Synthesis, characterization and biological evaluation of two cyclometalated iridium(III) complexes containing a glutathione S-transferase inhibitor.

{"full_text": " Journal of Inorganic Biochemistry 238 (2023) 112050\n\n\n Contents lists available at ScienceDirect\n\n\n Journal of Inorganic Biochemistry\n journal homepage: www.elsevier.com/locate/jinorgbio\n\n\n\n\nSynthesis, characterization and biological evaluation of two cyclometalated\niridium(III) complexes containing a glutathione S-transferase inhibitor\nJian Zhao a, c, *, 1, Ya Gao a, 1, Weiyu He b, Wei Wang b, Weiwei Hu c, **, Yanyan Sun b, **\na\n School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China\nb\n School of Chemistry and Life Sciences, Suzhou University of Science and Technology, Suzhou 215009, China\nc\n Jiangsu Key Laboratory of Regional Resource Exploitation and Medicinal Research, Huaiyin Institute of Technology, Huaian 223003, 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: The cyclometalated iridium(III) compounds have been intensively studied for health-related applications due to\nIridium(III) complexes their outstanding luminescent properties and multiple anticancer modes of action. Herein, two iridium(III)\nGST inhibitor compounds Ir-1 and Ir-3 containing glutathione S-transferase inhibitor (GSTi) were developed and studied\nSynthesis\n together with two unfunctionalized compounds Ir-2 and Ir-4 as a comparison. Biological study indicated that\nAntitumor\nApoptosis\n GSTi-bearing complexes Ir-1 and Ir-3 exert a synergistic effect on the inhibition of cancer cells. The photo\u00ad\nCell uptake physical properties of Ir-1 ~ Ir-4 were investigated by UV/vis absorption and fluorescence spectroscopy and\n rationalized with TD-DFT calculations. As expected, GSTi-bearing complexes Ir-1 and Ir-3 exhibited considerable\n cytotoxicity against both A549 and cisplatin-resistant A549/cis cancer cells, much higher than the unfunction\u00ad\n alized iridium compounds Ir-2 and Ir-4. Further study indicated that Ir-1 and Ir-3 mainly localize in the\n mitochondria of tumor cells, and exert their cytotoxicity via generating ROS and inhibiting GST activity. The flow\n cytometry investigations demonstrated that Ir-1 and Ir-3 can arrest the cell cycle in S phase and induce the cell\n death through apoptosis process. Overall, the complexation of GST inhibitors with cyclometalated iridium(III)\n agents provides an effective way for potentiating the cytotoxicity of iridium(III) anticancer agents and resensi\u00ad\n tizing the efficacy against cisplatin resistant cancer cells.\n\n\n\n\n1. Introduction modification, which display multiple modes of action such as\n mitochondria-mediated cell death pathway, inhibition of protein-\n The platinum-based anticancer drugs, cisplatin and its analogues protein interaction, and deregulation of the cellular redox balance\nhave shown great success in the clinic for the treatment of a wide variety [16\u201323]. Distinctly, the cyclometalated iridium(III) compounds are\nof cancers, which stimulates the development of non\u2011platinum metal- kinetically inert under physiological conditions, thereby exerting their\nbased anticancer agents [1\u20134]. The diverse coordination modes, vari\u00ad anticancer activity through non-covalent interaction with the thera\u00ad\nable spatial structures, tunable kinetic reactivities, and rich photo- peutic targets [24,25], which is different from platinum agents that\nphysicochemical properties of the metal-based compounds provide covalently bind to the DNA [26]. The irreversible interaction of the\nmore opportunities to design anticancer agents with ideal properties and platinum drugs to biomolecules often cause serious side effects [27,28].