Polypyridyl Os(II) complexes as efficient human non-small cell lung cancer photosensitizers with enhanced singlet oxygen generation via the fused π-ring elongation

{"full_text": " Inorganica Chimica Acta 578 (2025) 122537\n\n\n Contents lists available at ScienceDirect\n\n\n Inorganica Chimica Acta\n journal homepage: www.elsevier.com/locate/ica\n\n\nResearch paper\n\nPolypyridyl Os(II) complexes as efficient human non-small cell lung cancer\nphotosensitizers with enhanced singlet oxygen generation via the fused\n\u03c0-ring elongation\nFeng Chen a,* , Kelun Cui a, Shufen Si b, Yong Liu a , Songlin Xue a, Gaoji Wang a , Xu Liang a,* ,\nChunyin Zhu a , Qiu-Yun Chen a,*\na\n School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013 PR China\nb\n Northern Light Quality Inspection Technical Service Co., Ltd., Nanjing 210033 PR China\n\n\n\n\nA R T I C L E I N F O A B S T R A C T\n\nKeywords: Photodynamic therapy as a complementary cancer treatment strategy has attracted rising interests. Here, five\nPolypyridyl osmium complex polypyridyl Os(II) complexes Os-1 \u00a1 Os-5 with the general formula of [(DIP)2OsL](PF6)2 have been synthesized\nSinglet oxygen and fully characterized by 1H/13C NMR, HRMS and elemental analysis. Their electronic properties were studied\nPhotosensitizer\n by electrochemistry, and DFT and TD-DFT calculations. A significant enhancement of singlet oxygen (1O2)\nAntiproliferative activity\n generation was observed with \u03c0 extension on the coordinative ligands, that Os-3 with dibenzo[a,c]dipyrido[3,2-\n h:2\u2032,3\u2032-j]phenazine ligand showed the highest induction capacity under blue LED light (465 nm in acetonitrile),\n with the quantum yield (\u0424\u0394S) of 0.65 in comparison to that of [(bpy)3RuCl2] (\u0424\u0394(S0), 0.57); Os-3 remained the\n highest 1O2 generation ability under red LED irradiation (640 nm). All complexes showed potent photo\u00ad\n cytotoxicity against MGC-803 and HGC-27 human gastric cancer cells, giving IC50 value low as 0.37 \u00b5M (blue\n LED light) and 0.32 \u00b5M (blue LED light), and PI value was high as 15 in A549 cancer cells inhibition. The cellular\n 1\n O2 detection by SOSG showed a concentration-dependent manner when co-administered with Os-3 in HGC-27\n cells, and the absorbed Os content was up to 96.1 ng/106 cells in A549 cells for Os-3. Subcellular colocalization\n indicated that those Os(II) complexes are less likely targeting mitochondria. Together, the enhancement of 1O2\n generation by ligand modification may provide a feasible strategy for the design of new photosensitizers, and\n such type of Os(II) complexes have the potential application as new human gastric cancer photosensitizers.\n\n\n\n\n1. Introduction the traditional porphyrin PSs, transition-metal included PSs possessed\n several apparent advantages, like adjustable and longer emission, higher\n To date, cisplatin and its analogs carboplatin or oxaliplatin are still in emissive quantum yields, larger Stoke shift, photobleaching resistance,\nroutine use in chemo-therapy for various cancers treatment [1]; the etc [10,11]; thus are promising photosensitizer candidates for next\nsuccess but intrinsically attached defects of cisplatin or other platinum- generation of PSs for cancer treatment. So far, great efforts for devel\u00ad\nbased chemotherapeutic drugs have aroused and flourished the inten\u00ad opment of transition-metal based PSs, exemplarily, TLD-1433, a Ru(II)\nsive antiproliferative investigation on other platinum group transition PS for curing non-muscle invasive bladder cancer [12], and WST11, a Pd\nmetals for the last two decades, e.g. Ru(II) [2,3], Ir(III) [4,5,6], Re(I) (II) derivative as bacteriopheophorbide [13], have been achieved. Me\u00ad\n[7,8], and Au(III) [9], and more importantly, the photodynamic therapy. chanically, PS is evoked from the ground state to an excited singlet state\n Photodynamic therapy (PDT), with noninvasive and high selective under an irradiative excitation, and undergo an intersystem crossing\nqualities, has emerged as a prominent complementary process to (ISC) process to the triplet state. Subsequently it can decay to the ground\nplatinum-based chemotherapy for the treatment of cancers or other state by the luminescence emission through two pathways, i.e., type I,\ndiseases [10]. The clinical use of porphyrin-based molecules as the first which typically generate reactive oxygen species, e.g., O2\u22c5- and OH\u22c5, by\ngeneration of photosensitizers (PSs), for instance Photofrin and Proto\u00ad water or biomolecules oxidation (electron transfer in mechanism); and\nporphyrin IX (PpIX), could retrospect to last 90 s [10]. In comparison to type II, majorly induces singlet oxygen (1O2) generation (excited energy\n\n\n * Corresponding authors.\n E-mail address: fengjchen@ujs.edu.cn (F. Chen).\n\nhttps://doi.org/10.1016/j.ica.2025.122537\nReceived 4 November 2024; Received in revised form 1 January 2025; Accepted 1 January 2025\nAvailable online 3 January 2025\n0020-1693/\u00a9 2025 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.