Utilization of Rhenium(I) Polypyridine Complexes Featuring a Dinitrophenylsulfonamide Moiety as Biothiol‐Selective Phosphorogenic Bioimaging Reagents and Photocytotoxic Agents

{"full_text": " Full Papers\n doi.org/10.1002/ejic.202100364\n\n\n\n\nUtilization of Rhenium(I) Polypyridine Complexes Featuring\na Dinitrophenylsulfonamide Moiety as Biothiol-Selective\nPhosphorogenic Bioimaging Reagents and Photocytotoxic\nAgents\nGuang-Xi Xu,[a] Lawrence Cho-Cheung Lee,[a] Cyrus Wing-Ching Kwok,[a]\nPeter Kam-Keung Leung,[a] Jing-Hui Zhu,[a] and Kenneth Kam-Wing Lo*[a, b, c]\n\nWe report herein a series of rhenium(I) polypyridine complexes moiety to the DNPS quenching unit. However, upon treatment\nfeaturing a 2,4-dinitrophenylsulfonamide (DNPS) unit as phos- with glutathione (GSH), the DNPS moiety was removed,\nphorogenic bioimaging reagents and photocytotoxic agents. resulting in emission enhancement of the solutions (I/Io = 12.6\u2013\nThe biothiol-selective rhenium(I) polypyridine complexes [Re- 22.2). After reaction of the DNPS complexes with GSH in living\n(N^N)(CO)3(py-DNPS)](CF3SO3) (py-DNPS = 3-((2,4-dinitrophenyl- cells, intense intracellular emission and potent photocytotox-\nsulfonyl)aminomethyl)pyridine) and their DNPS-free counter- icity were both observed. Additionally, the modification of the\nparts [Re(N^N)(CO)3(pyridine)](CF3SO3) were synthesized and diimine ligand with a tosylamide unit conferred on the\ncharacterized. Upon photoexcitation, the DNPS complexes complexes an endoplasmic reticulum (ER)-targeting ability,\nexhibited very weak luminescence as a result of photoinduced which can be exploited for selective bioimaging and photo-\nelectron transfer (PET) from the excited rhenium(I) diimine cytotoxic applications.\n\n\nIntroduction oxygen (1O2) cannot be totally avoided due to a lack of cancer\n selectivity.[7] Thus, the introduction of a GSH-responsive unit to\nAs the most common biothiol in cells, glutathione (GSH) plays a the photosensitizers is expected to modulate their 1O2 gen-\ncrucial role in biological processes such as xenobiotic metabo- eration efficiency and allow them to selectively produce\nlism, intracellular redox status regulation, and cell cytotoxic 1O2 in cancer cells, which are known to display an\ndifferentiation.[1] Due to the high reactivity of the sulfhydryl elevated GSH level compared to normal cells.[8]\ngroup of GSH, significant effort has been devoted to the design Endoplasmic reticulum (ER) is the largest cellular organelle\nof GSH-responsive bioimaging probes based on different in eukaryotic cells that is responsible for the synthesis, folding,\nreaction mechanisms including nucleophilic reaction,[2] Michael and post-translational modification of intracellular proteins.[9a,b]\naddition,[3] and disulfide cleavage.[4] The development of GSH- It is also involved in the storage of Ca2 + ions and lipid\nactivatable photosensitizers for photodynamic therapy (PDT) biosynthesis.[9c,d] Perturbation of the protein-folding ability of ER\nhas also attracted considerable attention in the past few causes dysregulation of ER functions and leads to ER stress,\ndecades.[5] PDT is an attractive modality for cancer therapy due which is known to be associated with various pathological\nto its non-invasive nature and minimal adverse effects.[6] conditions including heart disease, stroke, and neurodegener-\nHowever, the damage to ambient normal tissues caused by the ative diseases.[10] Notably, GSH and its oxidized form (GSSG) are\nphotosensitizers through the generation of cytotoxic singlet an important thiol redox couple for the regulation of redox\n homeostasis in the ER.[11] On the basis of previous ER-targeting\n probes,[12,13] real-time imaging of ER through a GSH-activation\n[a] G.-X. Xu, Dr. L. C.-C. Lee, C. W.-C. Kwok, P. K.-K. Leung, J.-H. Zhu, Prof. K. K.- pathway is anticipated to be a useful strategy to understand its\n W. Lo\n Department of Chemistry\n physiological functions.\n City University of Hong Kong In view of the rich photophysical properties and tunable\n Tat Chee Avenue, Kowloon, Hong Kong, P. R. China cellular uptake behavior of transition metal complexes,[14]\n E-mail: bhkenlo@cityu.edu.hk\n[b] Prof. K. K.-W. Lo\n iridium(III) and ruthenium(II) complexes have been developed\n State Key Laboratory of Terahertz and Millimeter Waves as GSH-responsive probes for bioimaging[15] and photosensi-\n City University of Hong Kong tizers for PDT.[16] However, to the best of our knowledge, GSH-\n Tat Chee Avenue, Kowloon, Hong Kong, P. R. China\n[c] Prof. K. K.-W. Lo\n sensitive phosphorogenic rhenium(I) polypyridine complexes\n Center of Functional Photonics have been rarely examined.[17] We envisage that the incorpo-\n City University of Hong Kong ration of a GSH-responsive 2,4-dinitrophenylsulfonamide\n Tat Chee Avenue, Kowloon, Hong Kong, P. R. China\n (DNPS) unit into rhenium(I) polypyridine complexes will afford a\n Supporting information for this article is available on the WWW under\n https://doi.org/10.1002/ejic.202100364 new generation of GSH-responsive agents for biological\n Part of the joint \u201cMetals in Medicine\u201d Special Collection with ChemMed- applications. Herein, we report the synthesis and character-\n Chem. ization of a series of rhenium(I) polypyridine complexes\n\nEur. J. Inorg. Chem. 2021, 3432 \u2013 3442 3432 \u00a9 2021 Wiley-VCH GmbH\n\f 10990682c, 2021, 34, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejic.202100364 by Lomonosov Moscow State University, Wiley Online Library on [12/05/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License\n Full Papers\n doi.org/10.1002/ejic.202100364\n\n\ncontaining a DNPS moiety [Re(N^N)(CO)3(py-DNPS)](CF3SO3) involved the reaction of 3-(aminomethyl)pyridine with 2,4-\n(py-DNPS = 3-((2,4-dinitrophenylsulfonyl)aminomethyl)pyridine; dinitrophenylsulfonyl chloride in dry THF. A tosylamide group\nN^N = 4-N-((p-toluenesulfonylamino)ethyl)aminomethyl-4\u2019- was introduced as an ER-targeting unit to the diimine ligand of\nmethyl-2,2\u2019-bipyridine (bpy-tosylamide) (1 a), 3,4,7,8-tetrameth- complexes 1 a and 1 b. The ligand bpy-tosylamide was prepared\nyl-1,10-phenanthroline (Me4-phen) (2 a), 4,7-diphenyl-1,10-phe- by reductive amination of 4-formyl-4\u2019-methyl-2,2\u2019-bipyridine\nnanthroline (Ph2-phen) (3 a), 1,10-phenanthroline (phen) (4 a)) (bpy-CHO) with N-(2-aminoethyl)-4-methylbenzenesulfonamide.\nand their DNPS-free counterparts [Re- Reaction of the precursor [Re(N^N)(CO)3(CH3CN)](CF3SO3) with\n(N^N)(CO)3(pyridine)](CF3SO3) (N^N = bpy-tosylamide (1 b), Me4- py-DNPS in refluxing THF led to the formation of complexes\nphen (2 b), Ph2-phen (3 b), phen (4 b)) (Figure 1). The design of 1 a\u20134 a. The DNPS-free complexes 1 b\u20134 b were also prepared\ncomplexes 1 a\u20134 a involved the modification of rhenium(I) for comparison studies. All the complexes were characterized\npolypyridine complexes with DNPS as a thiol-sensitive emission by ESI-MS, 1H and 13C NMR, IR spectroscopy, and gave\nquenching moiety. The complexes are expected to show very satisfactory elemental analysis.