\nfunctionalities [5\u201311]. To date, numerous non\u2011platinum metal-based Consequently, the development of iridium(III) anticancer agents has the\ncompounds have been designed and explored as potential anticancer potential to overcome the limitations of the platinum drugs.\nagents, and several of them have successfully entered clinical trials for Glutathione S-transferase(s) (GSTs) are a class of xenobiotic metab\u00ad\ncancer treatment not only as chemotherapeutic agents but also as olizing enzymes, which have a vital physiological function in detoxi\u00ad\nphotosensitizer [12\u201315]. fying process via catalyzing the conjugation of glutathione (GSH) with\n The cyclometalated octahedral iridium(III) compounds are a class of detrimental electrophilic agents [29,30]. Notably, GSTs are highly\nwell-studied anticancer agents due to their limited side effects and facile overexpressed in many cancer cells, especially in drug-resistant cancer\n\n\n * Corresponding author at: School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.\n ** Corresponding authors.\n E-mail addresses: zhaojianzhaokuan@163.com (J. Zhao), huaianwwh@163.com (W. Hu), sunyy0628@163.com (Y. Sun).\n 1\n J. Zhao and Y. Gao contributed equally to this work.\n\nhttps://doi.org/10.1016/j.jinorgbio.2022.112050\nReceived 27 July 2022; Received in revised form 12 October 2022; Accepted 21 October 2022\nAvailable online 27 October 2022\n0162-0134/\u00a9 2022 Elsevier Inc. All rights reserved.\n\fJ. Zhao et al. Journal of Inorganic Biochemistry 238 (2023) 112050\n\n\n\n\nFig. 3. Co-incubation of the iridium(III) compounds with Mito-Tracker Red in A549 cells. Ir-1 and Ir-3 were excited at 405 nm and emission was collected at 520 \u00b1\n20 nm. Ir-2 and Ir-4 were excited at 405 nm and emission was collected at 590 \u00b1 20 nm. MTR was excited at 579 nm and the emission was collected at 599 nm. Scale\nbar: 20 \u03bcm. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)\n\n\n 2.7. Intracellular ROS level detection\nTable 2\nCellular accumulation of complexes Ir-1 ~ Ir-4 (30 \u03bcM) in A549 cells after 6 h\n It has been demonstrated that many metal-based anticancer agents\nand 12 h incubation by ICP-MS.\n have the potential to alter the cellular redox balance and elevate intra\u00ad\n Compound Ir (ng/106 cells)a\n cellular ROS levels, resulting in cancer cell death. Therefore, the intra\u00ad\n 6h 12 h cellular ROS levels in A549 and A459/cis cells after treatment with Ir-1\n Ir-1 42.5 \u00b1 3.8 50.6 \u00b1 4.1 ~ Ir-4 were investigated with 2\u2032 ,7\u2032 -dichlorodihydrofluorescein diacetate\n Ir-2 13.8 \u00b1 1.5 18.6 \u00b1 2.0 (H2DCF-DA) as an ROS-sensitive fluorescent probe. As shown in Fig. 4,\n Ir-3 45.7 \u00b1 4.0 55.3 \u00b1 5.2 Ir-1 and Ir-3 increased ROS levels in both A549 and A549/cis cells as\n Ir-4 11.5 \u00b1 1.3 17.4 \u00b1 2.1\n evident by the green fluorescence, especially for Ir-3 with relatively\n a\n Values represent the mean \u00b1 SD from three independent experiments. intense fluorescence, whereas Ir-2 and Ir-4-treated A549 and A549/cis\n cells exhibited weak green fluorescence, demonstrating the low pro\u00ad\n duction of intracellular ROS. Taken together, Ir-1 and Ir-3 can exert a\n synergistic anticancer effect via generating ROS and inhibiting GST\n\n\n 5\n\fJ. Zhao et al. Journal of Inorganic Biochemistry 238 (2023) 112050\n\n\n\n\n Fig. 4. Confocal fluorescence images of ROS production in A549 and A549/cis cells treated with Ir-1 ~ Ir-4 at a concentration of 20 \u03bcM. Scale bar: 60 \u03bcm.