0 ACKNOWLEDGMENTS\nWe thank SERB (SRG/2022/000030), the Government of\n catalysis, reactive oxygen generation and endoperoxide formation.\n Phys. Chem. Chem. Phys. 2023, 25, 20001\u221220008.\n (16) Dharmaraja, A. T. Role of Reactive Oxygen Species (ROS) in\nIndia, for financial support. B.K. acknowledges Banaras Hindu Therapeutics and Drug Resistance in Cancer and Bacteria. J. Med.\nUniversity, India, for providing fund under the IoE scheme Chem. 2017, 60, 3221\u22123240.\n(file no. R/Dev/D/IoE/Incentive/2021-22/32449). A.A.M., (17) Jin, Z.; El-Deiry, W. S. Overview of cell death signaling\nR.K., A.M., and A.K.Y thank the Ministry of Education, the pathways. Cancer Biol. Ther. 2005, 4, 147\u2212171.\n (18) Matthews, H. K.; Bertoli, C.; de Bruin, R. A. M. Cell cycle\nGovernment of India, for the Prime Minister\u2019s Research\n control in cancer. Nat. Rev. Mol. Cell Biol. 2022, 23, 74\u221288.\nFellowship. We sincerely thank Ashish Kumar Maurya for his (19) Banerjee, S.; Chakravarty, A. R. Metal Complexes of Curcumin\nsupport during this work. for Cellular Imaging, Targeting, and Photo-induced Anticancer\n Activity. Acc. Chem. Res. 2015, 48, 2075\u22122083.\n\u25a0 REFERENCES\n (1) Sung, H.; Ferlay, J.; Siegel, R. L.; Laversanne, M.;\n (20) Huang, C.; Liang, C.; Sadhukhan, T.; Banerjee, S.; Fan, Z.; Li,\n T.; Zhu, Z.; Zhang, P.; Raghavachari, K.; Huang, H. In-vitro and In-\n vivo Photocatalytic Cancer Therapy with Bio-compatible Iridium(III)\nSoerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics Photocatalysts. Angew. Chem., Int. Ed. 2021, 60, 9474\u22129479.\n2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide (21) Huang, H.; Banerjee, S.; Qiu, K.; Zhang, P.; Blacque, O.;\nfor 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209\u2212 Malcomson, T.; Paterson, M. J.; Clarkson, G. J.; Staniforth, M.;\n249. Stavros, V. G.; Gasser, G.; Chao, H.; Sadler, P. J. Targeted photoredox\n (2) Liang, G.; Sadhukhan, T.; Banerjee, S.; Tang, D.; Zhang, H.; Cui, catalysis in cancer cells. Nat. Chem. 2019, 11, 1041\u22121048.\nM.; Montesdeoca, N.; Karges, J.; Xiao, H. Reduction of Platinum(IV) (22) Fan, Z.; Xie, J.; Sadhukhan, T.; Liang, C.; Huang, C.; Li, W.; Li,\nProdrug Hemoglobin Nanoparticles with Deeply Penetrating Ultra- T.; Zhang, P.; Banerjee, S.; Raghavachari, K.; Huang, H. Highly\nsound Radiation for Tumor-Targeted Therapeutically Enhanced Efficient Ir (III)-Coumarin Photo-Redox Catalyst for Synergetic\nAnticancer Therapy. Angew. Chem., Int. Ed. 2023, 62, No. e2023010. Multi-Mode Cancer Photo-Therapy. Chem.\ufffdEur. J. 2022, 28,\n (3) Zhao, X.; Liu, J.; Fan, J.; Chao, H.; Peng, X. Recent progress in No. e202103346.\nphotosensitizers for overcoming the challenges of photodynamic (23) Navas, L. E.; Carnero, A. NAD+ metabolism, stemness, the\ntherapy: from molecular design to application. Chem. Soc. Rev. 2021, immune response, and cancer. Signal Transduction Targeted Ther.