\nweak emission due to efficient photoinduced electron transfer\n(PET) from the excited rhenium(I) polypyridine unit to the DNPS\nmoiety. We anticipate that upon reaction with GSH, the DNPS Photophysical properties\nunit will be removed from the complexes, leading to substan-\ntially increased emission intensities and lifetimes and enhanced The electronic absorption data of the ligand py-DNPS and the\n1\n O2 generation efficiency. Since the tosylamide unit is known to rhenium(I) polypyridine complexes at 298 K are presented in\nspecifically bind to ATP-sensitive K + channels in the ER Table S1 and the electronic absorption spectra are shown in\nmembrane, complexes 1 a and 1 b containing a bpy-tosylamide Figure S1. Complexes 1 a\u20134 a showed intense spin-allowed\nunit are expected to display ER-targeting capability. intraligand (1IL) (\u03c0!\u03c0*) (N^N and pyridine) absorption at\n \ufffd 250\u2013320 nm (\u025b on the order of 104 dm3 mol 1 cm 1) and\n weaker spin-allowed metal-to-ligand charge-transfer (1MLCT)\nResults and Discussion (d\u03c0(Re)!\u03c0*(N^N)) absorption bands/shoulders at \ufffd 320\u2013\n 390 nm, which is in accordance with previously reported\nSynthesis rhenium(I) complexes.[18d,e,19] Notably, the DNPS complexes 1 a\u2013\n 4 a exhibited stronger absorption in the UV region than their\nRhenium(I) polypyridine complexes were chosen as the model DNPS-free counterparts 1 b\u20134 b due to the DNPS unit.\nluminophore in this study due to their interesting photophysical Upon irradiation, the rhenium(I) polypyridine complexes\ncharacteristics and tunable cellular uptake and localization showed green to yellow emission in degassed solutions under\nproperties.[18] The DNPS moiety was introduced to the pyridine ambient conditions and in low-temperature alcohol glass. The\nligand as it can be cleaved by GSH, which will allow modulation photophysical data are listed in Table 1. Importantly, complexes\nof the emission properties and photoinduced 1O2 generation of 1 a\u20134 a revealed much weaker emission intensity (\u03a6em = 0.003\u2013\nthe complexes. The synthetic procedure of the ligand py-DNPS\n\n Table 1. Photophysical data of the rhenium(I) polypyridine complexes.\n Complex Medium (T [K]) \u03bbem [nm] \u03c4o [\u03bcs] \u03a6em\n\n 1a CH2Cl2 (298) 537 0.19 0.007\n CH3CN (298) 550 0.12 0.003\n Glass[a] (77) 490 4.31\n 1b CH2Cl2 (298) 535 0.69 0.18\n CH3CN (298) 557 0.24 0.04\n Glass[a] (77) 492 4.36\n 2a CH2Cl2 (298) 515 0.12 0.015\n CH3CN (298) 516 < 0.1 0.004\n Glass[a] (77) 465 (max), 498, 535 34.73\n 2 b[17b] CH2Cl2 (298) 490 sh, 510 11.88 0.57\n CH3CN (298) 485 sh, 515 8.70 0.28\n Glass[a] (77) 466 (max), 499, 535 50.57\n 3a CH2Cl2 (298) 541 0.18 0.017\n CH3CN (298) 551 < 0.1 0.008\n Glass[a] (77) 504, 530 sh 22.69\n 3 b[17b] CH2Cl2 (298) 542 9.08 0.46\n CH3CN (298) 558 4.04 0.13\n Glass[a] (77) 508 19.85\n 4a CH2Cl2 (298) 531 0.21 0.043\n CH3CN (298) 546 < 0.1 0.009\n Glass[a] (77) 492 11.29\n 4b CH2Cl2 (298) 531 2.79 0.33\n CH3CN (298) 546 1.60 0.18\n Glass[a] (77) 497 10.19\n\nFigure 1. Structures of the rhenium(I) polypyridine complexes. [a] EtOH/MeOH (4 : 1, v/v).\n\n\nEur. J. Inorg. Chem. 2021, 3432 \u2013 3442 www.eurjic.org 3433 \u00a9 2021 Wiley-VCH GmbH\n\f 10990682c, 2021, 34, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejic.202100364 by Lomonosov Moscow State University, Wiley Online Library on [12/05/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License\n Full Papers\n doi.org/10.1002/ejic.202100364\n\n\n0.043) compared with their DNPS-free counterparts 1 b\u20134 b Phosphorogenic responses toward GSH\n(\u03a6em = 0.04\u20130.57) in solutions at 298 K, as a result of emission\nquenching by the appended DNPS moiety. Complexes 1 a,b, As the electron-withdrawing DNPS moiety is readily cleaved\n3 a,b, and 4 a,b displayed a broad emission band that showed a upon reaction with GSH through thiol-induced elimination,[15c]\nred-shift upon changing the solvent from less polar CH2Cl2 to the sensitivity of complexes 1 a\u20134 a toward GSH was studied.\nmore polar CH3CN, which is a typical feature of triplet metal-to- After incubation with GSH (1 mM) in aerated aqueous buffer at\nligand charge-transfer (3MLCT) (d\u03c0(Re)!\u03c0*(N^N)) emission.[18d,e] 298 K for 12 h, solutions of complexes 1 a\u20134 a showed significant\nIn contrast, the Me4-phen complexes 2 a,b exhibited a struc- emission enhancement with extended emission lifetimes (I/Io =\ntured emission band with very long emission lifetimes (34.73 12.6\u201322.2, \u03c4 = 0.13\u20131.20 \u03bcs) (Table 3 and Figure 2). These photo-\nand 50.57 \u03bcs, respectively) in alcoholic glass at 77 K, indicative physical changes were ascribed to thiol-induced removal of the\nof the involvement of triplet intraligand (3IL) (\u03c0!\u03c0*) (Me4-phen) quenching DNPS moiety (Scheme 1), resulting in the formation\ncharacter in the 3MLCT (d\u03c0(Re)!\u03c0*(Me4-phen)) emissive of the strongly emissive aminomethylpyridine complexes 1 aP\u2013\nstate.[18d,19] 4 aP (Table S2). As shown in Figure 3, incubation of complex 1 a\n with GSH led to a drop of absorption at 260 nm and an increase\n at 360 nm with sharp isosbestic points at 260 and 300 nm. This\nElectrochemical properties indicates the clean conversion of the complex into its\n aminomethylpyridine counterpart 1 aP, which was confirmed by\nThe electrochemical properties of the rhenium(I) polypyridine a peak at m/z = 776 in the ESI-mass spectrum of the CH2Cl2\ncomplexes were investigated by cyclic voltammetry and the extract of the reaction mixture (Figure S2). Time-dependent\ndata are listed in Table 2. With reference to the previous emission enhancement studies indicated that after incubation\nelectrochemical studies of related rhenium(I) polypyridine of complex 1 a (10 \u03bcM) with GSH (1 mM), the emission intensity\ncomplexes,[20] the quasi-reversible couples of the complexes at of the solutions increased gradually and equilibrated in\n+ 1.54 to + 1.69 V and 1.17 to 1.41 V versus SCE were < 30 min (Figure 4). Since the emission intensity of a bioprobe\nassigned to the metal-centered rhenium(II)/(I) couple and the should be independent on pH, at least in the physiological\nreduction of diimine ligands, respectively. The additional quasi- range,[21] the effect of pH on the response of complex 1 a\nreversible couples of complexes 1 a\u20134 a at 0.75 to 0.81 V toward GSH was evaluated. Figure S3 illustrates that the\nwere attributed to the reduction of the py-DNPS ligand, as a emission intensities of both complex 1 a and its aminometh-\nsimilar reduction couple was observed for the uncoordinated ylpyridine counterpart 1 aP remained stable in the pH range of\npy-DNPS ligand at a slightly more cathodic potential ( 0.88 V). 