\n\fF. Chen et al. Inorganica Chimica Acta 578 (2025) 122537\n\n\n\n\n Scheme 1. Illustrated synthesis route of Os-1 \u2212 Os-5.\n\n\n light irradiation even in the absence of oxygen, such complex induced\n photocatalytic oxidation of endogenous 1,4-dihydronicotinamide\n adenine dinucleotide, leading to ferroptosis, that is mediated by gluta\u00ad\n thione degradation, lipid peroxide accumulation in living cells [25].\n Nevertheless, unsatisfactory amount of 1O2 was inductively obtained\n for many complexes due to the more sophisticated conditions [21,26],\n like low ISC efficiency or the fast nonradiative deactivation process by\n intramolecular vibrational relaxation [27,28]. Accordingly, rational\n design, for instance complex with rigid molecular structure, is required\n to reduce the vibrational relaxation rate [29,30], thus may will facilitate\n the enhancement of 1O2 quantum yield; other strategies to modulate the\n 1\n O2 production, e.g. plasmonic nanoparticles [31,32], aggregates [33],\n or FRET strategy [34], etc, were also endeavored, to boost the 1O2\n generation. Capitalized on this, we seek to design and synthesize a series\n of Os(II)-based photosensitizers having potent 1O2 generation capacity,\n and to study the structure\u2013activity-relationship. In current work, five Os\n (II) polypyridyl complexes with the general formula of [(DIP)2OsL]\n (PF6)2, where DIP is 4,7-diphenyl-1,10-phenanthroline, and L are\n dipyrido[3,2-a:2\u2032,3\u2032-c]phenazine(dppz, L1), benzo[i]dipyrido[3,2-\nFig. 1. UV\u2013vis spectra of complexes Os-1 \u2212 Os-5 in acetonitrile; inset is a:2\u2032,3\u2032-c]phenazine (dppn, L2), dibenzo[a,c]dipyrido[3,2-h:2\u2032,3\u2032-j]phen\u00ad\nabsorbance of Os-1 \u2212 Os-5 in 500\u20131000 nm range. azine(dppp, L3), 11,12-diphenyldipyrido[3,2-a:2\u2032,3\u2032-c]phenazine\n (dppzb, L4), 11,12-di(naphthalen-2-yl)dipyrido[3,2-a:2\u2032,3\u2032-c]phenazine\ntransfer in mechanism) [14,15]. The property of 1O2, for example short (dppzn, L5), have been synthesized and characterized. CV and DFT/TD-\nlifetime (< 3 \u00b5s) and low diffusion distance (2\u20134 \u00d7 106 cm2 s\u2212 1), DFT calculations were performed to study the electronic property. The\n 1\nendowed PDT with highly regionalized quality [16]. Many transition- O2 generation capacity by Os-1 \u00a1 Os-5 under blue and red LED lights\nmetal based PSs can generate sufficient singlet oxygen [11,17]; among irradiation was also determined. In vitro antiproliferative activity\nthose, Ru(II) complexes undoubtedly are the most investigated PSs in against three human cancer cell lines, i.e., A549 human non-small cell\nPDT [18,19]. However, low oxygen concentration and minimal light lung cancer, MGC-803, and HGC-27 (undifferentiated) human gastric\npenetration have enormously limited their further in vivo application. cancer cells was also investigated. The cellular 1O2 generation, cell up\u00ad\nBenefiting from the significant heavier metal effect, the analogous Os(II) take, and subcellular colocalization were studied as well.\ncomplexes which were far less developed and studied [20], might show\nan significant red-shift up to a deep red to near inferred region in 2. Materials and experimental section\ncomparison to the respective Ru(II) complexes. The possible \u2018biological\nwindow\u2019 (700\u20131000 nm) localization and excitation for Os(II) com\u00ad All solvents (reagent grade) were obtained from commercial re\u00ad\nplexes led to an optimal light penetration and more practical application sources, and used without further purification. Ammonium hexa\u00ad\ntargeting deeper tissual solid tumors [21]. Furthermore, the character\u00ad chloroosmate(IV) was purchased from Xiya Reagent Chemical Co., Ltd\nistic full absorbance and longer excited-state lifetime provoke better (Shandong, China); 1,10-phenanthroline-5,6-dione, 2,3-diaminonaph\u00ad\nsensitivity to trace amount of oxygen for Os(II) complexes [22]. thalene, phenanthrene-9,10-diamine, 4,5-dibromo-1,2-phenylene-\nMcFarland and coworkers have developed a series of panchromatic Os diamine and tetrakis(triphenyl phosphine)palladium were purchased\n(II) polypyridyl PSs derived from the scaffold of TLD-1433, i.e. from Leyan Chemical Co., Ltd (Shanghai, China); 2-naphthaleneboronic\nTLD1822, TLD1824 and TLD1829, have shown potent PDT efficacy acid was obtained from Macklin Biochemical Technology Co., Ltd\nunder both red and near-infrared light in normoxic and hypoxic condi\u00ad (Shanghai, China); 4,7-diphenyl-1,10-phenanthroline (DIP) was ob\u00ad\ntions [23]. Gasser and Chao et al. synthesized various structurally simple tained from Titan Technology Co., Ltd (Shanghai, China). 9,10-anthra\u00ad\nbut hypoxically active osmium(II) polypyridyl complexes, [Os(4,7- cenediyl-bis-(methylene) dimalonic acid (ABDA) and 1,3-\ndiphenyl-1,10-phenanthroline)2L]2+, with 1O2 quantum as high as Diphenylisobenzofuran (DPBF) were obtained from Admas. 