\n50, 4185\u22124219. 2021, 6, 2.\n (4) Panda, T. R.; Manikandan, M.; Vaidya, S. P.; Chhatar, S.; Sinha, (24) Tyagi, K.; Dixit, T.; Venkatesh, V. Recent advances in catalytic\nS.; Mehrotra, M.; Chakraborty, S.; Gadre, S.; Duari, P.; Ray, P.; Patra, anticancer drugs: Mechanistic investigations and future prospects.\nM. The Power of Kinetic Inertness in Improving Platinum Anticancer Inorg. Chim. Acta 2022, 533, No. 120754.\nTherapy by Circumventing Resistance and Ameliorating Nephrotox- (25) Swaminathan, S.; Deepak, J. R.; Karvembu, R. Interweaving\nicity. Angew. Chem., Int. Ed. 2023, 62, No. e202303958. catalysis and cancer using Ru- and Os-arene complexes to alter\n (5) Vigueras, G.; Gasser, G. Anticancer platinum-based photo- cellular redox state: A structure-activity relationship (SAR) review.\noxidants in a new light. Nat. Chem. 2023, 15, 896\u2212898. Coord. Chem. Rev. 2023, 491, No. 215230.\n (6) Rottenberg, S.; Disler, C.; Perego, P. The rediscovery of (26) Banerjee, S.; Sadler, P. J. Transfer hydrogenation catalysis in\nplatinum-based cancer therapy. Nat. Rev. Cancer 2021, 21, 37\u221250. cells. RSC Chem. Biol. 2021, 2, 12\u221229.\n\n 7501 https://doi.org/10.1021/acs.inorgchem.4c00650\n Inorg. Chem. 2024, 63, 7493\u22127503\n\fInorganic Chemistry pubs.acs.org/IC Article\n\n (27) Fan, Z.; Huang, J.; Huang, H.; Banerjee, S. Metal-Based (44) Mari, C.; Pierroz, V.; Ferrari, S.; Gasser, G. Combination of\nCatalytic Drug Development for Next-Generation Cancer Therapy. Ru(II) complexes and light: new frontiers in cancer therapy. Chem.\nChemMedChem. 2021, 16, 2480\u22122486. Sci. 2015, 6, 2660\u22122686.\n (28) Soldevila-Barreda, J. J.; Metzler-Nolte, N. Intracellular catalysis (45) Heinemann, F.; Karges, J.; Gilles, G. Critical Overview of the\nwith selected metal complexes and metallic nanoparticles: advances Use of Ru(II) Polypyridyl Complexes as Photosensitizers in One-\ntoward the development of catalytic metallodrugs. Chem. Rev. 2019, Photon and Two-Photon Photodynamic Therapy. Acc. Chem. Res.\n119, 829\u2212869. 2017, 50, 2727\u22122736.\n (29) Soldevila-Barreda, J. J.; Sadler, P. J. Approaches to the design of (46) Mari, C.; Pierroz, V.; Rubbiani, R.; Patra, M.; Hess, J.; Spingler,\ncatalytic metallodrugs. Curr. Opin. Chem. Biol. 2015, 25, 172\u2212183. B.; Oehninger, L.; Schur, J.; Ott, I.; Salassa, L.; Ferrari, S.; Gasser, G.\n (30) Li, Y.-L.; Li, A.-J.; Huang, S.-L.; Vittal, J. J.; Yang, G.-Y. DNA Intercalating Ru(II) Polypyridyl Complexes as Effective\nPolypyridyl Ru(II) or cyclometalated Ir(III) functionalized architec- Photosensitizers in Photodynamic Therapy. Chem.\ufffdEur. J. 2014,\ntures for photocatalysis. Chem. Soc. Rev. 2023, 52, 4725\u22124754. 20, 14421\u221214436.