6\u20139, indicating that complex 1 a can give reliable emission\nOn the basis of the low-temperature emission energy (E00 = response toward GSH at physiological pH ( \ufffd 7.0\u20138.0).\n2.46\u20132.67 eV, Table 1) and the redox potentials (E\u00b0[Re2 + / + ]) of The selectivity of complex 1 a toward GSH was examined by\ncomplexes 1 a\u20134 a (+ 1.61 to + 1.69 V), the excited-state redox emission measurements. The emission changes of complex 1 a\npotentials (E\u00b0[Re2 + / + *]) were determined to range from 0.85\nto 1.07 V versus SCE. These values are more negative than the\nreduction potential of the coordinated py-DNPS ligand ( 0.75\n Table 3. Emission enhancement factors and lifetimes of a mixture of\nto 0.81 V), demonstrating that PET from the excited complexes 1 a\u20134 a (10 \u03bcM) and GSH (1 mM) in aerated potassium\nrhenium(I) polypyridine unit to the appended DNPS moiety is phosphate buffer (50 mM, pH 7.4)/MeOH (9 : 1, v/v) upon incubation at\nthermodynamically favorable (\u0394Go = 0.06 to 0.31 eV), which 298 K for 12 h.[a]\nis believed to contribute to efficient emission quenching. Complex I/Io[b] \u03c4 [\u03bcs]\n\n 1a 18.2 0.13\n 2a 12.6 1.20\n 3a 12.9 1.10\n 4a 22.2 0.59\n\n [a] In the absence of GSH, the emission lifetimes of the complexes could\nTable 2. Electrochemical data of the rhenium(I) polypyridine complexes not be determined accurately. [b] Io and I are the emission intensities of a\nand the free ligand py-DNPS.[a] solution of the complexes in the absence and presence of GSH (1 mM),\n respectively.\n Compound Oxidation, E1/2 [V] Reduction, E1/2 or Ec [V]\n [b]\n 1a + 1.69 0.78,[b] 1.31,[b] 1.64,[b] 1.93[b]\n 1b + 1.64[b] 1.22,[c] 1.61, 1.85[b]\n 2a + 1.61[b] 0.75,[b] 1.41,[b] 1.66,[b] 1.87[b]\n 2b + 1.54[b] 1.30,[b] 1.75, 1.98[b]\n 3a + 1.62[b] 0.79,[b] 1.21,[b] 1.58,[b] 1.89[b]\n 3b + 1.61[b] 1.23,[c] 1.5, 1.71[b]\n 4a + 1.66[b] 0.81,[b] 1.17,[b] 1.45[b]\n 4b + 1.58[b] 1.16,[c] 1.41\n py-DNPS 0.88, 1.39[b]\n\n[a] In CH3CN (0.1 M TBAP) at 298 K, glassy carbon electrode, sweep rate =\n100 mV s 1, all potentials are versus SCE. [b] Quasi-reversible couples. [c] Scheme 1. Reaction of the rhenium(I) DNPS complexes 1 a\u20134 a with a thiol\nIrreversible waves. (HS R) yielding complexes 1 aP\u20134 aP.\n\n\nEur. J. Inorg. Chem. 2021, 3432 \u2013 3442 www.eurjic.org 3434 \u00a9 2021 Wiley-VCH GmbH\n\f 10990682c, 2021, 34, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejic.202100364 by Lomonosov Moscow State University, Wiley Online Library on [12/05/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License\n Full Papers\n doi.org/10.1002/ejic.202100364\n\n\n\n\nFigure 2. Emission spectra of complexes 1 a\u20134 a (10 \u03bcM) in the absence (black) and presence (red) of GSH (1 mM) in aerated potassium phosphate buffer\n(50 mM, pH 7.4)/MeOH (9 : 1, v/v) upon incubation at 298 K for 12 h. Excitation wavelength = 355 nm.\n\n\n\n\nFigure 3. UV-Vis absorption spectral traces of a mixture of complex 1 a\n(10 \u03bcM) and GSH (1 mM) in aerated potassium phosphate buffer (50 mM, Figure 4. Time-dependent emission curve of complex 1 a (10 \u03bcM) with GSH\npH 7.4)/MeOH (9 : 1, v/v) upon incubation at 298 K from 0 to 1 h. (1 mM) in aerated potassium phosphate buffer (50 mM, pH 7.4)/MeOH (9 : 1,\n v/v) at 298 K. Excitation wavelength = 355 nm.\n\n\n(10 \u03bcM) upon incubation with a variety of biologically relevant\nmolecules including amino acids, reactive oxygen species, and Cellular studies\nreactive nitrogen species (1 mM) are summarized in Figure 5.\nThe emission of complex 1 a only showed enhancement after The cellular uptake efficiencies, cytotoxicity, and bioimaging\ntreatment with GSH and cysteine (Cys) due to thiol-induced properties of the rhenium(I) polypyridine complexes were\nDNPS elimination. Since the concentration of GSH in an studied by inductively coupled plasma-mass spectrometry (ICP-\nintracellular microenvironment (1\u201310 mM) is much higher than MS), the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium\nthat of Cys (30\u2013100 \u03bcM),[22] GSH is considered as the most bromide (MTT) assay, and laser-scanning confocal microscopy\nreactive biothiol to the DNPS complexes, and the interference (LSCM), respectively. Human cervix carcinoma (HeLa) cells were\ncaused by Cys in cells is negligible. selected as the model cell line. As shown in Table 4, after\n The significant emission enhancement, good selectivity incubation with the rhenium(I) polypyridine complexes (10 \u03bcM)\nagainst competitive biomolecules, and pH-insensitive properties for 2 h, an average HeLa cell contained 0.12\u20131.31 fmol of\nreveal that the rhenium(I) DNPS complexes are promising complexes. The cellular uptake efficiency of the complexes\ncandidates as GSH-responsive reagents for cellular applications. followed the orders: 3 a > 2 a > 1 a \ufffd 4 a and 3 b > 2 b > 1 b \ufffd 4 b,\n which is in line with the lipophilicity of the complexes due to\n\nEur. J. Inorg. Chem. 2021, 3432 \u2013 3442 www.eurjic.org 3435 \u00a9 2021 Wiley-VCH GmbH\n\f 10990682c, 2021, 34, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejic.202100364 by Lomonosov Moscow State University, Wiley Online Library on [12/05/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License\n Full Papers\n doi.org/10.1002/ejic.202100364\n\n\n\n\nFigure 5. Emission enhancement factors (I/Io) at 555 nm of complex 1 a\n(10 \u03bcM) in the presence of various reagents (1 mM) in aerated potassium\nphosphate buffer (50 mM, pH 7.4)/MeOH (9 : 1, v/v) upon incubation at 298 K Figure 6. Relative cellular uptake of rhenium associated with an average\nfor 12 h. Excitation wavelength = 355 nm. HeLa cell after incubation with complexes 1 a (black) and 3 a (red) (10 \u03bcM) at\n 37 \u00b0C, 4 \u00b0C, and after preincubation with CCCP (20 \u03bcM), colchicine (12.5 \u03bcM),\n chlorpromazine (1 \u03bcM) and \u03b2-cyclodextrin (5 mM). Uptake values at 37 \u00b0C\n were taken as reference in each complex.\nTable 4. Cellular uptake and cytotoxicity (IC50, 24 h) of the rhenium(I)\npolypyridine complexes toward HeLa cells.