1H- and\n 13\n0.415, these complexes have shown promising phototoxicity in 2D cell C NMR spectra were recorded on a JNM-ECX 400 MHz NMR spec\u00ad\nlayers and multicellular tumor spheroids, as well as on CT26 tumor- trometer. UV \u2212 vis spectra were measured on a UV-3600 Plus spec\u00ad\nbearing BALB/c mice upon NIR irradiation [24]. Zhang et al. reported trometer (Tokyo, Japan).\nan osmium-peroxo complex that can release a peroxo ligand O\u2022\u2212 2 upon\n\n\n 2\n\fF. Chen et al. Inorganica Chimica Acta 578 (2025) 122537\n\n\n\n\n Fig. 2. Diagram of molecular orbital energy level with the electron density of the HUMO and LUMO for complexes Os-1 \u2212 Os-5.\n\n\n3. Instruments and basic methods 132.1, 130.7, 129.7, 129.4, 128.9, 128.7, 127.9, 126.7, 126.6, 126.3,\n 126.2; HRMS-[M]2+ Found: 569.1575 m/z, calculated: 569.1574 m/z.\n3.1. Synthesis and characterization Anal. Calcd for [C66H42F12N8OsP2]: C, 55.54; H, 2.97; N, 7.85. Found: C,\n 55.67; H, 3.12; N, 7.79.\n The chelated ligands of dipyrido[3,2-a:2\u2032,3\u2032-c]phenazine(dppz, L1) Os-2 [(DIP)2Os(dppn)](PF6)2. Yield: 318 mg, 60 %.1H NMR (400\n[35], benzo[i]- dipyrido[3,2-a:2\u2032,3\u2032-c]phenazine (dppn, L2) [36], MHz, CDCl3) \u03b4H 7.50\u20137.69 (m, 22H), 7.75\u20137.79 (m, 6H), 8.15\u20138.19 (m,\ndibenzo[a,c]dipyrido[3,2-h:2\u2032,3\u2032-j]phenazine(dppp, L3) [37], 11,12- 2H), 8.27 (d, J = 12 Hz, 4H), 8.32 (d, J = 4 Hz, 2H), 8.43 (d, J = 8 Hz,\ndiphenyldipyrido[3,2-a:2\u2032,3\u2032-c]phenazine(dppzb, L4) and 11,12-di 2H), 8.84\u20138.88 (m, 2H), 8.15\u20138.21 (m, 2H); 13C NMR (100 MHz, CDCl3)\n(naphthalen-2-yl)dipyrido[3,2-a:2\u2032,3\u2032-c]phenazine(dppzn, L5) [38] were \u03b4C 152.9, 152.8, 151.6, 151.5, 150.1, 150.0, 149.8, 149.2, 148.9, 135.0,\nobtained according to the reported synthetic procedures. The osmium 134.8, 132.9, 130.8, 129.9, 129.8, 129.5, 129.0, 128.9, 128.8, 128.4,\n(II) precursor Os(DIP)2Cl2 were synthesized according to the reported 128.1, 128.0, 127.9, 126.9, 126.4, 126.2; HRMS-[M]2+ Found:\nmethod [24,39]. 594.1652 m/z, calculated: 594.1652 m/z. Anal. Calcd for\n All Os(II) complexes were synthesized according an established [C70H44F12N8OsP2(H2O)0.4]: C, 56.63; H, 3.04; N, 7.55. Found: C, 56.68;\nprocedure [24]. In general, to a solution of [Os(DIP)2Cl2] (1 eq.) in H, 3.32; N, 7.58.\ndegassed ethylene glycol (20 mL) was added the coordinative ligands Os-3 [(DIP)2Os(dppp)](PF6)2. Yield: 228 mg, 42 %.1H NMR (400\n(1.1 eq.). The mixture was heated at 125 \u25e6 C under N2 for 24 h. After the MHz, d6-DMSO) \u03b4H 7.67\u20137.70 (m, 8H), 7.72\u20137.75 (m, 12H), 7.79 (d, J =\nsolution was cooling to room temperature, a saturated aqueous solution 8 Hz, 2H), 7.83 (dd, J1 = 8 Hz, J2 = 8 Hz, 4H), 7.79\u20138.05 (m, 4H),\nof ammonium hexafluorophosphate (10 mL) was added, and the dark 8.31\u20138.40 (m, 10H), 8.96 (d, J = 8 Hz, 2H), 9.65 (d, J = 8 Hz, 2H), 9.80\nbrown precipitate was immediately formed; the solid was obtained by (d, J = 8 Hz, 2H); 13C NMR (100 MHz, d6-DMSO) \u03b4C 152.1, 150.1, 147.9,\nfiltration, washed with deionized water (25 mL \u00d7 3) and diethyl ether 147.8, 147.7, 141.5, 138.5, 135.2, 135.1, 131.9, 131.4, 130.2, 130.1,\n(25 mL \u00d7 3). The crude product was then purified by silica column 129.7, 129.2, 128.8, 128.5, 128.3, 127.9, 126.7, 126.3, HRMS-[M]2+\nchromatography (DCM/MeOH, 30:1) and preparative thin layer chro\u00ad Found: 619.1729 m/z, calculated: 619.1730 m/z. Anal. Calcd for\nmatography (DCM/MeOH, 35:1), with black-purple solids were [C74H46F12N8OsP2(H2O)2.2]: C, 56.72; H, 3.24; N, 7.15. Found: C, 56.71;\nobtained. H, 3.40; N, 7.18.\n Os-1 [(DIP)2Os(dppz)](PF6)2. Yield: 273 mg, 53 %. 1H NMR (400 Os-4 [(DIP)2Os(dppzb)](PF6)2. Yield: 347 mg, 62 %. 1H NMR (400\nMHz, CDCl3) \u03b4H 7.51\u20137.66 (m, 20H), 7.73 (d, J = 4 Hz, 2H), 7.78 (d, J = MHz, CDCl3) \u03b4H 7.19\u20137.25 (m, 5H), 7.32 (d, J = 4 Hz, 2H), 7.51\u20137.60\n4 Hz, 2H), 7.91 (d, J = 4 Hz, 2H), 8.06 (d, J = 4 Hz, 2H), 8.26 (d, J = 4 (m, 16H), 7.63\u20137.68 (m, 6H), 7.76 (d, J = 8 Hz, 3H), 7.79 (d, J = 4 Hz,\nHz, 4H), 8.30\u20138.43 (m, 8H), 9.42 (s, 2H); 13C NMR (100 MHz, CDCl3) \u03b4C 2H), 7.88\u20137.91 (m, 2H), 8.22\u20138.28 (m, 6H), 8.34 (d, J = 8 Hz, 2H), 8.38\n152.7, 152.2, 151.3, 149.9, 149.8, 149.1, 148.9, 142.6, 139.2, 134.7, (d, J = 4 Hz, 2H), 8.43 (d, J = 8 Hz, 2H), 8.28\u20138.32 (m, 2H); 13C NMR\n\n\n 3\n\fF. Chen et al. Inorganica Chimica Acta 578 (2025) 122537\n\n\n\n\nFig. 3. A)the time-dependent absorption spectra of abda (60 \u03bcM) in the presence of Os-3 (10 \u03bcM) in acetonitrile under blue light irradiation (13 mW/cm2) in 60 min;\nb)Absorbance change at 398 nm of Os-1 \u2212 Os-5 in comparison to Ru(bpy)3 Cl2 ; c) The time-dependent absorption of DPBF (40 \u03bcM) in the presence of Os-3 (10 \u03bcM) in\nacetonitrile under red light irradiation (40 mW/cm2); d) Absorbance change at 415 nm of Os-1 \u2212 Os-5. (For interpretation of the references to colour in this figure\nlegend, the reader is referred to the web version of this article.)