\n (31) DiLuzio, S.; Connell, T. U.; Mdluli, V.; Kowalewski, J. F.; (47) Paul, S.; Kundu, P.; Kondaiah, P.; Chakravarty, A. R. BODIPY-\nBernhard, S. Understanding Ir(III) Photocatalyst Structure\u2212Activity Ruthenium(II) Bis-Terpyridine Complexes for Cellular Imaging and\nRelationships: A Highly Parallelized Study of Light-Driven Metal Type-I/-II Photodynamic Therapy. Inorg. Chem. 2021, 60, 16178\u2212\nReduction Processes. J. Am. Chem. Soc. 2022, 144, 1431\u22121444. 16193.\n (32) Schmid, L.; Glaser, F.; Schaer, R.; Wenger, O. S. High Triplet (48) Li, J.; Zeng, L.; Xiong, K.; Rees, T. W.; Jin, C.; Wu, W.; Chen,\nEnergy Iridium(III) Isocyanoborato Complex for Photochemical Yu.; Jia, L.; Chao, H. A biotinylated ruthenium(II) photosensitizer for\nUpconversion, Photoredox and Energy Transfer Catalysis. J. Am. tumor-targeted two-photon photodynamic therapy. Chem. Commun.\nChem. Soc. 2022, 144, 963\u2212976. 2019, 55, 10972\u221210975.\n (33) Deng, Z.; Li, H.; Chen, S.; Wang, Na; Liu, G.; Liu, D.; Ou, W.; (49) Steinke, S. J.; Gupta, S.; Piechota, E. J.; Moore, C. E.; Kodanko,\nXu, F.; Wang, X.; Lei, D.; Lo, P.-C.; Li, Y. Y.; Lu, J.; Yang, M.; He, M.- J. J.; Turro, C. Photocytotoxicity and photoinduced phosphine ligand\nL.; Zhu, G. Near-infrared-activated anticancer platinum(IV) com- exchange in a Ru(II) polypyridyl complex. Chem. Sci. 2022, 13,\nplexes directly photooxidize biomolecules in an oxygen-independent 1933\u22121945.\nmanner. Nat. Chem. 2023, 15, 930\u2212939. (50) Chen, Q.; Cuello-Garibo, J. A.; Bretin, L.; Zhang, L.; Ramu, V.;\n (34) (a) Karges, J.; Heinemann, F.; Jakubaszek, M.; Maschietto, F.; Aydar, Y.; Batsiun, Y.; Bronkhorst, S.; Husiev, Y.; Beztsinna, N.; Chen,\nSubecz, C.; Dotou, M.; Vinck, R.; Blacque, O.; Tharaud, M.; Goud, L.; Zhou, X. Q.; Schmidt, C.; Ott, I.; Jager, M. J.; Brouwer, A. M.;\nB.; Zah\u00ednos, E. V.; Spingler, B.; Ciofini, I.; Gasser, G. Rationally Snaar-Jagalska, B. E.; Bonnet, S. Photosubstitution in a trisheteroleptic\nDesigned Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes ruthenium complex inhibits conjunctival melanoma growth in a\nas Photosensitizers for Photodynamic Therapy. J. Am. Chem. Soc. zebrafish orthotopic xenograft model. Chem. Sci. 2022, 13, 6899\u2212\n2020, 142, 6578\u22126587. (b) Notaro, A.; Gasser, G. Monomeric and\n 6919.\ndimeric coordinatively saturated and substitutionally inert Ru(II) (51) Havrylyuk, D.; Hachey, A. C.; Fenton, A.; Heidary, D. K.;\npolypyridyl complexes as anticancer drug candidates. Chem. Soc. Rev.\n Glazer, E. C. Ru(II) photocages enable precise control over enzyme\n2017, 46, 7317\u22127337.\n activity with red light. Nat. Commun. 2022, 13, 3636.\n (35) Heinemann, F.; Karges, J.; Gasser, G. Critical Overview of the\n (52) Gandioso, A.; Izquierdo-Garc\u00eda, E.; Mesdom, P.; Arnoux, P.;\nUse of Ru(II) Polypyridyl Complexes as Photosensitizers in One-\n Demeubayeva, N.; Burckel, P.; Saubam\u00e9a, B.; Bosch, M.; Frochot, C.;\nPhoton and Two-Photon Photodynamic Therapy. Acc. Chem. Res.