\n Complex Amount of rhenium [fmol][a] IC50 [\u03bcM]\n\n 1a 0.13 \ufffd 0.01 33.7 \ufffd 2.5 complex 1 a was negligible (Figure 6). This result highlights that\n 1b 0.12 \ufffd 0.01 36.4 \ufffd 0.8 caveolae-mediated endocytosis is also important for the cellular\n 2a 0.44 \ufffd 0.02 12.7 \ufffd 2.0 uptake of complex 3 a. The cytotoxicity of all the rhenium(I)\n 2b 0.55 \ufffd 0.01 16.9 \ufffd 1.0\n 3a 1.31 \ufffd 0.01 6.50 \ufffd 2.0 polypyridine complexes toward HeLa cells was presented as\n 3b 0.99 \ufffd 0.01 10.3 \ufffd 0.5 half-maximal inhibitory concentration (IC50) values, which are\n 4a 0.14 \ufffd 0.01 32.9 \ufffd 0.3 summarized in Table 4. The results indicate that the orders of\n 4b 0.20 \ufffd 0.01 39.4 \ufffd 1.3\n cytotoxicity of the complexes are 3 a > 2 a > 1 a \ufffd 4 a and 3 b >\n[a] Amount of rhenium associated with an average HeLa cell upon 2 b > 1 b \ufffd 4 b, which is in accordance with their cellular uptake\nincubation with the rhenium(I) polypyridine complexes (10 \u03bcM) at 37 \u00b0C\nfor 2 h, as determined by ICP-MS. efficiencies.\n The phosphorogenic response of the rhenium(I) polypyr-\n idine complexes in live cells was investigated by regulating the\n intracellular concentration of GSH. After incubation with\nthe increasing hydrophobic nature of the diimine ligands: phen complex 1 a (10 \u03bcM) for 2 h, HeLa cells showed moderate\n< Me4-phen < Ph2-phen. It is possible that the reduced cellular emission (Figure 7), which is due to the reaction of the complex\nuptake efficiency of complexes 1 a and 1 b was caused by the with intracellular GSH to give the emissive aminomethylpyridine\nbulky bpy-tosylamide. The uptake mechanism of complexes 1 a complex 1 aP. Interestingly, much stronger intracellular emis-\nand 3 a was studied in more detail. Incubation of HeLa cells\nwith complexes 1 a and 3 a at 4 \u00b0C led to lower uptake efficiency\ncompared to the cells at 37 \u00b0C (Figure 6), indicating that the\ncomplexes were taken up by the cells via an energy-dependent\npathway, which was further confirmed by the reduced uptake\nwhen the cells were treated with the metabolic inhibitor\ncarbonyl cyanide 3-chlorophenylhydrazone (CCCP) (Figure 6).[23a]\nNext, the influence of different internalization pathway inhib-\nitors on the uptake of complexes 1 a and 3 a was investigated.\nThe changes in the cellular uptake efficiency of the complexes\nwere negligible when HeLa cells were preincubated with the\npinocytosis inhibitor colchicine (Figure 6).[23b] However, pretreat-\nment of the cells with chlorpromazine,[23c] a typical clathrin-\nmediated endocytosis inhibitor, induced drastic reduction in\nthe cellular uptake of the complexes (Figure 6), demonstrating\nthat the complexes were internalized into the cells through\nclathrin-mediated endocytosis. Additionally, pretreatment with\n Figure 7. LSCM images of HeLa cells pretreated without or with GSH ethyl\n\u03b2-cyclodextrin,[23d] a caveolae-mediated endocytosis inhibitor, ester (1 mM, 37 \u00b0C, 2 h) or NEM (500 \u03bcM, 37 \u00b0C, 20 min), followed by washing\nresulted in a decrease in the intracellular amount of rhenium with phosphate-buffered saline (PBS) and incubation with complexes 1 a and\nfor the cells incubated with complex 3 a, whereas the effect on 1 b (10 \u03bcM, 37 \u00b0C, 2 h, \u03bbex = 405 nm). Scale bar = 25 \u03bcm.\n\n\nEur. J. Inorg. Chem. 2021, 3432 \u2013 3442 www.eurjic.org 3436 \u00a9 2021 Wiley-VCH GmbH\n\f 10990682c, 2021, 34, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejic.202100364 by Lomonosov Moscow State University, Wiley Online Library on [12/05/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License\n Full Papers\n doi.org/10.1002/ejic.202100364\n\n\nsion was observed when the cells had been pretreated with It is well known that the 1O2 generation efficiency of\nGSH ethyl ester (a source of exogenous GSH, 1 mM, 2 h) rhenium(I) polypyridine complexes is strongly associated with\n(Figure 7). However, when HeLa cells were pretreated with the their long triplet-state lifetimes.[18a,25] For this reason, the\nthiol scavenger N-ethylmaleimide (NEM, 500 \u03bcM, 20 min), they exploration of the rhenium(I) DNPS complexes as controllable\nshowed extremely weak emission (Figure 7), which is a conse- photosensitizers for PDT is of great interest. The 1O2 generation\nquence of the reduced level of intracellular GSH. Importantly, quantum yields (\u03a6\u0394) of the rhenium(I) polypyridine complexes\ncells stained with the DNPS-free complex 1 b (10 \u03bcM) displayed were determined in aerated DMSO using 1,3-diphenylisobenzo-\nnegligible changes in emission intensity in response to GSH furan (DPBF) as a 1O2 scavenger and the results are presented in\nethyl ester or NEM pretreatment (Figure 7), which further Table 5. The \u03a6\u0394 values of complexes 1 b\u20134 b ranged from 0.20\nsupported that the observed intracellular emission was due to to 0.75, which are much higher than those of complexes 1 a\u20134 a\nthe specific reaction of the rhenium(I) DNPS complexes with (0.06\u20130.15). These results are attributable to the higher emission\nGSH. quantum yields and extended lifetimes of complexes 1 b\u20134 b.[26]\n The ER-targeting ability of complexes 1 a and 1 b, both of Since the emission intensities and 1O2 sensitization proper-\nwhich contain a bpy-tosylamide ligand, was evaluated by LSCM. ties of complexes 1 a\u20134 a rely on the removal of the DNPS unit\nHeLa cells treated with complex 1 a (10 \u03bcM, 2 h) revealed a upon reaction with GSH, the dependence of the photocytotox-\nstrong emission intensity in the perinuclear region (Figure 8a). icity of complex 3 a on the incubation time in the dark was\nCo-staining experiments with ER-Tracker Green indicated that studied. HeLa cells were treated with complex 3 a (1 \u03bcM) for 2 h\nthe complex was mainly accumulated in the ER, with a in the dark and thoroughly washed with PBS. Then the cells\nPearson\u2019s colocalization correlation coefficient (PCCC) of 0.89 were incubated in fresh medium for different periods (1\u201312 h)\n(Figure 8a). A similar result was also observed for complex 1 b in the dark, followed by irradiation at 365 nm for 5 min (or\n(PCCC = 0.85) (Figure 8b). However, the tosylamide-free com- incubation in the dark as a control), and further incubated in\nplexes 2 a\u20134 a and 2 b\u20134 b displayed significantly different fresh medium for 24 h in the dark, before analyzed by the MTT\nintracellular distribution; for example, complex 3 a showed assay. As shown in Figure 10, upon incubation in the dark for\nstrong colocalization with MitoTracker Deep Red FM (PCCC = 12 h, complex 3 a displayed negligible cytotoxicity toward HeLa\n0.93) (Figure 9), most likely due to its lipophilic and cationic cells with cell viability > 95 %. However, the cell viability\ncharacter. Similar mitochondria-staining properties of related decreased significantly from 82 % (1 h) to 9 % (12 h) upon\nlipophilic and cationic transition metal complexes have been irradiation (\u03bbex = 365 nm, 5 min, light dose = 5 mW cm\u20132) and the\ndocumented.