\n\n\n(100 MHz, CDCl3) \u03b4C 152.9, 152.2, 151.5, 151.4, 150.1, 149.9, 149.8, B3LYP/6-31G(d,p) (C, N, H) + SDD (Os) basis set.\n149.1, 148.8, 145.8, 141.9, 139.5, 139.2, 134.8, 130.6, 130.0, 129.9,\n129.8, 129.5, 128.9, 128.8, 128.1, 128.0, 127.6, 126.8, 126.3, 126.2 3.4. Partition coefficient (Log P) determination\nHRMS-[M]2+ Found: 645.1890 m/z, calculated: 645.1887 m/z. Anal.\nCalcd for [C78H50F12N8OsP2(H2O)1.2]: C, 58.51; H, 3.30; N, 7.00. Found: Solutions of Octanol-saturated water (OSW) and water-saturated\nC, 58.53; H, 3.50; N, 6.91. octanol (WSO), were prepared by mixing analytical grade octanol and\n Os-5 [(DIP)2Os(dppzn)](PF6)2. Yield: 383 mg, 65 %. 1H NMR (400 aqueous solution. Aliquots of osmium solutions of Os-1 \u00a1 Os-5 in OSW\nMHz, CDCl3) \u03b4 7. 23 (d, J = 8 Hz, 2H), 7.49\u20137.67 (m, 26H), 7.75\u20137.81 were added to equal volumes of WSO and shaken for 24 h. The aqueous\n(m, 8H), 7.93\u20138.04 (m, 5H), 8.22\u20138.29 (m, 4H), 8.33 (s, 2H), 8.40 (s, and octanol layers were subsequently separated into different tubes, and\n3H), 8.50 (d, J = 8 Hz, 2H), 9.44 (s, 2H); 13C NMR (100 MHz, CDCl3) \u03b4C the absorbance of each solution was analyzed by UV\u2013vis spectroscopy.\n153.0, 152.3, 151.6, 151.5, 150.1, 150.0, 149.8, 149.1, 148.8, 145.8, Partition coefficient was calculated by the following equation:\n142.0, 139.6, 136.9, 134.8, 133.0, 130.6, 129.9, 129.8, 129.5, 128.9, ( )\n128.8, 128.7, 128.1, 127.9, 127.4, 127.2, 126.9, 126.4, 126.0; HRMS- logPO/W = log [Os]WSO /[Os]OSW\n[M]2+ Found: 695.2040 m/z, calculated: 695.2043 m/z. Anal. Calcd for\n[C86H54F12N8OsP2(H2O)1.8]: C, 60.33; H, 3.40; N, 6.55. Found: C, 60.33;\n 3.5. Singlet oxygen determination\nH, 3.60; N, 6.61.\n Indirect method 1:\n3.2. Electrochemical study 1,3-Diphenylisobenzofuran (DPBF) was dissolved in acetonitrile and\n diluted to give a final concentration of 60 \u03bcM and kept in the dark. Os(II)\n Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) complexes in acetonitrile at a concentration of 20 \u03bcM were also pre\u00ad\nof Os-1 \u00a1 Os-5 were performed using a CHI-730D electrochemistry pared. After mixing 2 mL of DPBF solution with Os(II) complex sus\u00ad\nworkstation based on a reported procedure [40]. The workstation con\u00ad pension, curves and the absorbance at 415 nm were recorded every 3\nsists of a three-electrode-compartment cell: glass carbon electrode (\u03a6 = min under red light (640 nm, 40 mW/cm2) on a UV \u2212 vis spectrometer.\n3 mm) served as the working electrode, while platinum wire and Ag/ Indirect method 2 (1O2 quantum yield included):\nAgCl electrodes were used as the counter and reference electrodes, Acetonitrile solutions of Os-1 \u2013 Os-5 (20 \u03bcM) and 9,10-anthracene\u00ad\nrespectively, with tetrabutyl ammonium perchlorate (TBAP) as a sup\u00ad diyl-bis-(methylene) dimalonic acid (ABDA, 100 \u03bcM) were prepared in\nporting electrolyte, and o-dichlorobenzene (o-DCB) was used as the the dark and mixed. Mixtures were measured using UV\u2013vis spectro\u00ad\nsolvent. photometer after different blue light (465 nm, 13 mW/cm2) irradiation\n durations. The absorbance changes of ABDA at 378 nm were also\n3.3. Density functional theory calculations and time-dependent DFT recorded, [Ru(bpy)3Cl2] was used as standard photosensitizer to quan\u00ad\ncalculations tify the quantum yields (\u0424\u0394S) of 1O2. Singlet oxygen generation yield\n was calculated by the following formula [42]:\n Density functional theory (DFT) and TD-DFT calculations were per\u00ad \u0424\u0394(S) = \u0424\u0394(S0) \u00d7 (Ss/Ss0) \u00d7 100 %.\nformed with the Gaussian 09 program package [41]. The frontier mo\u00ad \u0424\u0394(S) = yield of Os(II) complexes, \u0424\u0394(S0) = yield of Ru(bpy)3Cl2,\nlecular orbital and energy levels of Os-1 \u00a1 Os-5 were calculated at the Ss = slope of compounds, Ss0 = slope of Ru(bpy)3Cl2.\n\n 4\n\fF. Chen et al. Inorganica Chimica Acta 578 (2025) 122537\n\n\nTable 1\nHalf inhibition concentration (IC50) values of Os-1 \u2212 Os-5 in the dark, upon\nirradiation at 640 nm (red light) and 465 nm (blue light) against A549, MGC-803\nand HGC-27 cancer cell lines. Values are average of three independent tests.\n Complex cancer cell dark 640 nm PI- 564 nm PI-\n lines 1 2\n\n Os-1 A549 9.45 \u00b1 8.51 \u00b1 1.1 4.85 \u00b1 1.9\n 1.60 0.83 0.34\n MGC-803 1.17 \u00b1 0.39 \u00b1 3 0.37 \u00b1 3.2\n 0.12 0.05 0.03\n HGC-27 0.87 \u00b1 0.32 \u00b1 2.7 0.38 \u00b1 2.3\n 0.15 0.02 0.04\n\n\n Os-2 A549 89.21 \u00b1 39.31 \u00b1 2.3 5.89 \u00b1 15\n 6.5 4.71 0.61\n MGC-803 1.20 \u00b1 0.56 \u00b1 2.1 0.39 \u00b1 3.1\n 0.12 0.04 0.04\n HGC-27 1.00 \u00b1 0.49 \u00b1 2 0.39 \u00b1 2.6\n 0.20 0.05 0.03\n\n\n Os-3 A549 26.17 \u00b1 20.41 \u00b1 1.3 7.39 \u00b1 3.5\n 1.87 2.25 1.61\n MGC-803 1.26 \u00b1 0.79 \u00b1 1.6 0.47 \u00b1 2.7\n 0.28 0.06 0.03\n HGC-27 1.97 \u00b1 1.20 \u00b1 1.6 0.81 \u00b1 2.4\n 0.16 0.12 0.06\n\n\n Os-4 A549 10.67 \u00b1 15.26 \u00b1 n. 13.62 \u00b1 n.\n 1.42 1.73 d. 1.34 d.