\n March\u00e1n, V.; Gasser, G. Ru(II)-Cyanine Complexes as Promising\n2017, 50, 2727\u22122736.\n Photodynamic Photosensitizers for the Treatment of Hypoxic\n (36) Karges, J.; Kuang, S.; Maschietto, F.; Blacque, O.; Ciofini, I.;\nChao, H.; Gasser, G. Rationally designed ruthenium complexes for 1- Tumours with Highly Penetrating 770 nm Near-Infrared Light.\nand 2-photon photodynamic therapy. Nat. Commun. 2020, 11, 3262. Chem.\ufffdEur. J. 2023, 29, No. e202301742.\n (37) Howerton, B. S.; Heidary, D. K.; Glazer, E. C. Strained (53) Pierroz, V.; Rubbiani, R.; Gentili, C.; Patra, M.; Mari, C.;\nRuthenium Complexes Are Potent Light-Activated Anticancer Agents. Gasser, G.; Ferrari, S. Dual mode of cell death upon the photo-\nJ. Am. Chem. Soc. 2012, 134, 8324\u22128327. irradiation of a Ru(II) polypyridyl complex in interphase or mitosis.\n (38) Wachter, E.; Heidary, D. K.; Howerton, B. S.; Parkin, S.; Chem. Sci. 2016, 7, 6115\u22126124.\nGlazer, E. C. Light-activated ruthenium complexes photobind DNA (54) Pozza, M. D.; Mesdom, P.; Abdullrahman, A.; Otoya, T. D. P.;\nand are cytotoxic in the photodynamic therapy window. Chem. Arnoux, P.; Frochot, C.; Niogret, G.; Saubam\u00e9a, B.; Burckel, P.; Hall,\nCommun. 2012, 48, 9649\u22129651. J. P.; Hollenstein, M.; Cardin, C. J.; Gasser, G. Increasing the \u03c0-\n (39) Monro, S.; Col\u00f3n, K. L.; Yin, H.; Roque, J., III; Konda, P.; Expansive Ligands in Ruthenium(II) Polypyridyl Complexes: Syn-\nGujar, S.; Thummel, R. P.; Lilge, L.; Cameron, C. G.; McFarland, S. thesis, Characterization, and Biological Evaluation for Photodynamic\nA. Transition Metal Complexes and Photodynamic Therapy from a Therapy Applications. Inorg. Chem. 2023, 62, 18510\u221218523.\nTumor-Centered Approach: Challenges, Opportunities, and High- (55) Mariappan, M.; Maiya, B. G. Effects of Anthracene and Pyrene\nlights from the Development of TLD1433. Chem. Rev. 2019, 119, Units on the Interactions of Novel Polypyridylruthenium(II) Mixed-\n797\u2212828. Ligand Complexes with DNA. Eur. J. Inorg. Chem. 2005, 2005, 2164\u2212\n (40) Bonnet, S. Why develop photoactivated chemotherapy? Dalton 2173.\nTrans. 2018, 47, 10330\u221210343. (56) Tan, L.-F.; Chao, H.; Li, H.; Liu, Y.-J.; Sun, B.; Wei, W.; Ji, L.\n (41) Shi, G.; Monro, S.; Hennigar, R.; Colpitts, J.; Fong, J.; -N. J. Synthesis, characterization, DNA-binding and photocleavage\nKasimova, K.; Yin, H.; DeCoste, R.; Spencer, C.; Chamberlain, L.; studies of [Ru(bpy)2(PPIP)]2+ and [Ru(phen)2(PPIP)]2+. Inorg.\nMandel, A.; Lilge, L.; McFarland, S. A. Ru(II) dyads derived from \u03b1- Biochem. 2005, 99, 513\u2212520.\noligothiophenes: A new class of potent and versatile photosensitizers (57) Huang, H.; Zhang, P.; Chen, Y.; Qiu, K.; Jin, C.; Jia, L.; Chao,\nfor PDT. Coord. Chem. Rev. 2015, 282\u2212283, 127\u2212138. H. Synthesis, characterization and biological evaluation of labile\n (42) Lifshits, L. M.; Roque, J. A. III; Konda, P.; Monro, S.; Cole, H. intercalative ruthenium(II) complexes for anticancer drug screening.