[17,24] photocytotoxicity effect is most prominent from 1 to 3 h. The\n reduction of cell viability is attributable to the formation of the\n aminomethylpyridine complex 3 aP with efficient 1O2 photo-\n sensitization; the presence of this product was confirmed by\n ESI-MS (Figure S4). Although complex 3 a was converted to 3 aP\n during this dark incubation in fresh medium, the intracellular\n rhenium concentration remained steady (at \ufffd 1.3 fmol in an\n average HeLa cell). Thus, the variation of the photocytotoxicity\n of the complex at different incubation times should be a result\n of the formation of complex 3 aP. Summing up, all these results\n indicate that the cellular imaging capability and 1O2 photo-\n sensitization properties of complex 3 a can be readily modu-\n lated by intracellular GSH, which is known to be elevated in\n level in cancerous cells.\n\nFigure 8. LSCM images of HeLa cells pretreated with complexes (a) 1 a and\n(b) 1 b (10 \u03bcM, 2 h, \u03bbex = 405 nm) and then incubated with ER-Tracker Green\n(1 \u03bcM, 20 min, \u03bbex = 488 nm, \u03bbem = 500\u2013505 nm) at 37 \u00b0C. PCCC = 0.89 and\n0.85, respectively. Scale bar = 25 \u03bcm.\n\n\n Table 5. The 1O2 generation quantum yields of the rhenium(I) polypyridine\n complexes in aerated DMSO at 298 K (\u03bbex = 365 nm). DPBF was used as the\n 1\n O2 scavenger and methylene blue as the standard (\u03a6\u0394 = 0.52).\n Complex \u03a6\u0394\n\n 1a 0.06\n 1b 0.20\n 2a 0.09\n 2b 0.75\nFigure 9. LSCM images of HeLa cells pretreated with complex 3 a (10 \u03bcM, 3a 0.15\n2 h, \u03bbex = 405 nm) and then incubated with MitoTracker Deep Red FM 3b 0.73\n(100 nM, 20 min, \u03bbex = 635 nm, \u03bbem = 654\u2013674 nm) at 37 \u00b0C. PCCC = 0.93. Scale 4a 0.07\nbar = 25 \u03bcm. 4b 0.64\n\n\nEur. J. Inorg. Chem. 2021, 3432 \u2013 3442 www.eurjic.org 3437 \u00a9 2021 Wiley-VCH GmbH\n\f 10990682c, 2021, 34, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejic.202100364 by Lomonosov Moscow State University, Wiley Online Library on [12/05/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License\n Full Papers\n doi.org/10.1002/ejic.202100364\n\n\n (aminomethyl)pyridine, Re(CO)5Br, phen, Me4-phen, Ph2-phen, and\n DPBF were purchased from Acros. The ligand bpy-CHO,[28] N-(2-\n aminoethyl)-4-methylbenzenesulfonamide,[29] and the rhenium(I)\n complexes [Re(N^N)(CO)3(L)](CF3SO3) (N^N=Me4-phen, Ph2-phen,\n and phen; L=CH3CN, pyridine)[17] were prepared according to the\n literature procedures. All buffer components were of biological\n grade and used as received. Dulbecco\u2019s modified Eagle\u2019s medium\n (DMEM), (PBS), fetal bovine serum (FBS), penicillin/streptomycin,\n trypsin-EDTA, MitoTracker Deep Red FM, and ER-Tracker Green\n were purchased from Invitrogen. Autoclaved Milli-Q water was used\n for the preparation of the aqueous solutions. HeLa cells were\n obtained from American Type Culture Collection. The growth\n medium for cell culture contained DMEM mixture with 10 % FBS\n and 1 % penicillin/streptomycin.\n 4-N-((p-Toluenesulfonylamino)ethyl)aminomethyl-4\u2019-methyl-2,2\u2019-\n bipyridine (bpy-tosylamide): A mixture of bpy-CHO (198 mg,\nFigure 10. Viability of HeLa cells incubated with complex 3 a (1 \u03bcM) at 37 \u00b0C 1 mmol) and N-(2-aminoethyl)-4-methylbenzenesulfonamide\nfor 2 h in the dark, thoroughly washed with PBS and incubated in fresh (214 mg, 1 mmol) in EtOH (20 mL) was heated to reflux under an\nmedium for different periods (1, 2, 3, 6, 9, and 12 h) in the dark, followed by inert atmosphere of nitrogen for 3 h. The reaction mixture was\nfurther incubation in the dark (red bars) or under irradiation at 365 nm for cooled in an ice-bath, and solid NaBH4 (114 mg, 3 mmol) was slowly\n5 min (light dose = 5 mW cm 2) (green bars), and then incubated in fresh\nmedium in the dark for 24 h, prior to analysis by the MTT assay. High viability\n added. After stirring for 3 h at room temperature, water (15 mL)\n(> 95 %) was observed upon irradiation of the cells for 5 min in the absence was added to quench the reaction and the resulting mixture was\nof the complex. extracted with CH2Cl2 (20 mL \u00d7 3). The combined organic layer was\n dried over anhydrous MgSO4, filtered, and evaporated under\n vacuum to give a colorless oil, which was purified by column\n chromatography on silica gel using CH2Cl2/MeOH/NH4OH (50 : 1:0.2\n by volume) as the eluent. The solvent was removed under reduced\nConclusions pressure to afford the product as a colorless oil. Yield: 77 mg (55 %).\n 1\n H NMR (400 MHz, CDCl3, 298 K, TMS). \u03b4 = 8.58 (d, J = 4.8 Hz, 1H, H6\nIn this work, a series of rhenium(I) polypyridine complexes of bpy), 8.51 (d, J = 4.8 Hz, 1H, H6\u2019 of bpy), 8.23 (d, J = 9.1 Hz, 2H, H3\nfunctionalized with a DNPS moiety was synthesized and and H3\u2019 of bpy), 7.72 (d, J = 8.1 Hz, 2H, H3 and H5 of phenyl ring),\ncharacterized. Due to the efficient PET quenching by the DNPS 7.24 (d, J = 8.4 Hz, 2H, H2 and H6 of phenyl ring), 7.14 (dd, J = 8.7\nunit, complexes 1 a\u20134 a exhibited very weak emission after and 4.8 Hz, 2H, H5 and H5\u2019 of bpy), 3.74 (s, 2H, CH2NH at C4 of bpy),\n 3.02 (t, J = 5.7 Hz, 2H, CH2NHSO2), 2.71 (t, J = 5.4 Hz, 2H, NHCH2),\nphotoexcitation. However, upon incubation with GSH, strong\n 2.44 (s, 3H, CH3 on C4\u2019 of bpy), 2.37 (s, 3H, CH3 on C4 of phenyl\nemission enhancement of the solutions was observed. Addition- ring). MS (ESI, positive-ion mode): m/z 397 [M + H] +.\nally, the rhenium(I) DNPS complexes showed good reaction\n 3-((2,4-Dinitrophenylsulfonyl)aminomethyl)pyridine (py-DNPS): A\nselectivity and pH-independent emission intensity. Cellular\n mixture of 3-(aminomethyl)pyridine (162 mg, 1.5 mmol) and dini-\nuptake experiments indicated that energy-dependent endocy- trophenylsulfonyl chloride (398 mg, 1.5 mmol) in dry THF (20 mL)\ntosis is the main uptake pathway for the complexes. Upon was heated to reflux for 6 h. The mixture was evaporated to dryness\nactivation by intracellular GSH, the rhenium(I) DNPS complexes under reduced pressure to give a yellow solid. The solid was\ndisplayed intriguing photophysical properties, including intense dissolved in CH2Cl2 (20 mL) and washed with H2O (20 mL \u00d7 3). The\nemission and 1O2 photosensitization behavior. Colocalization organic layer was dried over anhydrous MgSO4, filtered, and\n evaporated to dryness yielding a yellow solid, which was purified\nstudies demonstrated the ER-targeting property for complexes\n by column chromatography on silica gel using CH2Cl2/MeOH (50 : 1,\n1 a and 1 b that were appended with a tosylamide moiety. Also, v/v) as the eluent. The solvent was removed under reduced\nthe photocytotoxicity of complex 3 a was found to be depend- pressure to afford the product as a pale yellow solid. Yield: 210 mg\nent on the post-treatment incubation time for the conversion (40 %). 