\n MGC-803 1.14 \u00b1 0.85 \u00b1 1.3 0.68 \u00b1 1.7\n 0.06 0.04 0.04\n HGC-27 0.94 \u00b1 0.95 \u00b1 n. 0.56 \u00b1 1.7\n 0.28 0.25 d. 0.17\n\n\n Os-5 A549 8.90 \u00b1 6.08 \u00b1 1.5 4.43 \u00b1 2\n 0.96 0.82 0.61\n MGC-803 2.19 \u00b1 2.20 \u00b1 n. 1.09 \u00b1 2\n 0.21 0.15 d. 0.06\n HGC-27 3.10 \u00b1 3.02 \u00b1 1 1.09 \u00b1 2.8\n 0.28 0.15 0.14\n\nPI = Phototherapeutic index, defined as [IC50 ]dark / [IC50 ]light; n.d. = not\ndetermined. Fig. 4. a) Cellular uptake of Os-1 and Os-3 in A549 and HGC-27 cells measured\n by ICP-MS; Statistical significance was calculated with two-tailed Student\u2019s t-\n test, (*p < 0.05, **p < 0.01 or ***p < 0.001), all the experiments were per\u00ad\n3.6. Antiproliferative activity by CCK-8 assay formed as duplicates of triplicates; b) Mitochondria-localized dye MitoTracker\n Green (ex: 488 nm, em: 513\u2013550 nm); c) Nucleus-specific dye Hoechst 33,342\n The antiproliferative activity of Os-1 \u00a1 Os-5 was studied by the CCK- (ex: 405 nm, em: 409\u2013448 nm); d) Luminescence of Os-3; e) Merged image. (For\n8 assay. In general, exponentially grow cancer cells (1 \u00d7 105 cells per interpretation of the references to colour in this figure legend, the reader is\nwell) were seeded in a 96-well plate. After 24 h incubation for attach\u00ad referred to the web version of this article.)\nment, cells were incubated with different concentrations of Os(II)\ncomplexes from a stock solution (10 mM in DMSO), i.e., 100, 50, 25, samples were digested with 70 % nitric acid (1 mL, 60 \u25e6 C, 16 h) and then\n12.5, 6.25, 3.13, 1.56, 0.78, 0.39, and 0.19 \u00b5M, for 12 h. Supernatant diluted in 1: 100 (1 % HCl solution in MQ water) before analyzing on\nwas then replaced with fresh culture medium and cells were subjected to ICP-MS. The Os isotopes at 188, 189, and 190 were monitored. The\nLED light irradiation at 465 nm (blue LED light) or 640 nm (red LED cellular uptake of Os was associated with the number of cells.\nlight) for 1 h, and incubated for an additional 24 h. Cells without irra\u00ad\ndiation were replaced with fresh culture medium and maintained in the 3.8. In-cell 1O2 detection\ndark as control. Then 10 \u00b5L of CCK-8 (Adamas Life) working solution\nwas added and incubated for another 1 h. Absorbance at 450 nm was HGC-27 cancer cells were incubated with different concentrations of\nmeasured on an TECAN (Infinite M Nano) microplate reader. Data were Os-3 (0.1, 1, and 2.5 \u00b5M) from a stock solution of 1 mM in DMSO for 8 h,\nreported as the mean \u00b1 standard deviation (n = 3). The relative IC50 and subsequently co-administered with the green fluorescent probe\nvalues of Os-1 \u00a1 Os-5 were determined by plotting the percentage of SOSG (2.5 \u00b5M, in DMSO) for 30 min. Next, the supernatant was removed\nviability versus concentration on a logarithmic graph. and cancer cells were washed with PBS buffer 3 times. After that, cells\n were exposed to blue LED irradiation (465 nm, 13 mW/cm2) for 1 h, and\n the green fluorescence was instantly observed on an OLYMPUS fluo\u00ad\n3.7. Cellular uptake\n rescence microscope (CKX53, excitation wavelength, 488 nm; emission\n wavelength, 495\u2013555 nm), cells treated with Os-3 in the dark were set as\n Cells were seeded at a density of 5 \u00d7 106 in a 10 cm cell culture dish,\n positive control, cell with SOSG only was set as negative control.\nand were administered with 10 \u03bcM of complexes Os-1 and Os-3 from a\nstock solution of 10 mM in DMSO, and the mixture was co-incubated for\nanother 4 h. The medium was then removed; and cells were trypsinized,\nharvested, centrifuged, resuspended in PBS, and countered. Next,\n\n 5\n\fF. Chen et al. Inorganica Chimica Acta 578 (2025) 122537\n\n\n\n\nFig. 5. In-cell singlet oxygen investigation with Os-3 using SOSG as the fluorescent probe by fluorescence microscope (excited at 488 nm; emission at 495\u2013555 nm).\n\n\n3.9. Subcellular localization by confocal microscopy 5, the electrochemical characterizations were performed in o-dichloro\u00ad\n benzene (o-DCB) solutions containing 2 mM Os-1 to Os-5 and 0.1 M\n A549 cells were seeded and incubated in confocal dishes overnight at TBAP as the supporting electrolytes (Fig. S17 and Fig. S18). The inves\u00ad\n37 \u25e6 C (5 % CO2). The next day, a solution (5 \u03bc M, in DMSO) of complex tigated five complexes Os-1 to Os-5 exhibit multi-redox potential peaks,\nOs-3 was added to replace cell medium, and complex was incubated indicates the powerful multi-electron donating and accepting properties\nwith cancer cells in the dark for 4 h. Next, the MitoTracker Green dye in as a result of its larger molecular skeleton (Table S1) [45]. Cyclic vol\u00ad\nDMSO was added at a final concentration of 75 nM, and a Hoechst tammetry of Os-1 \u00a1 Os-5 (Fig. S17 and Table S1) exhibited the oxida\u00ad\n33,342 solution (in DMSO) was added to the dishes after 20 min. Cells tion processes in the range of + 0.97 V \u00a1 +1.19 V, which are assignable\nwere washed with PBS and imaged on an OLYMPUS SpinSR confocal to the Os(II/III) couples, this is probably due to the powerful electron-\nmicroscope. withdrawing property of DIP ligand [46]; while the reductive electro\u00ad\n chemistry of Os-1 \u00a1 Os5 was more complicated, the most anodic pro\u00ad\n4. Results and discussion cess for those Os(II) complexes, that centered at \u2212 0.38 V \u00a1 -0.76 V, were\n assigned to the DIP based reduction process, the second and third\n4.1. Synthesis and characterization reduction waves are assigned to the coordinative ligands L1-L5 [46,47].