\nD.; von Dohlen, D.; Kim, S.; Deep, G.; Thummel, R. P.; Cameron, C. Dalton Trans. 2016, 45, 13135\u221213145.\nG.; Gujar, S.; McFarland, S. A. Near-infrared absorbing Ru(II) (58) Mitchell, R. J.; Kriger, S. M.; Fenton, A. D.; Havrylyuk, D.;\ncomplexes act as immunoprotective photodynamic therapy (PDT) Pandeya, A.; Sun, Y.; Smith, T.; DeRouchey, J. E.; Unrine, J. M.; Oza,\nagents against aggressive melanoma. Chem. Sci. 2020, 11, 11740\u2212 V.; Blackburn, J. S.; Wei, Y.; Heidary, D. K.; Glazer, E. C. A mono\n11762. adduct generating Ru(II) complex induces ribosome biogenesis stress\n (43) Bonnet, S. Ruthenium-Based Photoactivated Chemotherapy. J. and is a molecular mimic of phenanthriplatin. RSC Chem. Biol. 2023,\nAm. Chem. Soc. 2023, 145, 23397\u221223415. 4, 344\u2212353.\n\n 7502 https://doi.org/10.1021/acs.inorgchem.4c00650\n Inorg. Chem. 2024, 63, 7493\u22127503\n\fInorganic Chemistry pubs.acs.org/IC Article\n\n (59) Yu, H.-j.; Liu, J.-p.; Hao, Z.-f.; He, J.; Sun, M.; Hu, S.; Yu, L.; (75) Ali, I.; Lone, M. N.; Aboul-Enein, H. Y. Imidazoles as potential\nChao, H. Synthesis, characterization and biological evaluation of anticancer agents. Med. Chem. Commun. 2017, 8, 1742\u22121773.\nruthenium(II) complexes [Ru(dtzp)(dppz)Cl]+ and [Ru(dtzp)- (76) Huang, H.; Zhang, P.; Chen, Y.; Ji, L.; Chao, H. Labile\n(dppz)CH3CN]2+ for photodynamic therapy. Dyes Pigm. 2017, 136, ruthenium(II) complexes with extended phenyl-substituted terpyridyl\n416\u2212426. ligands: synthesis, aquation and anticancer evaluation. Dalton Trans.\n (60) Rilak, A.; Bratsos, I.; Zangrando, E.; Kljun, J.; Turel, I.; 2015, 44, 15602\u221215610.\nBugarcic\u030c, Z\u030c . D.; Alessio, E. New Water-Soluble Ruthenium(II) (77) Pen\u0303a, B.; David, A.; Pavani, C.; Baptista, M. S.; Pellois, J. P.;\nTerpyridine Complexes for Anticancer Activity: Synthesis, Character- Turro, C.; Dunbar, K. R. Cytotoxicity Studies of Cyclometallated\nization, Activation Kinetics, and Interaction with Guanine Derivatives. Ruthenium(II) Compounds: New Applications for Ruthenium Dyes.\nInorg. Chem. 2014, 53, 6113\u22126126. Organometallics 2014, 33, 1100\u22121103.\n (61) Catalano, V. J.; Craig, T. J. Monometallic and Dimetallic (78) Roy, S.; Colombo, E.; Vinck, R.; Mari, C.; Rubbiani, R.; Patra,\nRuthenium(II)\u2212Terpyridine Complexes Employing the Tetradentate M.; Gasser, G. Increased Lipophilicity of Halogenated Ruthenium(II)\nLigands Dipyridylpyrazolyl, Dipyridyloxadiazole, and Their Dimethyl Polypyridyl Complexes Leads to Decreased Phototoxicity in vitro\nDerivatives. Inorg. Chem. 2003, 42, 321\u2212334. when Used as Photosensitizers for Photodynamic Therapy.\n (62) Puckett, C. A.; Barton, J. K. Methods to explore cellular uptake ChemBioChem. 