1H NMR (400 MHz, CD3OD, 298 K, TMS). \u03b4 = 8.71 (d, J =\nto the DNPS-free product 3 aP inside the cells, which enables 2.2 Hz, 1H, H3 of dinitrophenyl ring), 8.51 (dd, J = 6.3 and 2.2 Hz,\n 1H, H5 of dinitrophenyl ring), 8.46 (s, 1H, H2 of pyridine), 8.39 (dd,\nmore efficient photosensitization of cytotoxic 1O2. We anticipate\n J = 3.4 and 1.4 Hz, 1H, H6 of pyridine), 8.19 (d, J = 6.7 Hz, 1H, H6 of\nthat further modification of the complexes with other biocom- dinitrophenyl ring), 7.81 (d, J = 8.0 Hz, 1H, H4 of pyridine), 7.37\u20137.33\npatible moieties would lead to the development of new (m, 1H, H5 of pyridine), 4.40 (s, 2H, CH2NH). MS (ESI, positive-ion\nbiological reagents for theranostic applications. mode): m/z 339 [M + H] +.\n [Re(CO)3(bpy-tosylamide)Br]: A mixture of Re(CO)5Br (217 mg,\n 0.53 mmol) and bpy-tosylamide (210 mg, 0.53 mmol) in toluene\nExperimental Section (20 mL) was refluxed under an inert atmosphere of nitrogen for 4 h.\n The mixture was evaporated to dryness to give a yellow solid.\nGeneral Information: All solvents were of analytical grade and\n Recrystallization of the solid from CH2Cl2/diethyl ether to afford the\npurified according to standard procedures.[27] Dinitrobenzenesulfon-\n complex as yellow crystals. Yield: 355 mg (90 %). 1H NMR (300 MHz,\nyl chloride was purchased from Alfa. N-(2-Aminoethyl)-4-meth-\n CD3OD, 298 K, TMS). \u03b4 = 8.93 (d, J = 5.7 Hz, 1H, H6 of bpy), 8.81 (d,\nylbenzenesulfonamide, sodium borohydride, NEM, GSH, GSH ethyl\n J = 5.7 Hz, 1H, H6\u2019 of bpy), 8.59 (s, 1H, H3 of bpy), 8.49 (s, 1H, H3\u2019 of\nester, Cys, MTT, 4,4\u2019-dimethyl-2,2\u2019-bipyridine, selenium dioxide, and\n bpy), 7.76\u20137.73 (m, 2H, H3 and H5 of phenyl ring), 7.59 (d, J =\nsodium metabisulfite were purchased from Sigma-Aldrich. Silver\n 5.7 Hz, 1H, H5 of bpy), 7.53 (d, J = 5.7 Hz, 1H, H5\u2019 of bpy), 7.38\u20137.36\ntrifluoromethanesulfonate, triethylamine, magnesium sulfate, 3-\n (m, 2H, H2 and H6 of phenyl ring), 3.99 (s, 2H, CH2NH at C4 of bpy),\n\nEur. J. Inorg. Chem. 2021, 3432 \u2013 3442 www.eurjic.org 3438 \u00a9 2021 Wiley-VCH GmbH\n\f 10990682c, 2021, 34, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejic.202100364 by Lomonosov Moscow State University, Wiley Online Library on [12/05/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License\n Full Papers\n doi.org/10.1002/ejic.202100364\n\n\n3.04 (t, J = 6.0 Hz, 2H, CH2NHSO2), 2.73 (t, J = 6.0 Hz, 2H, NHCH2), \u03b4 = 195.41, 156.29, 155.83, 155.44, 155.42, 153.01, 152.75, 151.80,\n2.64 (s, 3H, CH3 at C4\u2019 of bpy), 2.41 (s, 3H, CH3 at C4 of phenyl ring). 143.42, 139.74, 137.23, 129.38, 129.33, 127.61, 126.63, 1256.56,\nIR (KBr) ~v/cm 1: 3451 (N H), 2020 (C\ufffdO), 1902 (C\ufffdO). MS (ESI, 125.34, 123.57, 123.30, 121.46, 119.35, 50.89, 42.23, 20.20, 20.02. IR\npositive-ion mode): m/z 747 [M + H] +, 668 [M Br ] +. (KBr) ~v/cm 1: 3451 (N H), 2031 (C\ufffdO), 1925 (C\ufffdO), 1148 (CF3SO3 ),\n 1030 (CF3SO3 ). MS (ESI, positive-ion mode): m/z 746 [M CF3SO3 ] +.\n[Re(CO)3(bpy-tosylamide)(CH3CN)](CF3SO3): A mixture of Re-\n Anal. Calcd. for ReC30H29F3N5O8S2\u00b7CH3CN: C 38.49; H 3.12; N 7.48;\n(CO)3(bpy-tosylamide)Br (200 mg, 0.27 mmol) and Ag(CF3SO3) found: C 38.55; H 3.36; N 7.37 %.\n(76.8 mg, 0.3 mmol) in CH3CN (200 mL) was refluxed under an inert\natmosphere of nitrogen for 12 h in the dark. The off-white AgBr [Re(Me4-phen)(CO)3(py-DNPS)](CF3SO3) (2 a): The synthetic proce-\nprecipitate was removed by filtration using celite. The filtrate was dure was similar to that of complex 1 a, except that [Re(Me4-\nevaporated under reduced pressure to give a yellow solid. phen)(CO)3(CH3CN)](CF3SO3) (100 mg, 0.18 mmol) was used instead\nRecrystallization of the solid from CH2Cl2/diethyl ether to afford the of [Re(bpy-tosylamide)(CO)3(CH3CN)](CF3SO3). Subsequent recrystal-\ncomplex as yellow crystals. Yield: 114 mg (60 %). 1H NMR (300 MHz, lization of the yellow solid from CH2Cl2/diethyl ether afforded the\nCDCl3, 298 K, TMS). \u03b4 = 8.85 (s, 1H, H3 of bpy), 8.79 (d, J = 5.6 Hz, 1H, complex as yellow crystals. Yield: 118 mg (78 %). 1H NMR (300 MHz,\nH6 of bpy), 8.73 (d, J = 5.6 Hz, 1H, H6\u2019 of bpy), 8.69 (s, 1H, H3\u2019 of CD3OD, 298 K, TMS). \u03b4 = 9.43 (s, 2H, H2 and H9 of Me4-phen), 8.66\nbpy), 7.79\u20137.76 (m, 2H, H3 and H5 of phenyl ring), 7.5 (d, J = 5.2 Hz, (d, J = 2.2 Hz, 1H, H3 of dinitrophenyl ring), 8.59 (d, J = 5.1 Hz, 1H,\n1H, H5 of bpy), 7.42 (d, J = 5.2 Hz, 1H, H5\u2019 of bpy), 7.31\u20137.28 (m, 2H, H6 of pyridine), 8.40 (s, 2H, H5 and H6 of Me4-phen), 8.36 (dd, J =\nH2 and H6 of phenyl ring), 4.21\u20133.99 (m, 2H, CH2NH at C4 of bpy), 6.4 and 2.3 Hz, 1H, H5 of dinitrophenyl ring), 8.24 (s, 1H, H2 of\n3.01 (t, J = 1.6 Hz, 2H, CH2NHSO2), 2.86\u20132.83 (m, 2H, NHCH2), 2.71 (s, pyridine), 7.93 (d, J = 8.6 Hz, 1H, H4 of pyridine), 7.66 (d, J = 6.7 Hz,\n3H, CH3 at C4\u2019 of bpy), 2.41 (s, 3H, CH3 at C4 of phenyl ring), 2.23 (s, 1H, H6 of dinitrophenyl ring), 7.25\u20137.20 (m, 1H, H5 of pyridine), 4.06\n3H, CH3CN). IR (KBr) ~v/cm 1: 3451 (N H), 2020 (C\ufffdO), 1902 (C\ufffdO), (s, 2H, CH2NH at C3 of pyridine), 2.90 (s, 6H, CH3 at C4 and C7 of\n1147 (CF3SO3 ), 1029 (CF3SO3 ). MS (ESI, positive-ion mode): m/z Me4-phen), 2.77 (s, 6H, CH3 at C3 and C8 of Me4-phen). 13C NMR\n707 [M CF3SO3 ] +. (150 MHz, CD3OD, 298 K, TMS), \u03b4 = 195.52, 154.12, 151.57, 150.13,\n 150.05, 149.01, 148.04, 144.98, 138.73, 138.06, 137.10, 136.43,\n[Re(bpy-tosylamide)(CO)3(py-DNPS)](CF3SO3) (1 a): A mixture of 131.37, 129.63, 126.49, 125.82, 124.00, 120.13, 42.94, 16.54, 13.98. IR\n[Re(CO)3(bpy-tosylamide)(CH3CN)](CF3SO3) (100 mg, 0.14 mmol) and (KBr) ~v/cm 1: 3446 (N H), 2030 (C\ufffdO), 1921 (C\ufffdO), 1160 (CF3SO3 ),\npy-DNPS (47 mg, 0.14 mmol) in dry THF (20 mL) was refluxed under\n 1031 (CF3SO3 ). MS (ESI, positive-ion mode): m/z 846 [M CF3SO3 ] +.\nan inert atmosphere of nitrogen for 12 h. The mixture was Anal. Calcd. for ReC32H27F3N6O12S2\u00b7H2O: C 37.94; H 2.68; N 8.29;\nevaporated to dryness under reduced pressure to give an orange found: C 37.96; H 2.87; N 8.34 %.\nsolid, which was purified by column chromatography on silica gel\nusing CH2Cl2/MeOH (50 : 1, v/v) as the eluent. The solvent was [Re(Ph2-phen)(CO)3(py-DNPS)](CF3SO3) (3 a): The synthetic proce-\nremoved under reduced pressure to yield an orange solid. dure was similar to that of complex 1 a, except that [Re(Ph2-\nRecrystallization of the solid from CH2Cl2/diethyl ether to afford the phen)(CO)3(CH3CN)](CF3SO3) (100 mg, 0.15 mmol) was used instead\ncomplex as orange crystals. Yield: 88 mg (63 %). 1H NMR (400 MHz, of [Re(bpy-tosylamide)(CO)3(CH3CN)](CF3SO3). Subsequent recrystal-\nCD3OD, 298 K, TMS). \u03b4 = 9.19 (d, J = 5.6 Hz, 1H, H6 of bpy), 9.13 (d, lization of the yellow solid from CH2Cl2/diethyl ether afforded the\nJ = 5.6 Hz, 1H, H6\u2019 of bpy), 8.76 (d, J = 2.1 Hz, 1H, H6 of pyridine), complex as yellow crystals. Yield: 109 mg (75 %). 