Anticancer activity of 8-hydroxyquinoline-triphenylphosphine rhodium(III) complexes targeting mitophagy pathways.

{"full_text": " European Journal of Medicinal Chemistry 272 (2024) 116478\n\n\n Contents lists available at ScienceDirect\n\n\n European Journal of Medicinal Chemistry\n journal homepage: www.elsevier.com/locate/ejmech\n\n\nResearch paper\n\nAnticancer activity of 8-hydroxyquinoline-triphenylphosphine rhodium(III)\ncomplexes targeting mitophagy pathways\nXiao-Qiong Huang a, 1, Run-Chun Wu a, 1, Jian-Min Liang a, Zhen Zhou a, **, Qi-Pin Qin a, b, *,\nHong Liang b, ***\na\n Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road,\nYulin 537000, PR China\nb\n State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai\nRoad, Guilin, 541004, 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: Metallodrugs exhibiting distinct mechanisms of action compared with cisplatin hold promise for overcoming\nRh(III) complexes cisplatin resistance and improving the efficacy of anticancer drugs. In this study, a new series of rhodium (Rh)\nTriphenylphosphine-8-hydroxyquinolines (III) complexes containing tris(triphenylphosphine)rhodium(I) chloride [(TPP)3RhCl] (TPP = triphenylphos\u00ad\nCell apoptosis\n phine, TPP=O = triphenylphosphine oxide) and 8-hydroxyquinoline derivatives (H-XR1\u2013H-XR4), namely [Rh\nATP\nMitophagy pathways\n (XR1)2(TPP)Cl]\u22c5(TPP=O) (Yulin Normal University-1a [YNU-1a]), [Rh(XR2)2(TPP)Cl] (YNU-1b), [Rh\n (XR3)2(TPP)Cl] (YNU-1c), and [Rh(XR4)2(TPP)Cl] (YNU-1d), was synthesized and characterized via X-ray\n diffraction, mass spectrometry and IR. The cytotoxicity of the compounds YNU-1a\u2013YNU-1d in Hep-G2 and\n HCC1806 human cancer cell lines and normal HL-7702 cell line was evaluated. YNU-1c exhibited cytotoxicity\n and selectivity in HCC1806 cells (IC50 = 0.13 \u00b1 0.06 \u03bcM, selectivity factor (SF) = 384.6). The compounds YNU-\n 1b and YNU-1c, which were selected for mechanistic studies, induced the activation of apoptotic pathways and\n mitophagy. In addition, these compounds released cytochrome c, cleaved caspase-3/pro-caspase-3 and down\u00ad\n regulated the levels of mitochondrial respiratory chain complexes I/IV (M1 and M4) and ATP. The compound\n YNU-1c, which was selected for in vivo experiments, exhibited tumor growth inhibition (58.9 %). Importantly,\n hematoxylin and eosin staining and TUNEL revealed that HCC1806 tumor tissues exhibited significant apoptotic\n characteristics. YNU-1a\u2013YNU-1d compounds are promising drug candidates that can be used to overcome\n cisplatin resistance.\n\n\n\n\n1. Introduction DNA, through noncovalent interactions [3,4]. In the 1960s, cisplatin\n was accidently discovered and demonstrated to possess potent anti\u00ad\n Transition metals have major advantages over organic compounds cancer properties [1,5]. Since then, metal-based chemotherapeutic\nfor the development of new therapeutic drugs, including varying ge\u00ad drugs have gained widespread attention from chemists. Although the\nometries, coordination numbers, oxidation states, and thermodyna\u00ad rhodium (Rh)(III) center is kinetically inert, a few studies have exam\u00ad\nmic\u2013kinetic characteristics [1\u20133]. Metal complexes may be used as ined its biological effects [6]. Recent studies have indicated that the\nscaffolds, and a desired therapeutic value can be obtained by incorpo\u00ad incorporation of appropriate ligands increases the reactivity of Rh\nrating different metal ions and active organic ligands. In vivo, metal ions complexes toward biological targets [6]. These complexes exhibit\nexist in the form of electron-deficient cations and are readily linked to promising anticancer activity and distinct mechanisms of action (MoAs)\nbiological targets of electron-rich biomolecules, such as proteins and compared with platinum drugs. For example, several Rh(III) complexes\n\n\n\n * Corresponding author. Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal Uni\u00ad\nversity, 1303 Jiaoyudong Road, Yulin 537000, PR China.\n ** Corresponding author.\n *** Corresponding author.\n E-mail addresses: zhouzhen0515@126.com (Z. Zhou), qpqin2018@126.com (Q.-P. Qin), hliang@mailbox.gxnu.edu.cn (H. Liang).\n 1\n These authors contributed equally to this work.\n\nhttps://doi.org/10.1016/j.ejmech.2024.116478\nReceived 26 January 2024; Received in revised form 2 May 2024; Accepted 3 May 2024\nAvailable online 4 May 2024\n0223-5234/\u00a9 2024 Elsevier Masson SAS. All rights reserved.\n\fX.-Q. Huang et al. European Journal of Medicinal Chemistry 272 (2024) 116478\n\n\ninhibit cell proliferation through various mechanisms, such as mito\u00ad cells were evaluated via the MTT assay, and a series of in vitro and in\nchondrial dysfunction, autophagy, or immunological pathways [6\u201313]. vivo experiments were performed using YNU-1a\u2013YNU-1d compounds\nRh-based anticancer complexes can be categorized into two types based with promising activity.\non their structure: half-sandwich complexes and cyclometalate com\u00ad\nplexes [14]. Notably, Guo et al. synthesized a series of organometallic 2. Results and discussion\nhalf-sandwich Rh(III) complexes with the structural formula [(\u03b76-are\u00ad\nne)/(\u03b75-Cp*)Rh(XY)Cl]0/+ (Cp*: C5(CH3)5; XY: bidentate chelating li\u00ad 2.1. Synthesis and stability of YNU-1a\u2013YNU-1d\ngands), which resulted in cell cycle arrest, disruption of lysosomal\nintegrity [15], and generation of reactive oxygen species (ROS) [12,16]. YNU-1a\u2013YNU-1d compounds were synthesized via the reaction of H-\n A survey by Njardarson revealed that nitrogen heterocycles account XR1\u2013H-XR4 (0.2 mmol) and (TPP)3RhCl (0.1 mmol; CAS number:\nfor 59 % of the small molecule drugs approved by the FDA in 2014 [17], 14694-95-2) in mixtures of CH3OH (1.5 mL) and CH2Cl2 (0.1 mL),\nwith each drug containing at least one nitrogen heterocycle. The com\u00ad respectively, and the mixtures were heated at 80 \u25e6 C for 72 h. The\npound 8-hydroxyquinoline (8-OHQ) contains a pyridine ring that pro\u00ad red\u2013brown products of YNU-1a\u2013YNU-1d eventually appeared, which\nvides an N-donor ligand fused with a phenol, which further provides an were isolated and characterized (Scheme 1).\nO-donor ligand; 8-OHQ is the backbone of drugs that form (N, O) The structure of the novel YNU-1a\u2013YNU-1d complexes was char\u00ad\nfive-membered chelate rings with metal ions [18\u201320]. Derivatives of acterized via X-ray crystallography (Figs. 1\u20134 and Tables S1\u2013S12), IR\n8-OHQ exhibit biological activity in several diseases (e.g., 5-nitro-8-\u00ad (Figs. S1\u2013S4), ESI-MS (Figs. S5\u2013S12) and HNMR (S13\u2013S15). As shown in\nOHQ for infectious diseases and 5-chloro-7-iodo-8-OHQ for neuropa\u00ad Figs. 1\u20134, the Rh(III) center in YNU-1a\u2013YNU-1d adopted a six-\nthies) [18\u201320]. Recently, many novel quinoline metal complexes, which coordinated octahedral geometry. Furthermore, YNU-1a\u2013YNU-1d\nhave shown promising anticancer activity in vitro and in vivo, have been compounds were tested for stability in Tris-HCl buffer via ESI-MS\nreported, including ruthenium(II) [21\u201324], copper(II) [25\u201327], cobalt (Figs. S5\u2013S12). The main peaks in the mass spectra of YNU-1a\u2013YNU-\n(II) [25,28], nickel(II) [25,29], zinc(II) [26,30], lanthanide(III) [31], 1d compounds were detected at 681.35, 791.00, 819.15, and 996.95,\niron(III) [32], platinum(II) [33], vanadium(IV) [34], and Rh(III) [8, respectively, at 0 h, which remained unchanged even after 48 h\n35\u201338] complexes. Enyedy reported the activity of 8-OHQ\u2013amino acid (Figs. S5\u2013S12), indicating that YNU-1a\u2013YNU-1d compounds were stable\nhybrids and their [Rh(\u03b75-C5Me5) (H2O)3]2+ complexes, which exhibited\nhigh stability and were more effective in treating drug-resistant Colo\n320 cells than drug-sensitive Colo 205 cells [35]. Moreover, they\ninteracted with calf thymus DNA (ct-DNA) as well as human serum al\u00ad\nbumin, but DNA cleavage was not observed [36]. In addition, Chen and\nLiang synthesized the novel 8-OHQ\u2013Rh complex and found that the\nunsubstituted and methyl-substituted 8-OHQ\u2013Rh(III) complex can\ninduce tumor cell death by disrupting mitochondrial-related mecha\u00ad\nnisms [37,38]; however, the specific underlying MoAs remain unknown.\n Compounds conjugated to lipophilic cations, such as triphenyl\u00ad\nphosphine (Ph3P+, TPP), can accumulate in the mitochondria driven by\nplasma membrane potential (\u0394\u03c8p) and mitochondrial membrane po\u00ad\ntential (\u0394\u03c8m) [39\u201342]. Thus, TPP has been used as a mitochondrial\ntargeting moiety. In this study, we synthesized and characterized four\nmitochondria-targeting Rh(III) complexes: [Rh(XR1)2(TPP)Cl]\u22c5\n(TPP=O) (YNU-1a), [Rh(XR2)2(TPP)Cl] (YNU-1b), [Rh(XR3)2(TPP)Cl]\n(YNU-1c), and [Rh(XR4)2(TPP)Cl] (YNU-1d), bearing 2-methylquinoli\u00ad\nn-8-ol (H-XR1), 5,7-dichloro-8-OHQ (H-XR2), 5,7-dichloro-2-methy\u00ad\nl-8-OHQ (H-XR3), 2-methyl-5,7-dibromo-quinoline-8-ol (H-XR4), and\n(TPP)3RhCl. The anti-proliferative activities of these complexes on\n Fig. 1. ORTEP drawing of YNU-1a.\nHep-G2 and HCC1806 tumor cells and human normal liver HL-7702\n\n\n\n\n Scheme 1. Synthesis of YNU-1a\u2013YNU-1d compounds.\n\n 2\n\fX.-Q. Huang et al. European Journal of Medicinal Chemistry 272 (2024) 116478\n\n\n in Tris-HCl buffer for 48 h.\n\n 2.2. Crystallography\n\n The crystal structures of YNU-1a\u2013YNU-1d compounds were deter\u00ad\n mined for Rh(III) complexes using the 8-OHQ derivatives H-XR1\u2013H-\n XR4. The deposition numbers 2327096\u20132327099 indicate the CCDC\n numbers for YNU-1a\u2013YNU-1d. Data regarding the Rh(III) complexes\n YNU-1a\u2013YNU-1d are available for free at http://www.ccdc.cam.ac.uk.\n For these four Rh(III) complexes YNU-1a\u2013YNU-1d formed via\n N2O2PClRh, Rh(III) demonstrated a slightly distorted six-coordinated\n octahedral structure surrounded by two 8-OHQ derivative ligands\n (N^O\u2013Rh), one Cl atom, and one P atom (Figs. 1\u20134). The lengths of Rh\u2013N,\n Rh\u2013Cl, and Rh\u2013O bonds (Tables S1\u2013S12), ranging from 2.015(3) to\n 2.083(8), 2.3951(10) to 2.408(2), and 2.003(3) to 2.0379(19) \u00c5,\n respectively, were within the normal range.