2020, 21, 2966\u22122973.\nof ruthenium complexes. J. Am. Chem. Soc. 2007, 129, 46\u221247. (79) Frei, A.; Rubbiani, R.; Tubafard, S.; Blacque, O.; Anstaett, P.;\n (63) Huang, H.; Zhang, P.; Chen, H.; Ji, L.; Chao, H. Comparison Felgentrager, A.; Maisch, T.; Spiccia, L.; Gasser, G. Synthesis,\nbetween Polypyridyl and Cyclometalated Ruthenium(II) Complexes: Characterization, and Biological Evaluation of New Ru(II) Poly-\nAnticancer Activities against 2D and 3D Cancer Models. Chem.\ufffdEur. pyridyl Photosensitizers for Photodynamic Therapy. J. Med. Chem.\nJ. 2015, 21, 715\u2212725. 2014, 57, 7280\u22127292.\n (64) Fetzer, L.; Boff, B.; Ali, M.; Xiangjun, M.; Collin, J.-P.; Sirlin, (80) Mandal, A.; Rai, R.; Saha, S.; Kushwaha, R.; Wei, L.; Gogoi, H.;\nC.; Gaiddon, C.; Pfeffer, M. Library of Second-Generation Cyclo- Mandal, A. A.; Yadav, A. K.; Huang, H.; Dutta, A.; Dhar, P.; Banerjee,\nruthenate Compounds and Evaluation of Their Biological Properties S. Polypyridyl-based Co(III) complexes of vitamin B6 Schiff base for\nas Potential Anticancer Drugs: Passing the Nanomolar Barrier. Dalton photoactivated antibacterial therapy. Dalton Trans. 2023, 52, 17562\u2212\nTrans. 2011, 40, 8869\u22128878. 17572.\n (65) Ghosh, G.; Col\u00f3n, K. L.; Fuller, A.; Sainuddin, T.; Bradner, E.; (81) McFarland, S. A.; Mandel, A.; Dumoulin-White, R.; Gasser, G.\nMcCain, J.; Monro, S. M. A.; Yin, H.; Hetu, M. W.; Cameron, C. G.; Metal-based photosensitizers for photodynamic therapy: the future of\nMcFarland, S. A. Cyclometalated Ruthenium(II) Complexes Derived multimodal oncology? Curr. Opin. Chem. Biol. 2020, 56, 23\u221227.\nfrom \u03b1Oligothiophenes as Highly Selective Cytotoxic or Photo- (82) Rees, T. W.; Ho, P.; Hess, J. Recent Advances in Metal\ncytotoxic Agents. Inorg. Chem. 2018, 57, 7694\u22127712. Complexes for Antimicrobial Photodynamic Therapy. ChemBioChem\n (66) Bera, A.; Gautam, S.; Sahoo, S.; Pal, A. K.; Kondaiah, P.; 2023, 24, No. e202200796.\nChakravarty, A. R. Red light active Pt(IV)\u2212BODIPY prodrug as a (83) Arora, K.; Herroon, M.; Al-Afyouni, M. H.; Toupin, N. P.;\nmitochondria and endoplasmic reticulum targeted chemo-PDT agent. Rohrabaugh, T. N.; Loftus, L. M.; Podgorski, I.; Turro, C.; Kodanko,\nRSC Med. Chem. 2022, 13, 1526\u22121539. J. J. Catch and Release Photosensitizers: Combining Dual-Action Ru\n (67) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Complexes with Protease Inactivation for Targeting Invasive Cancers.\nRobb; Cheeseman, J. R; Scalmani, G.; Barone, S. V.; Petersson, G. A.; J. Am. Chem. Soc. 2018, 140, 14367\u221214380.\nNakatsuji, H.; Li, X. Gaussian 16, Revision A.03; Gaussian Inc.: (84) Zhang, L.; Wang, P.; Zhou, X.-Q.; Bretin, L.; Zeng, X.; Husiev,\nWallingford, CT, 2016. Y.; Polanco, E. A.; Zhao, G.; Wijaya, L. S.; Biver, T.; Le D\u00e9v\u00e9dec, S.\n (68) Yu, L.; Lee, K.-W.; Zhao, Y.