\n The 1st Red.-1st Ox. gaps of Os-1 to Os-5 are 1.76, 1.54, 1.93, 1.73, and\n The synthesis of Os(II) complexes Os-1 \u00a1 Os-5 was based on the 1.71 eV, respectively.\nprevious method [24], as shown in Scheme 1, all five complexes were\nfully characterized by 1H and 13C NMR, HRMS and elemental analysis 4.3. DFT calculations and TD-DFT calculations\n(Figs. S1\u2013S15). The octanol/water partition coefficients (log PO/W) of\nOs-1 \u00a1 Os-5 were also assessed, giving log P values of 1.11 (Os-1), 1.48 DFT calculations for five complexes were performed to better\n(Os-2), 0.64 (Os-3), 1.26 (Os-4), and 0.81 (Os-5). investigate the electronic property (Fig. 2). In general, Os-1 \u00a1 Os-5\n The UV\u2013vis spectra of complexes Os-1 \u00a1 Os-5 in both acetonitrile showed a HOMO-LUMO gap in the range of 2.19\u20133.41 eV. For complexes\nand cell culture medium (1 % DMSO contained) were determined, which Os-3 \u00a1 Os-5, the lowest unoccupied molecular orbital (LUMO) is mainly\nshowed a typical panchromatic absorption in the wavelength range of constituted of \u03c0* phenanthroline ligand orbitals, while the highest\n240 nm to ca. 760 nm; all five Os(II) complexes gave a similar absorption occupied molecular orbital (HOMO) resides almost exclusively on the\nfeature which are analogous to the Os(II) complex profiles reported by aromatic substituents (phenyls for Os-4, and naphthalenes for Os-5), the\nGasser and Chao et al.[24]; As shown in Fig. 1 and Fig. S16, major and electron distributions are contrary to that of complexes Os-1 and Os-2.\nintense peaks at ca. 280 nm, that are assignable to the IL \u03c0\u03c0* transitions The attachment of aromatic rings led to a gentle orbital stabilization of\nof DIP were observed, while the adjacent two broad peaks at ca. 450 and 0.3\u20130.5 eV for complexes Os-3 \u00a1 Os-5, leaving the LUMO energy\n500 nm can be attributed to the metal to ligand charge transfer (MLCT) (approx. 6.45 eV) barely perturbed. Hence, such distribution may\nof Os(d\u03c0) toward the chelated ligands(\u03c0*), and finally a weaker broad- demonstrate an apparent intramolecular charge transform (ICT) ab\u00ad\nband covering the region 650\u2013760 nm [43]. The latter can be sorption for these complexes [48]. Next, time-dependent DFT (TD-DFT)\nexplained by the spin-forbidden MLCT transitions due to the direct calculations were also performed. The simulated electronic absorption\nsinglet\u2013triplet transition of the Os(II) complexes [23,44]; which can be spectra were depicted in Figs. S19\u2013S23 and Tables S2\u2013S6. The frontier\nexplained by the strong spin\u2013orbit coupling of osmium, that often molecular orbitals and TD-DFT result of Os-1-Os-5 exhibited the ab\u00ad\nencountered in heavy atoms [24]. sorption of main bands are all assignable to UV\u2013vis absorptions, with the\n highest oscillator strengths (f) of Os-1-Os-5 in the range of 0.2 to 0.4.\n4.2. Electrochemical study The DFT and TD-DFT results further confirmed the ICT transform ab\u00ad\n sorptions for Os-1-Os-5.\n In order to further understand the electronic structure of Os-1 to Os-\n\n 6\n\fF. Chen et al. Inorganica Chimica Acta 578 (2025) 122537\n\n\n4.4. 1O2 generation 4.6. Cellular uptake\n\n Initially, the photo-stability of these Os(II) complexes was deter\u00ad The cell uptake of complexes Os-1 and Os-3 was determined in A549\nmined under blue LED light irradiation (Fig. S24), all Os(II) complexes and HGC-27 cancer cells using inductively coupled plasma mass spec\u00ad\nshowed high photo-stability in 60 min under irradiation. Next, the trometry (ICP-MS). As shown Fig. 4 and Table S9. Os-3 in A549 cells was\nsinglet oxygen generation capacity of complexes Os-1 \u00a1 Os-5 was found to have the highest cellular uptake of 96.1 ng/106 cells; and have\ndetermined using ABDA as a trapping agent, and Os (II) complexes with 68.2 ng/106 cells in HGC-27 cells after 4 h co-incubation; these are\nABDA in the dark was set as negative control (Fig. S25). As shown in higher than that of Os-1 in the A549 and HGC-27 cells, which were ca.\nFig. 3. and Fig. S26, ABDA can be degraded by all Os (II) complexes in 55 ng per 106 cells (53.3 vs 59.4), respectively; this is probably due to\n60 min under blue LED light irradiation (465 nm); as shown in Fig. 3b, the higher lipophilicity of ligand L3 in comparison to L1.