\n\n 2.3. In vitro antiproliferative activity\n\n The test compounds YNU-1a\u2013YNU-1d, parental compounds H-\n XR1\u2013H-XR4, and cisplatin as a control were evaluated for their anti\u00ad\n Fig. 2. ORTEP drawing of YNU-1b. proliferative activity in Hep-G2 (hepatocellular carcinoma cells),\n HCC1806 (breast squamous carcinoma cells), and normal liver cell line\n HL-7702 using the MTT assay [43,44]. The test compounds YNU-1a\u00ad\n \u2013YNU-1d exhibited high antiproliferative activity against the tumor cell\n lines (IC50 = 0.13\u20133.71 \u03bcM), whereas the parental compounds\n H-XR1\u2013H-XR4 showed low cytotoxicity with an IC50 value of >50 \u03bcM. In\n particular, the compound YNU-1c showed the highest cytotoxicity\n against HCC1806 cells with an IC50 value of 0.13 \u00b1 0.06 \u03bcM (Table 1),\n which was 69.38-fold higher than that of cisplatin, but it was less toxic\n to the normal cell line HL-7702 (IC50 > 50 \u03bcM). The overall trend in the\n potency of the compounds was as follows: YNU-1c > YNU-1d >\n YNU-1b > YNU-1a > cisplatin \u226b H-XR1\u2013H-XR4. Moreover, for the\n YNU-1c-treated group, the ratio of IC50 for HL-7702 to that for HCC1806\n (i.e., selectivity factor [6]) was the highest at 384.6, which indicates the\n selectivity of YNU-1c for the tumor cell line HCC1806. The multi\u00ad\n substituted 8-OHQ complexes (YNU-1b\u2013YNU-1d) exhibited better ac\u00ad\n tivity than the single-substituted complex (YNU-1a). Furthermore, the\n addition of a methyl group at 2-position of 8-OHQ increased the potency\n of the compound YNU-1c by 3.6-fold compared with that of compound\n YNU-1b for HCC1806 tumors. The methyl group may contribute to its\n Fig. 3. ORTEP drawing of YNU-1c. potency. Importantly, compared with the previously reported Rh com\u00ad\n plex containing 2-methyl-substituted 8-OHQ ligands [38], YNU-1c\n exhibited a higher potency against Hep-G2 and HCC1806 cells. More\u00ad\n over, the coordination of TPP to the metal Rh plays a key role [39\u201342].\n For a better comparison and considering the antitumor activity effects of\n compounds YNU-1b and YNU-1c, it is reasonable to select these\n\n Table 1\n Antiproliferative activity (IC50a, \u03bcM) of YNU-1a\u2013YNU-1d against HepG2,\n HCC1806, and HL-7702 cells for 48 h.\n Hep-G2 HCC1806 HL-7702 SF1b SF2c\n\n H-XR1 >50 >50 >50 ~1.0 1.0\n YNU-1a 3.71 \u00b1 0.61 3.01 \u00b1 0.75 >50 >16.6 >13.5\n H-XR2 >50 >50 >50 ~1.0 ~1.0\n YNU-1b 0.59 \u00b1 0.22 0.47 \u00b1 0.46 >50 >106.4 >84.7\n H-XR3 >50 >50 >50 ~1.0 ~1.0\n YNU-1c 0.19 \u00b1 0.08 0.13 \u00b1 0.06 >50 >384.6 >263.2\n H-XR4 >50 >50 >50 ~1.0 ~1.0\n YNU-1d 0.35 \u00b1 0.11 0.31 \u00b1 0.09 >50 >161.3 >142.9\n cisplatin 9.89 \u00b1 1.28 9.02 \u00b1 0.49 18.37 \u00b1 1.12 2.0 1.9\n Fig. 4. ORTEP drawing of YNU-1d. a\n IC50 values are expressed as the mean \u00b1 standard deviation of three inde\u00ad\n pendent experiments. Stock solutions of YNU-1a\u2013YNU-1d (2 mM) were made in\n DMSO. cisplatin (1.0 mM) was prepared in 0.154 M NaCl. All the experiments\n contained media with 0.5 % DMSO.\n b\n SF1 (selectivity factor 1) = IC50 (HL-7702)/IC50 (HCC1806).\n c\n SF2 (selectivity factor 2) = IC50 (HL-7702)/IC50 (Hep-G2).\n\n 3\n\fX.-Q. Huang et al. European Journal of Medicinal Chemistry 272 (2024) 116478\n\n\ncompounds for further biological activity studies. suggest that cytochrome c initiates the activation of caspase-3. To\n confirm these observations, the release of cytochrome c was examined\n2.4. Release of cytochrome c and caspase-3 cellular activation by immunofluorescence analysis. Fluorescence images were captured by\n confocal microscopy. HCC1806 cells were treated with YNU-1c (0.13\n It was previously reported that apoptosis induced by the 2-methyl-8- \u03bcM) and YNU-1b (0.47 \u03bcM) for 48 h. The green fluorescent intensity was\nhydroxyquinoline Rh(III) complex occurred by disrupting mitochondria increased (Fig. 6), which suggests that cytochrome c was released and\nfunction [38]. Mitochondrial dysfunction involves the release of cyto\u00ad further confirmed that YNU-1c and YNU-1b induces apoptosis through\nchrome c into the cytoplasm, which subsequently activates the the mitochondrial pathway. Similarly, the intensity of fluorescence\ncaspase-dependent death pathway, leading to apoptosis [45\u201350]. produced by YNU-1c-treated cells was significantly higher compared\nTherefore, we measured the expression of cytochrome c and cleaved with that of the YNU-1b-treated cells.