1H NMR (300 MHz,\n8.65 (s, 1H, H3 of dinitrophenyl ring), 8.56\u20138.50 (m, 3H, H5 of CD3OD, 298 K, TMS). \u03b4 = 9.77 (d, J = 5.4 Hz, 2H, H2 and H9 of Ph2-\ndinitrophenyl ring and H3 and H3\u2019 of bpy), 8.21 (s, 1H, H2 of phen), 8.72\u20138.71 (m, 2H, H6 of pyridine and H3 of dinitrophenyl\npyridine), 8.15 (d, J = 8.6 Hz, 1H, H6 of dinitrophenyl ring), 7.84\u20137.82 ring), 8.43 (dd, J = 6.7 and 2.2 Hz, 1H, H5 of dinitrophenyl ring), 8.37\n(m, 2H, H3 and H5 of phenyl ring), 7.71\u20137.69 (m, 3H, H4 of pyridine (s, 1H, H2 of pyridine), 8.21 (s, 2H, H5 and H6 of Ph2-phen), 8.17 (d,\nand H2 and H6 of phenyl ring), 7.35 (t, J = 7.8 Hz, 3H, H5 of pyridine J = 5.4 Hz, 2H, H3 and H8 of Ph2-phen), 8.00 (d, J = 8.6 Hz, 1H, H4 of\nand H5 and H5\u2019 of bpy), 4.64 (br, 1H, NH), 4.17 (s, 2H, CH2NH at C3 pyridine), 7.79\u20137.64 (m, 11H, H6 of dinitrophenyl ring and C6H5 at\nof pyridine), 4.04 (s, 2H, CH2NH at C4 of bpy), 2.97 (t, J = 5.7 Hz, 2H, C4 and C7 of Ph2-phen), 7.37\u20137.31 (m, 1H, H5 of pyridine), 4.13 (s,\nCH2NHSO2), 2.75 (t, J = 5.8 H, 2H, NHCH2), 2.64 (s, 3H, CH3 at C4\u2019 of 2H, CH2NH at C3 of pyridine). 13C NMR (150 MHz, CD3OD, 298 K,\nbpy), 2.42 (s, 3H, CH3 at C4 of phenyl ring). 13C NMR (150 MHz, TMS), \u03b4 = 195.44, 191.23, 153.82, 153.02, 150.18, 148.03, 147.15,\nCD3OD, 298 K, TMS), \u03b4 = 195.51, 155.77, 155.38, 154.59, 152.91, 138.99, 137.99, 137.46, 135.38, 131.47, 129.80, 129.67, 129.30,\n152.65, 152.62, 150.13, 148.09, 143.42, 138.85, 138.08, 137.47, 128.87, 127.40, 126.53, 126.10, 126.02, 120.17, 42.92. IR (KBr) ~v/cm 1:\n137.20, 131.62, 129.57, 129.38, 127.88, 126.72, 126.61, 126.05, 3446 (N H), 2031 (C\ufffdO), 1912 (C\ufffdO), 1158 (CF3SO3 ), 1029\n125.51, 120.22, 50.93. 43.01, 42.20, 20.29, 20.01. IR (KBr) ~v/cm 1: (CF3SO3 ). MS (ESI, positive-ion mode): m/z 972 [M CF3SO3 ] +. Anal.\n3451 (N H), 2031 (C\ufffdO), 1910 (C\ufffdO), 1145 (CF3SO3 ), 1029 Calcd. for ReC40H27F3N6O12S2: C 44.03; H 2.49; N 7.71; found: C 43.76;\n(CF3SO3 ). MS (ESI, positive-ion mode): m/z 1005 [M CF3SO3 ] +. H 2.69; N 7.59 %.\nAnal. Calcd. for ReC37H34F3N8O14S3\u00b7CH3OH: C 37.46; H 2.88; N 9.44;\nfound: C 37.59; H 2.62; N 9.17 %. [Re(phen)(CO)3(py-DNPS)](CF3SO3) (4 a): The synthetic procedure\n was similar to that of complex 1 a, except that [Re-\n[Re(bpy-tosylamide)(CO)3(pyridine)](CF3SO3) (1 b): The synthetic (phen)(CO)3(CH3CN)](CF3SO3) (100 mg, 0.20 mmol) was used instead\nprocedure was similar to that of complex 1 a, except that pyridine of [Re(bpy-tosylamide)(CO)3(CH3CN)](CF3SO3). Subsequent recrystal-\n(22 mg, 0.28 mmol) was used instead of py-DNPS. Subsequent lization of the yellow solid from CH2Cl2/diethyl ether afforded the\nrecrystallization of the orange solid from CH2Cl2/diethyl ether complex as yellow crystals. Yield: 114 mg (74 %). 1H NMR (300 MHz,\nafforded the complex as orange crystals. Yield: 81 mg (76 %). 1H CO(CD3)2, 298 K, TMS). \u03b4 = 9.91 (d, J = 4.6 Hz, 2H, H2 and H9 of\nNMR (300 MHz, CD3OD, 298 K, TMS). \u03b4 = 9.22 (d, J = 5.6 Hz, 1H, H6 phen), 9.11 (d, J = 7.4 Hz, 2H, H4 and H7 of phen), 8.76 (d, J = 2.1 Hz,\nof bpy), 9.15 (d, J = 5.6 Hz, 1H, H6\u2019 of bpy), 8.63 (s, 1H, H3 of bpy), 1H, H3 of dinitrophenyl ring), 8.62 (s, 1H, H6 of pyridine), 8.58\u20138.53\n8.50 (s, 1H, H3\u2019 of bpy), 8.4 (d, J = 5.1 Hz, 2H, H2 and H6 of pyridine), (m, 2H, H2 of pyridine and H5 of dinitrophenyl ring), 8.38\u20138.31 (m,\n7.93 (t, J = 7.7 Hz, 1H, H4 of pyridine), 7.83 (d, J = 5.6 Hz, 1H, H3 of 4H, H3, H5, H6, and H8 of phen), 8.18 (d, J = 8.6 Hz, 1H, H4 of\nphenyl ring), 7.74\u20137.71 (m, 3H, H2, H5 and H6 of phenyl ring), 7.41\u2013 pyridine), 7.87 (d, J = 8.1 Hz, 1H, H6 of dinitrophenyl ring), 7.35\u20137.31\n7.37 (m, 4H, H3 and H5 of pyridine and H5 and H5\u2019 of bpy), 4.03 (s, (m, 1H, H5 of pyridine), 4.3 (s, 2H, CH2NH at C3 of pyridine). 13C NMR\n2H, CH2NH at C4 of bpy), 2.97 (t, J = 5.9 Hz, 2H, CH2NHSO2), 2.73 (t, (150 MHz, CO(CD3)2, 298 K, TMS), \u03b4 = 154.88, 151.26, 151.22, 150.22,\nJ = 5.9 Hz, 2H, NHCH2), 2.64 (s, 3H, CH3 at C4\u2019 of bpy), 2.43 (s, 3H, 148.04, 146.47, 140.69, 139.48, 138.15, 137.26, 132.08, 131.40,\nCH3 at C4 of phenyl ring). 13C NMR (150 MHz, CD3OD, 298 K, TMS), 128.34, 127.62, 127.13, 126.42, 120.44, 43.37. IR (KBr) ~v/cm 1: 3451\n\nEur. J. Inorg. Chem. 2021, 3432 \u2013 3442 www.eurjic.org 3439 \u00a9 2021 Wiley-VCH GmbH\n\f 10990682c, 2021, 34, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejic.202100364 by Lomonosov Moscow State University, Wiley Online Library on [12/05/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License\n Full Papers\n doi.org/10.1002/ejic.202100364\n\n\n(N H), 2031 (C\ufffdO), 1918 (C\ufffdO), 1144 (CF3SO3 ), 1026 (CF3SO3 ). MS tions ranging from 10 4 to 10 7 M in growth medium/DMSO (99 : 1,\n(ESI, positive-ion mode): m/z 777 [M CF3SO3 ] +. Anal. Calcd. for v/v). Wells containing untreated cells were used as blank controls.\nReC28H19F3N6O12S2: C 35.82; H 2.04; N 8.95; found: C 35.84; H 2.06; N The microplate was incubated at 37 \u00b0C under a 5 % CO2 atmosphere\n8.71 %. for 24 h. Then, MTT in PBS (10 \u03bcL, 5 mg mL 1) was added to each\n well and the microplate was incubated at 37 \u00b0C under a 5 % CO2\nPhysical Measurements and Instrumentation: 1H and 13C NMR\n atmosphere for 4 h. The growth medium was then removed, and\nspectra were recorded on a Bruker AVANCE III 300, 400, or 600 MHz DMSO (200 \u03bcL) was added to each well. The microplate was further\nNMR spectrometer at 298 K. Positive-ion ESI-mass spectra were incubated at 37 \u00b0C for 15 min. The absorbance of the solutions at\nrecorded on an API-3200 Triple-Q MS/MS mass spectrometer at 570 nm was measured with a Powerwave XS MQX200R microplate\n298 K. IR spectra of samples in potassium bromide (KBr) pellets spectrophotometer (BioTek Instruments Inc., Winooski, VT). The IC50\nwere obtained using a Thermo Scientific Nicolet iS50 FTIR values of the complexes were determined from dose dependence\nspectrometer in the range of 4000\u2013400 cm 1. Elemental analyses of surviving cells after exposure to the complexes.\nwere carried out on an Elementar Analysensytreme GmbH Vario\nMICRO elemental analyzer. Electronic absorption and steady-state Live-cell Confocal Imaging: HeLa cells in growth medium were\nemission spectra were obtained from an Agilent 8453 diode array seeded on sterilized coverslip in 35-mm tissue culture dish and\nspectrophotometer and HORIBA FluoroMax-4 spectrofluorometer, grown at 37 \u00b0C under a 5 % CO2 atmosphere. After 48 h incubation,\nrespectively. Luminescence quantum yields were measured by the the growth medium was replaced by a medium containing the\noptically diluted method[30] using degassed [Re- rhenium(I) polypyridine complexes (10 \u03bcM) in medium/DMSO\n(phen)(CO)3(pyridine)](CF3SO3) (\u03a6em = 0.18, \u03bbex = 355 nm) as the (99 : 1, v/v) at 37 \u00b0C under a 5 % CO2 atmosphere for 2 h. The growth\nstandard solution.