\nthe conjugative \u03c0 extension of coordinative ligands from L1 to L3 has\ngiven an pronounced enhancement in the 1O2 generation rate for Os-1 4.7. Subcellular localization and in cell 1O2 determination\n\u00a1 Os-3, in the order of Os-1 < Os-2 < Os-3, complex Os-3 gave the\nhighest efficiency that oxidized ABDA in 30 min which is comparable to The subcellular localization of Os-3 in A549 human non-small cell\nRu(bpy)3Cl2, however, the \u03c0 extensions by covalent bonding for Os-4 lung cancer cells was determined by confocal microscopy using\nand Os-5 have rarely changed the generation rate in comparison to Os- Hoechst33342 (nucleus) and MitoTracker Green (MTG, mitochondrial)\n2. The 1O2 quantum yield of five Os (II) complexes were in the range of as tracking dyes (Fig. 4b). The luminescence of Os-3 was appeared as a\n0.36\u20130.65 (Fig. S26 and Table S7), where Os-3 with a quantum yield diffused signal in A549 cells after 4 h incubation (Fig. 4d), and showed\nvalue of 0.65, is apparently higher than Ru(bpy)3Cl2 (0.57 in ACN), and weak signal overlap with MTG, suggested that Os-3 has a low tendency\nis higher than those of Os(II) complexes by Gilles et al. [24]. 1O2 gen\u00ad to target mitochondria. While only limited accumulation of Os-3 in the\neration in aqueous solutions by Os-1 \u00a1 Os-5 was also determined with nucleus, as shown by the absence of colocalization with Hoechst 33,342\nthe same method above to investigate the influence of aqua (DMSO/ and MitoTracker Green (Fig. 4c and 4e).\nH2O, 1:9) on the quantum yield, as shown in Fig. S27 and Table S7, the Next, the in-cell 1O2 generation by Os-3 under the concentrations of\n1\n O2 quantum yields of Os-1 \u00a1 Os-5 were significantly lower with 0.1, 1 and 2.5 \u00b5M, was investigated in HGC-27 human gastric cancer\nquantum yield values in the range of 0.14\u20130.27. cells, using SOSG as the green fluorescent sensor, cells with SOSG only\n Next, the 1O2 generation by the Os (II) complexes were also inves\u00ad were applied as negative control. As shown in Fig. 5, the fluorescence\ntigated under red LED irradiation (640 nm) with DPBF as the trapping signals in cells by three different concentrations of Os-3 were observed,\nagent, Os (II) complexes with DPBF in the dark was also set as negative and exhibited a concentration-dependent manner, that the intensity has\ncontrol (Fig. S28); all complexes showed a similar efficiency trend to been enhanced when co-administered with 2.5 \u00b5M of Os-3 under blue\nthat of blue LED light irradiation, Os-3 remained the most pronounced LED light irradiation, while only weak fluorescence signals in HGC-27\n1\n O2 generation ability among five Os(II) complexes that the inductively cells with Os-3 were seen in the dark. The different observed fluores\u00ad\ngenerated 1O2 by Os-3 can decompose DPBF within 1 min (Fig. 3c and d, cence signals demonstrated the PDT mechanism of action of such Os(II)\nFig. S29, and Fig. S30). The conjugative \u03c0-ring elongation from Os-1 to complexes in cancer cells.\nOs-3 have improved the rigidity of the molecules, thus may have\ndiminished the vibrational relaxation rate of energy transfer, that 5. Conclusions\nresulted into an apparent enhancement of 1O2 generation [29].\n In summary, we have designed and synthesized five polypyridyl Os\n4.5. Antiproliferative activity in vitro (II) complexes Os-1 \u00a1 Os-5, these complexes were fully characterized\n by NMR, HRMS and elemental analysis; Os-1 \u00a1 Os-5 showed a\n Anticancer activity of five Os(II) complexes against three cancerous panchromatic UV\u2013vis absorption character. The electronic properties of\ncell lines, A549 human non-small cell lung cancer, MGC-803, and HGC- Os-1 \u00a1 Os-5 were investigated by CV and DFT calculations. An obvious\n 1\n27 (undifferentiated) human gastric cancer cells was determined with O2 generation enhancement tendency was observed when \u03c0 ring of the\ntwo LED light irradiations: 640 nm (red LED light) and 465 nm (blue coordinative ligand was conjugatively elongated, led to a rising order of\nLED light), and compared with the control group (in the dark), cisplatin Os-1 < Os-2 < Os-3 under either blue or red LED irradiation, and the\n 1\nand 5-ALA were investigated as positive control. As shown in Table 1, O2 quantum yield (\u0424\u0394S) of Os-3 was even higher than the reference\nOs-1 \u00a1 Os-5 showed low cytotoxicity towards A549 cells, with most of complex Ru(bpy)3Cl2 (0.65 VS 0.57), however the covalent \u03c0 ring bond\nthe IC50 values over 10 \u00b5M in the dark. Gratifyingly, Os-2 induced a for Os-4 and Os-5 did not facilitate further 1O2 generation in comparison\nsignificant photocytotoxicity against A549 cells under blue LED light to that of the parent structure-Os-2. Os-1 \u00a1 Os-5 exhibited potent\nirradiation, with PI value as high as 15, while for the rest of the PI values antiproliferative activity against MGC-803 and HGC-27 human gastric\nare all lower than 5. Of note, all Os(II) complexes could induce an potent cancer cells, with IC50 values low as 0.37 \u00b5M (blue LED light) and 0.32\ncell viability deduction against human gastric cancer cells, i.e. MGC-803 \u00b5M (blue LED light), Os-2 gave the highest PI value (PI = 15) in A549\nand HGC-27 cell lines, with IC50 values in the range of 0.32 to 2.2 \u00b5M, cancer cell inhibition. Cell uptake of Os-1 and Os-3 in A549 and HGC-27\nthe major of which are nanomolar levels. While regretfully, all com\u00ad cells was in the range of 53\u201396 ng/106 cells. In cell 1O2 detection dis\u00ad\nplexes showed obvious cytotoxicity against gastric cancer cells even in played a concentration-dependent manner, and the complex was not\nthe dark, with the IC50 values fell within the scope of 0.87\u20133.10 \u00b5M, accumulated in nucleus, nor targeting mitochondria upon entering cells.