\ncaspase-3 via Western blot analysis to determine whether YNU-1b and\nYNU-1c induce apoptosis in HCC1806 cells through the mitochondrial 2.5. Mitophagy studies\npathway. As expected, YNU-1c prominently upregulated the expression\nof cytochrome c and cleaved caspase-3 compared with YNU-1b Autophagy occurs in response to stressful conditions such as hypoxia,\nfollowing exposure to HCC1806 cells (Fig. 5). In addition, the ratio of starvation, and radiation and acts as a cytoprotective mechanism [51].\ncleaved caspase-3/pro-caspase-3 was increased (Fig. 5). These results In general, autophagy is maintained at a basal level, which contributes\n to cell survival and homeostasis [51]. A crucial form of autophagy,\n known as mitophagy, selectively removes damaged mitochondria via\n the PINK1\u2013Parkin pathway [52]. When mitochondria are depolarized,\n PINK1 and Parkin accumulate in the mitochondria, ubiquitylate mito\u00ad\n chondrial outer membrane proteins, and recruit autophagy-associated\n proteins, such as p62 and LC3, ultimately leading to mitophagy\n [53\u201355]. To determine whether YNU-1b and YNU-1c promote auto\u00ad\n phagy, Western blot analysis was used to detect autophagy-related\n proteins.\n The expression levels of PINK1 and Parkin were higher in both YNU-\n 1b- and YNU-1c-treated groups than in the control group (Fig. 5),\n indicating that the PINK1\u2013Parkin pathway was activated. The conver\u00ad\n sion of LC3-I to its lipidation form LC3-II, a specific marker of auto\u00ad\n phagy, was observed in cells treated with YNU-1b and YNU-1c. YNU-1c\n showed a higher conversion rate of LC3-I to LC3-II (n = 3) than YNU-1b.\n YNU-1c also downregulated the expression of p62, further confirming\n the autophagic process in HCC1806 cells. In addition, the levels of\n FUNDC1 protein did not change significantly, but the expression of\n Beclin-1 was upregulated by YNU-1c. These results indicated that YNU-\n 1b and YNU-1c can induce mitochondrial autophagy, with YNU-1c\n exerting a greater effect. This finding highlights the importance of\n adding the 2-methyl group to 8-OHQ in YNU-1c.\n\n 2.6. Mitochondrial respiratory complex activities and ATP energy\n\n As an important organelle involved in cellular metabolism, mito\u00ad\n chondria play a vital role in providing the primary source of ATP. The\n electron transport chain is a series of enzyme complexes that is present\n within mitochondria. Because some metallic chemotherapeutic agents\n inhibit M1, M4, and ATP [55\u201358], we hypothesized that YNU-1b and\n YNU-1c may exhibit similar effects. To determine the effect of YNU-1b\n and YNU-1c on mitochondrial respiration, the levels of M1, M4, and\n ATP were measured in HCC1806 cells using M1, M4, and ATP assay kits,\n respectively.