[31] Unless otherwise specified, all the solutions medium was removed, and the cell layer was washed gently with\nprepared for photophysical studies were degassed with at least PBS (1 mL \u00d7 3). After that, the coverslip was mounted onto a\nfour successive freeze-pump-thaw cycles and stored in a 10-cm3 sterilized glass slide and imaged using a Leica TCS SPE (inverted\nround-bottomed flask equipped with a sidearm 1-cm fluorescence configuration) confocal microscope and a 63 \u00d7 oil-immersion\ncuvette and sealed from the atmosphere by a Rotaflo HP6/6 quick- objective lens. In the co-staining experiments, HeLa cells were\nrelease Teflon stopper. Cyclic voltammetric measurements were incubated with complex 1 a or 1 b (10 \u03bcM) for 2 h and then\ncarried out using a CH Instruments Electrochemical Workstation CHI incubated with ER-Tracker Green (1 \u03bcM, \u03bbex = 488 nm, \u03bbem = 500\u2013\n750 A. 505 nm) for 20 min. The procedure for HeLa cells treated with\n complex 3 a was similar to that of complexes 1 a and 1 b except\nSinglet Oxygen (1O2) Quantum Yield Determination: An aerated that MitoTracker Deep Red FM (100 nM, \u03bbex = 635 nm, \u03bbem = 654\u2013\nDMSO solution (2 mL) containing the rhenium(I) polypyridine 674 nm) was used. The colocalization coefficient was determined\ncomplexes and DPBF (10 \u03bcM) was introduced to a 1-cm path length by the program ImageJ (Version 1.4.3.67).\nquartz cuvette and irradiated at 365 nm. Methylene blue was used\nas a reference for 1O2 sensitization (\u03a6\u0394 = 0.52).[32] The absorbance of Intracellular Biothiol-sensing Studies: HeLa cells in growth\nmethylene blue and the complexes at 365 nm was adjusted to medium were seeded on sterilized coverslip in two 35-mm tissue\nabout 0.15. The absorbance of DPBF at 410 nm was monitored culture dishes and grown at 37 \u00b0C under a 5 % CO2 atmosphere.\nevery 10 s. A DMSO solution of DPBF without the complexes was After 48 h, the growth medium in dishes was removed and\nexamined to determine its photostability under identical irradiation replaced with fresh medium and medium containing NEM\nconditions. The \u03a6\u0394 of the complex was determined by comparing (500 \u03bcM), respectively at 37 \u00b0C under a 5 % CO2 atmosphere. After\n\u03a6\u0394 of rhenium(I)-sensitized DPBF photooxidation to \u03a6\u0394 of meth- 20 min incubation, the growth medium was removed, and the cell\nylene blue-sensitized DPBF photooxidation (as reference) and layer was washed gently with PBS (1 mL \u00d7 3). The cells were then\ncalculated by the following equation: treated with complex 1 a or 1 b (10 \u03bcM) in medium/DMSO (99 : 1,\n v/v). After incubation for 2 h, the medium was removed, and each\n cell layer was washed with PBS (1 mL \u00d7 3). The coverslip was\n msample \ufffd FMB\nFsample\n D \u00bc FMB\n D \ufffd\n mounted onto a sterilized glass slide and then imaged using a Leica\n mMB \ufffd Fsample TCS SPE confocal microscope. The procedure for HeLa cells treated\n with GSH ethyl ester (1 mM, 2 h) was similar to that of NEM.\nwhere m is the slope of a linear fit of the change in absorbance of\nDPBF at 410 nm against the irradiation time and F is the absorption Photocytotoxicity Assays: HeLa cells were seeded in two 96-well\ncorrelation factor, which is given as F = 1\u201310\u2013AL (A = absorbance at flat-bottomed microplates ( \ufffd 10 000 cells per well) in a growth\n365 nm and L = path length of the cuvette). medium (100 \u03bcL) and grown at 37 \u00b0C under a 5 % CO2 atmosphere.\n After 24 h incubation, the growth medium was replaced by\nICP-MS Measurements: HeLa cells were grown in a 35-mm tissue medium containing complex 3 a (1 \u03bcM) in medium/DMSO (99 : 1,\nculture dish and incubated at 37 \u00b0C under a 5 % CO2 atmosphere for v/v). Wells containing untreated cells were used as blank controls.\n48 h. After the treatment, the growth medium was replaced by a After incubation at 37 \u00b0C under a 5 % CO2 atmosphere for 2 h, the\nmedium containing the rhenium(I) polypyridine complexes (10 \u03bcM) medium was removed and the cell layer was gently washed with\nin growth medium/DMSO (99 : 1, v/v) and incubated at 37 \u00b0C under PBS (100 \u03bcL) and further incubated in fresh medium for different\na 5 % CO2 atmosphere. After 2 h incubation, the medium was periods (1, 2, 3, 6, 9, and 12 h) in the dark. Then, the growth\nremoved, and the cell layer was washed gently with PBS (1 mL \u00d7 3). medium was replaced by a phenol red-free medium and one of the\nThe cells were trypsinized and harvested with PBS (2 mL). The microplates was illuminated at 365 nm (5 mW cm 2) for 5 min, while\nresultant solution was heated with 65 % HNO3 (2 mL) at 70 \u00b0C for the other microplate was kept in dark for 5 min. After irradiation,\n2 h, cooled to room temperature, and analyzed using an NexION the medium was removed and fresh growth medium was added,\n2000 ICP-MS (PerkinElmer SCIEX Instruments). and the cells were incubated in the dark for another 24 h. Then,\nDark Cytotoxicity Assays: HeLa cells were seeded in a 96-well flat- MTT in PBS (10 \u03bcL, 5 mg mL 1) was added to each well, and the\nbottomed microplate ( \ufffd 10 000 cells per well) in a growth medium microplates were incubated for 4 h. The growth medium was then\n(100 \u03bcL) and grown at 37 \u00b0C under a 5 % CO2 atmosphere. After removed, and DMSO (200 \u03bcL) was added to each well. The\n24 h incubation, the growth medium was replaced by a medium microplates were further incubated at 37 \u00b0C for 15 min. The\ncontaining the rhenium(I) polypyridine complexes, at concentra- absorbance of the solution at 570 nm was measured with a\n\n\n\nEur. J. Inorg. Chem. 2021, 3432 \u2013 3442 www.eurjic.org 3440 \u00a9 2021 Wiley-VCH GmbH\n\f 10990682c, 2021, 34, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejic.202100364 by Lomonosov Moscow State University, Wiley Online Library on [12/05/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License\n Full Papers\n doi.org/10.1002/ejic.202100364\n\n\nPowerwave XS MQX200R microplate spectrophotometer (BioTek [6] a) S. Monro, K. L. Colon, H. Yin, J. Roque III, P. Konda, S. Gujar, R. P.\nInstruments Inc., Winooski, VT). Thummel, L. Lilge, C. G. Cameron, S. A. McFarland, Chem. Rev. 2019, 119,\n 797\u2013828; b) C. Imberti, P. Zhang, H. Huang, P. J. Sadler, Angew. Chem.\nESI-MS Analysis of Cell Extracts: HeLa cells grown for 48 h were Int. Ed. 2020, 59, 61\u201373; Angew. Chem. 2020, 132, 61\u201373; c) J. 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