\n\n\nactivity. treatment with Ir-2 and Ir-4, respectively, demonstrating that Ir-1 and\n Ir-3 can produce significant impact on A549 cells. Notably, the popu\u00ad\n2.8. Apoptosis study lation of apoptotic cells induced by Ir-1 (36.2%) and Ir-3 (23.3%) was\n much higher than that of NBDHEX (8.3%) and was superior and/or\n Based on the results of cytotoxicity test, the apoptosis analysis of comparable to that of cisplatin (31.9%). Besides, cisplatin and NBDHEX\ncisplatin, NBDHEX and Ir-1 ~ Ir-4 against A549 and A549/cis cells was can not only induce cell apoptosis, but also necrosis (11.6% and 18.4%).\nperformed by flow cytometry with Annexin-V FITC and propidium io\u00ad Moreover, Ir-1 and Ir-3 induced the apoptosis of A549/cis cells with\ndide (PI) staining. As shown in Figs. 5 and 6, four areas in the diagrams apoptotic rates of 40.6% and 24.8%, respectively, confirming the\nrepresent different cell states: necrotic cells (Q1), late apoptotic (Q2), considerable cytotoxicity against A549/cis cells. These results clearly\nliving cells (Q3), and early apoptotic cells (Q4). In comparison with the demonstrating that the complexation with NBDHEX conferred the\nuntreated cells, both Ir-1 ~ Ir-4 treatment increased incidences of early- iridium(III) complexes with great potential for improving their cyto\u00ad\nto late-stage apoptosis (14.2% - 36.2%) in A549 cancer cells. Besides, toxicity and overcoming the drug resistance.\nonly 63.1% and 76.6% of the Ir-1 and Ir-3-treated cells are intact,\nrespectively, while 79.2% and 85.8% of A549 cells remain intact after\n\n\n\n\n Fig. 5. Apoptosis analysis of A549 cells treated with cisplatin (CDDP), NBDHEX, Ir-1 ~ Ir-4 at the concentrations of IC50 values for 48 h.\n\n 6\n\fJ. Zhao et al. Journal of Inorganic Biochemistry 238 (2023) 112050\n\n\n\n\n Fig. 6. Apoptosis analysis of A549/cis cells treated with cisplatin (CDDP), NBDHEX, Ir-1 ~ Ir-4 at the concentrations of IC50 values for 48 h.\n\n\n2.9. Cell cycle arrest analysis of the cell cycle. Besides, NBDHEX arrested A549 cells mainly in the S\n phase of the cell cycle, which is in line with the previous literature [51]\n The perturbation effects of Ir-1 ~ Ir-4, cisplatin and NBDHEX on cell that S or G2/M phases arrest were observed for most of the anticancer\ncycle distribution in A549 cells were analyzed by flow cytometry. As drugs in current use due to the DNA binding or interaction with target\nshown in Fig. S18, exposure of A549 cells to cisplatin led to a moderate proteins. However, both Ir-2 and Ir-4 arrest the cell cycle at G0-G1\naccumulation of cells mainly at S phase along with a minor G2/M phase phase compared to the untreated control, while Ir-1 and Ir-3 blocked\n\n\n\n\n Fig. 7. Flow cytometry analysis on cell cycle distributions in A549 cells treated with Ir-1 ~ Ir-4 (30 \u03bcM) for 24 h (A: control; B: Ir-1; C: Ir-2; D: Ir-3; E: Ir-4).\n\n 7\n\fJ. Zhao et al. Journal of Inorganic Biochemistry 238 (2023) 112050\n\n\nthe cell cycle at S phase (Fig. 7), indicating that Ir-1 and Ir-3 have the Appendix A. Supplementary data\npotential to inhibit DNA synthesis. In addition, no sub-G1 population\nwas observed, suggesting that Ir-1 ~ Ir-3 might not induce apoptosis in Experimental methods for synthesis and characterization; biological\nthis condition. Overall, Ir-1 and Ir-3 have different modes of action assays; 1H, 13C NMR and ESI-MS spectra for target compounds; other\ncompared with Ir-2 and Ir-4 due to the synergistic effect of iridium(III) supplementary results. Supplementary data to this article can be found\ncomplexes and NBDHEX. online at https://doi.org/10.1016/j.jinorgbio.2022.112050.\n\n3. 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