\n After 48 h of exposure, the activities of M1 and M4 were decreased in\n the YNU-1c-treated group, with values of 37.38 \u00b1 2.29 U/mg protein\n and 31.84 \u00b1 1.35 U/mg protein (Table 2 and S13\u2013S15), respectively,\n which were significantly lower compared with the control sample\n (66.67 \u00b1 4.00 U/mg protein, 53.18 \u00b1 3.09 U/mg protein) and the YNU-\n 1b-treated group (49.03 \u00b1 1.29 U/mg protein, 40.69 \u00b1 0.98 U/mg\n protein). In addition, the YNU-1c-treated group exhibited a decrease in\n ATP content to 1.77 \u00b1 0.03 \u03bcM after 48 h of exposure, which was lower\n compared with that in the control group (3.51 \u00b1 0.10 \u03bcM) and the YNU-\n 1b-treated group (2.08 \u00b1 0.10 \u03bcM). This decrease in ATP content in\u00ad\n dicates that YNU-1b and YNU-1c disrupt mitochondrial function and\n impede energy production in HCC1806 cells (Table 2 and S13\u2013S15),\n ultimately leading to cancer cell death. Moreover, it was observed that\nFig. 5. Levels of mitophagy-related proteins induced by YNU-1c (0.13 \u03bcM) and both YNU-1b and YNU-1c affected mitochondrial respiration to varying\nYNU-1b (0.47 \u03bcM) in HCC1806 cells at 48 h, as determined via Western blot degrees by inhibiting M1, M4, and reducing ATP levels, with YNU-1c\nanalysis. (*) p < 0.05. exhibiting a greater effect.\n\n 4\n\fX.-Q. Huang et al. European Journal of Medicinal Chemistry 272 (2024) 116478\n\n\n\n\nFig. 6. The release of cytochrome c was assessed after exposure of HCC1806 cells to YNU-1c (0.13 \u03bcM) and YNU-1b (0.47 \u03bcM) for 48 h via confocal microscopy.\n\n\n group increased by only 6.8-fold, revealing that the indicated dose of\nTable 2\n YNU-1c effectively inhibited HCC1806 tumor growth (Tables S16\u2013S18).\nLevels of M1, M4, and ATP in HCC1806 cells treated with YNU-1c (0.13 \u03bcM) and\n Furthermore, the tumor weight of the YNU-1c-treated group was\nYNU-1b (0.47 \u03bcM) for 48 h (n = 3, p < 0.05).\n significantly reduced, resulting in a tumor growth inhibition rate of 58.9\n Group Complex Values % (Fig. 9). No notable body weight loss was observed in the YNU-1c-\n M1 Untreated cells 66.67 \u00b1 4.00 U/mg prot treated group (Tables S16\u2013S18), suggesting that the mice could tolerate\n YNU-1b 49.03 \u00b1 1.29 U/mg prot the dose of 5 mg/kg. Taken together, YNU-1c may serve as a theranostic\n YNU-1c 37.38 \u00b1 2.29 U/mg prot\n platform for inhibiting tumor growth.\n M4 Untreated cells 53.18 \u00b1 3.09 U/mg prot\n YNU-1b 40.69 \u00b1 0.98 U/mg prot\n YNU-1c 31.84 \u00b1 1.35 U/mg prot 2.9. Tumor pathology\n\n ATP Untreated cells 3.51 \u00b1 0.10 \u03bcM\n YNU-1b 2.08 \u00b1 0.10 \u03bcM\n The HCC1806 tumor tissues were harvested from the xenograft\n YNU-1c 1.77 \u00b1 0.03 \u03bcM model for pathological analysis. Hematoxylin and eosin (H&E) staining\n was done. Hematoxylin causes the nuclear chromatin and cytoplasmic\n nucleic acids to appear purple\u2013blue, whereas eosin stains the extracel\u00ad\n2.7. Apoptosis assay lular matrix and cytoplasm red [60,61].\n In mice administered YNU-1c (5 mg/kg dose), the tumor tissue\n The MTT assay revealed that YNU-1b and YNU-1c have a significant showed significantly different histological characteristics compared\neffect on the survival of HCC1806 cells. Therefore, apoptosis was with that of the untreated mice. As shown in Fig. 10, the tumor cells in\nassessed by flow cytometry using Annexin V-FITC and PI as indicators of the control group were uniformly stained without obvious necrotic\napoptotic and dead cells, respectively [59]. Fig. 7 shows the population areas; however, in the YNU-1c-treated group, significant cell damage\nof viable cells (FITC\u2212 /PI\u2212 ), early-stage apoptotic cells (FITC+/PI\u2212 ), (large pink-stained area) was observed, indicating that YNU-1c had\nand late-stage apoptotic cells (FITC+/PI+) [60] after treatment with visible antitumor effects by inducing apoptosis in vivo. In addition, the\nYNU-1c (0.13 \u03bcM) and YNU-1b (0.47 \u03bcM). HCC1806 cell apoptosis was TUNEL method was used to identify and quantify apoptotic cells [60,\n28.45 \u00b1 0.88 % for YNU-1b and 44.39 \u00b1 1.54 % for YNU-1c (Fig. 7). 