-Q.; Xu, Y.; Zhou, Y.; Li, M.; Kim, J. E.; Sun, W.; Bonnet, S. Cyclic Ruthenium-Peptide Conjugates as\nS. Metal Modulation: An Effortless Tactic for Refining Photoredox Integrin-Targeting Phototherapeutic Prodrugs for the Treatment of\nCatalysis in Living Cells. Inorg.Chem. 2023, 62, 18767\u221218778. Brain Tumors. J. Am. Chem. Soc. 2023, 145, 1496\u221214980.\n (69) Yadav, A. K.; Singh, V.; Kushwaha, R.; Dolui, D.; Rai, R.; Dhar, (85) Bera, A.; Nepalia, A.; Upadhyay, A.; Saini, D. K.; Chakravarty,\nP.; Dutta, A.; Koch, B.; Banerjee, S. Polypyridyl Co(II)-Curcumin A. R. Biotin and boron-dipyrromethene-tagged platinum(IV) prodrug\nComplexes as Photo-activated Anticancer and Antibacterial Agents. for cellular imaging and mito-targeted photocytotoxicity in red light.\nChemBioChem 2023, 24, No. e202300033. Dalton Trans. 2023, 52, 13339\u221213350.\n (70) Feng, T.; Tang, Z.; Karges, J.; Shen, J.; Jin, C.; Chen, Y.; Pan, (86) Ouyang, C.; Chen, L.; Rees, T. W.; Chen, Y.; Liu, J. K.; Ji, L.\nY.; He, Y.; Ji, L.; Chao, H. Exosome camouflaged coordination- N.; Long, J. G.; Chao, H. A mitochondria-targeting hetero-binuclear\nassembled Iridium(III) photosensitizers for apoptosis-autophagy- Ir(III)\u2212Pt(II) complex induces necrosis in cisplatin-resistant tumor\nferroptosis induced combination therapy against melanoma. Biomater. cells. Chem. Commun. 2018, 54, 6268\u22126271.\n2023, 301, No. 122212. (87) Bera, A.; Gautam, S.; Raza, M. K.; Kondaiah, P.; Chakravarty,\n (71) Wang, Y.; Mesdom, P.; Purkait, K.; Saubam\u00e9a, B.; Burckel, P.; A. R. Oxoplatin-B, a cisplatin-based platinum(IV) complex with\nArnoux, P.; Frochot, C.; Cariou, K.; Rossel, T.; Gasser, G. Ru(II)/ photoactive BODIPY for mitochondria specific \u201cchemo-PDT\u201d\n activity. J. Inorg. Biochem. 2021, 223, No. 111526.\nOs(II)-based carbonic anhydrase inhibitors as photodynamic therapy\nphotosensitizers for the treatment of hypoxic tumours. Chem. Sci.\n2023, 14, 11749\u221211760.\n (72) Zeng, L.; Chen, Y.; Liu, J.; Huang, H.; Guan, R.; Ji, L.; Chao, H.\nRuthenium(II) Complexes with 2-Phenylimidazo[4,5-f][1,10]-\nphenanthroline Derivatives that Strongly Combat Cisplatin-Resistant\nTumor Cells. Sci. Rep. 2016, 6, 19449.\n (73) Liu, Z.; Habtemariam, A.; Pizarro, A. M.; Clarkson, G. J.;\nSadler, P. J. Organometallic Iridium(III) Cyclopentadienyl Anticancer\nComplexes Containing C,N-Chelating Ligands. Organometallics 2011,\n30, 4702\u22124710.\n (74) Swathantraiah, J. G.; Srinivasa, S. M.; Motatis, A. K. B.;\nUttarkar, A.; Bettaswamygowda, S.; Thimmaiah, S. B.; Niranjan, V.;\nRangappa, S.; Subbegowda, R. K.; Ramegowda, T. N. Novel 1,2,5-\nTrisubstituted Benzimidazoles Potentiate Apoptosis by Mitochondrial\nDysfunction in Panel of Cancer Cells. ACS Omega 2022, 7, 46955\u2212\n46971.\n\n 7503 https://doi.org/10.1021/acs.inorgchem.4c00650\n Inorg. Chem. 2024, 63, 7493\u22127503\n\f", "pages_extracted": 11, "text_length": 87940}