\nwhich were much more cytotoxic than that of cisplatin and 5-ALA as The trend in 1O2 generation of these Os(II) complexes may provide a\nshown in Table S8. Os-1 \u00a1 Os-5 also showed an apparent growth in\u00ad useful strategy for the development of photosensitizers, and the potent\nhibition on all tested cancer cells under red LED light irradiation, the anticancer activity of Os-1 \u00a1 Os-5 may demonstrate a potential appli\u00ad\nIC50 value was low as 0.32 \u00b5M (PI = 2.7). The significant inhibition of cation in PDT and chemotherapeutic therapy in gastric cancer\ncell viability in MGC-803 and HGC-27 cells under blue light irradiation, treatment.\nconfirmed the potential application of these Os(II) complexes as prom\u00ad\nising photosensitizers and chemotherapeutic drugs in treatment of CRediT authorship contribution statement\ngastric cancers.\n Feng Chen: Data curation, Formal analysis, Funding acquisition,\n Methodology, Project administration, Writing \u2013 review & editing. Kelun\n Cui: Formal analysis, Investigation, Writing \u2013 review & editing. Shufen\n\n 7\n\fF. Chen et al. Inorganica Chimica Acta 578 (2025) 122537\n\n\nSi: Data curation, Methodology, Resources, Validation. Yong Liu: [17] Y. Zhang, B.-T. Doan, G. Gasser, Chem. Rev. 123 (2023) 10135\u201310155.\n [18] R.G. Kenny, C.J. Marmion, Chem. Rev. 119 (2019) 1058\u20131137.\nInvestigation, Methodology. Songlin Xue: Funding acquisition, Inves\u00ad\n [19] L. Conti, E. Macedi, C. Giorgi, B. Valtancoli, V. Fusi, Coord. Chem. Rev. 469 (2022)\ntigation, Methodology, Writing \u2013 original draft. Gaoji Wang: Funding 214656.\nacquisition, Investigation, Project administration, Writing \u2013 original [20] A. Herna\u0301ndez-Garc\u00eda, L. Markova\u0301, M.D. Santana, J. Pracharov\u030ca\u0301, D. Bautista, H.\ndraft, Writing \u2013 review & editing. Xu Liang: Methodology, Project Kostrhunova\u0301, V. Novohradsky, \u0301 V. Brabec, J. Ruiz, and J. Kasp\u030ca\u0301rkova\u0301, Inorg. Chem.\n 62 (2023) 6474\u20136487.\nadministration, Writing \u2013 original draft, Writing \u2013 review & editing. [21] M.-F. Wang, Y.-A. Deng, Q.-F. Li, S.-J. Tang, R. Yang, R.-Y. Zhao, F.-D. Liu, X. Ren,\nChunyin Zhu: Project administration, Supervision, Writing \u2013 review & D. Zhang, F. Gao, Chem. Commun. 58 (2022) 12676\u201312679.\nediting. Qiu-Yun Chen: Methodology, Project administration, Super\u00ad [22] J.A. Roque III, P.C. Barrett, H.D. Cole, L.M. Lifshits, G. Shi, S. Monro, D. von\n Dohlen, S. Kim, N. Russo, G. Deep, C.G. Cameron, M.E. Alberto, S.A. McFarland,\nvision, Writing \u2013 original draft, Writing \u2013 review & editing. Chem. Sci. 11 (2020) 9784\u20139806.\n [23] S. Lazic, P. Kaspler, G. Shi, S. Monro, T. Sainuddin, S. Forward, K. Kasimova,\nDeclaration of competing interest R. Hennigar, A. Mandel, S. McFarland, L. Lilge, Photochem. Photobiol. 93 (2017)\n 1248\u20131258.\n [24] A. Mani, T. Feng, A. Gandioso, R. Vinck, A. Notaro, L. Gourdon, P. Burckel,\n The authors declare that they have no known competing financial B. Saubame\u0301a, O. Blacque, K. Cariou, J.-E. Belgaied, H. Chao, G. Gasser, Angew.\ninterests or personal relationships that could have appeared to influence Chem. Int. Ed. 62 (2023) e202218347.\n [25] N. Lu, Z. Deng, J. Gao, C. Liang, H. Xia, P. Zhang, Nat. Commun. 13 (2022) 2245.\nthe work reported in this paper. [26] P. Zhang, Y. Wang, K. Qiu, Z. Zhao, R. Hu, C. He, Q. Zhang, H. Chao, Chem.\n Commun. 53 (2017) 12341\u201312344.\nAcknowledgements [27] J.J. Nogueira, M. Oppel, L. Gonz\u0301lez, Angew. Chem. Int. Ed. 54 (2015) 4375\u20134378.\n [28] J. Zhao, Y. Gao, R. Huang, C. Chi, Y. Sun, G. Xu, X.-Hua Xia, and S. Gou, J. Am.\n Chem. Soc. 145 (2023) 11633\u201311642.\n This work was partly supported by the National Natural Science [29] J.A. Treadway, B. Loeb, R. Lopez, P.A. Anderson, F.R. Keene, T.J. Meyer, Inorg.\nFoundation of China (Grant No. 22207046 and 22301108), Natural Chem. 35 (1996) 2242\u20132246.\nScience Foundation of Jiangsu Province (Grant No. BK20220528), and [30] K.M. Kuznetsov, K. Cariou, G. Gasser, Chem. Sci. 15 (2024), https://doi.org/\n 10.1039/d4sc04608k.\nthe Project Startup Foundation for Distinguished Scholars of Jiangsu [31] N. Macia, V. Kabanov, B. Heyne, J. Phys. Chem. C 124 (2020) 3768\u20133777.\nUniversity (4111310026, 5501310019, and 5501310014). [32] M.R. Younis, R. An, Y. Wang, G. He, B. Gurram, S. Wang, J. Lin, D. Ye, P. 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