61], which were labeled brown. Fig. 10 shows that the HCC1806 tumor\nThe results indicated that YNU-1c was significantly (p < 0.05) more cells exhibited clear characteristics of apoptosis (brown-stained areas),\neffective in promoting HCC1806 cell apoptosis than YNU-1b. The results consistent with the results of H&E staining. Statistical analysis revealed\nsuggest that the observed cytotoxicity of YNU-1b and YNU-1c in cancer that the apoptosis rate of tumors after treatment with YNU-1c was\ncells primarily occurs through the apoptotic pathway (see Fig. 8). 25.11 %, which indicates that YNU-1c induces tumor tissue necrosis.\n\n2.8. In vivo antitumor efficacy 3. Conclusion\n\n To determine the cytotoxic effect of YNU-1c in vivo, HCC1806 We designed and synthesized a series of selective and potent Rh(III)\ntumor-bearing nude mice (Balb/c) were established. These mice were complexes, YNU-1a\u2013YNU-1d, featuring H-XR1\u2013H-XR4 and (TPP)3RhCl,\nrandomly categorized into two groups (n = 6 in each group): control and and investigated their antiproliferative effects in vitro and in vivo. The\ntest groups. YNU-1c was intraperitoneally injected at a dose of 5.0 mg/ MTT assay revealed that YNU-1b and YNU-1c exerted higher anticancer\nkg every 2 days, and intraperitoneal saline was administered to the activity than cisplatin in the tested cancer cells. The methyl group may\ncontrol group. In the control group, the growth rate of HCC1806 tumors contribute to its potency. In terms of the underlying mechanism,\nwas extremely high, with the tumor volumes increasing ~16-fold after immunofluorescence analysis, Western blot analysis, and apoptosis as\u00ad\n21 days. However, the average tumor volume of the YNU-1c-treated says revealed that YNU-1b and YNU-1c induce apoptosis in HCC1806\n\n 5\n\fX.-Q. Huang et al. European Journal of Medicinal Chemistry 272 (2024) 116478\n\n\n\n\n Fig. 7. Apoptosis of HCC1806 cells induced by exposure to YNU-1c (0.13 \u03bcM) and YNU-1b (0.47 \u03bcM) for 48 h.\n\n\ncells. Furthermore, YNU-1b and YNU-1c induced the release of cyto\u00ad 4. Experimental methods\nchrome c from the mitochondrial intermembrane space into the cyto\u00ad\nplasm and further activated caspase-3. Finally, YNU-1b and YNU-1c 4.1. Synthesis of Rh complexes\ninduced apoptosis. This indicates the occurrence of mitochondrial\ndysfunction, and YNU-1b exhibited higher potency than YNU-1c. YNU-1a\u2013YNU-1d compounds were synthesized via the reaction of H-\nMoreover, Western blot analyses revealed that YNU-1b and YNU-1c L1\u2013H-L4 (0.2 mmol) and [(C6H5)3 P]3RhCl (0.1 mmol) in mixtures of\nactivated PINK1\u2013Parkin signaling, inhibited the expression of p62 pro\u00ad CH3OH (1.5 mL) and CH2Cl2 (0.1 mL), respectively, and the mixtures\ntein, and further increased the LC3-II/LC3-I ratio and Beclin1, indicating were heated at 80 \u25e6 C for 72 h. The red\u2013brown products of YNU-1a\u2013YNU-\nthat YNU-1b and YNU-1c induce mitophagy. In addition, the levels of 1d eventually appeared, which were isolated and characterized (Scheme\nM1, M4, and ATP were decreased. YNU-1c induced apoptosis in a higher 1).\nproportion of HCC1806 cells in vitro and in vivo than YNU-1b. Overall, Data regarding YNU-1a. ESI-MS: m/z = 681.35 for [M\u2013Cl\u2013\nYNU-1c containing a methyl group on its ligand exhibits the strongest (TPP=O)]\u00fe; IR (KBr): 3399, 3053, 1634, 1563, 1505, 1482, 1463, 1434,\nantitumor activity and is a potential anticancer metallodrug candidate 1377, 1332, 1283, 1177, 1161, 1113, 1093, 1070, 1038, 997, 885, 831,\nfor treating HCC1806 cells. 751, 722, 693, 641, 581, 542, 531, 513, 498, 482, and 460 cm\u2212 1; 1H\n NMR (400 MHz, DMSO\u2011d6): \u03b4 8.01 (d, J = 8.4 Hz, 2H), 7.64\u20137.59 (m,\n 20H), 7.55 (m, 10H), 7.28\u20137.25 (m, 2H), 7.23\u20137.18 (m, 2H), 7.10\u20137.05\n (m, 2H), 6.79 (m, 2H), 3.10 (s, 6H).\n Data regarding YNU-1b. ESI-MS: m/z = 791.05 for [M \u2212 Cl]\u00fe; IR\n\n\n 6\n\fX.-Q. Huang et al. European Journal of Medicinal Chemistry 272 (2024) 116478\n\n\n Materials.\n\n Abbreviations\n\n SF selectivity factor\n M1 mitochondrial respiratory chain complexes I\n M4 mitochondrial respiratory chain complexes IV\n ATP adenosine triphosphate\n 8-OHQ 8-hydroxyquinoline\n \u0394\u03c8p plasma membrane potential\n Ph3P+, TPP triphenylphosphine\n TPP=O triphenylphosphine oxide\n (TPP)3RhCl tris(triphenylphosphine)rhodium(I) chloride\n \u0394\u03c8m mitochondrial membrane potential\n H-XR1 2-methylquinolin-8-ol\n H-XR2 5,7-dichloro-8-OHQ\n H-XR3 5,7-dichloro-2-methyl-8-OHQ\n H-XR4 2-methyl-5,7-dibromo-quinoline-8-ol\n Hep-G2 hepatocellular carcinoma cells\n HCC1806 breast squamous carcinoma cells\n HL-7702 normal liver cell line\n MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide\n SF1 selectivity factor 1\n SF2 selectivity factor 2\nFig. 8. Populations for the apoptotic HCC1806 cells treated by YNU-1c (0.13 H&E hematoxylin and eosin (H&E) staining\n\u03bcM) and YNU-1b (0.47 \u03bcM) for 48 h. MoAs mechanisms of action\n ROS reactive oxygen species\n\n(KBr): 3428, 3057, 1962, 1904, 1816, 1620, 1555, 1493, 1483, 1450,\n1435, 1399, 1375, 1364, 1289, 1253, 1221, 1195, 1159, 1144, 1118,\n1093, 1056, 1028, 998, 978, 887, 848, 812, 777, 749, 694, 660, 619,\n547, 519, 499, 463, 440, and 417 cm\u2212 1.\n Data regarding YNU-1c. ESI-MS: m/z = 819.15 for [M \u2212 Cl]\u00fe; IR\n(KBr): 3447, 3055, 2987, 2154, 1603, 1582, 1573, 1550, 1499, 1482,\n1431, 1368, 1324, 1282, 1266, 1197, 1158, 1121, 1092, 1029, 999, 972,\n947, 873, 830, 783, 754, 746, 707, 695, 618, 529, 519, 499, 459, and\n438 cm\u2212 1; 1H NMR (400 MHz, DMSO\u2011d6): \u03b4 8.21 (d, J = 8.6 Hz, 2H),\n7.58 (s, 2H), 7.46 (d, J = 8.7 Hz, 2H), 7.33 (td, J = 7.4, 1.8 Hz, 3H),\n7.28\u20137.23 (m, 6H), 7.14 (td, J = 8.2, 2.8 Hz, 6H), 3.24 (s, 6H).\n Data regarding YNU-1d. ESI-MS: m/z = 996.95 for [M \u2212 Cl]\u00fe; IR\n(KBr): 3856, 3819, 3804, 3748, 3673, 3445, 3055, 1572, 1547, 1492,\n1482, 1426, 1364, 1321, 1263, 1191, 1151, 1119, 1091, 1028, 999, 952,\n936, 870, 829, 760, 746, 695, 675, 529, 514, and 497 cm\u2212 1; 1H NMR\n(400 MHz, DMSO\u2011d6): \u03b4 8.14 (d, J = 8.7 Hz, 2H), 7.79 (s, 2H), 7.47 (d, J\n= 8.7 Hz, 2H), 7.33 (t, J = 7.9 Hz, 3H), 7.28\u20137.23 (m, 6H), 7.13 (td, J =\n8.2, 2.7 Hz, 6H), 3.25 (s, 6H).\n\n\n4.2. Other experimental methods\n\n The antitumor mechanism of YNU-1a\u2013YNU-1d in HCC1806 cells\nwas determined as previously described [28,62]. In addition, the\ndetailed data relating to YNU-1a\u2013YNU-1d and information about ex\u00ad\n Fig. 10. Effect of YNU-1c on tumor tissue compared with the control group.\nperiments can be found in the Electronic Supporting Information\n\n\n\n\n Fig. 9. YNU-1c (5.0 mg/kg/q2d) exhibits antitumor effects in an in vivo HCC1806 mouse model.***p < 0.05.\n\n 7\n\fX.-Q. Huang et al. European Journal of Medicinal Chemistry 272 (2024) 116478\n\n\nCRediT authorship contribution statement [13] Y. Zheng, X.-X. Chen, D.-Y. Zhang, W.-J. Wang, K. Peng, Z.-Y. Li, Z.-W. Mao, C.-\n P. Tan, Activation of the cGAS-STING pathway by a mitochondrial DNA-targeted\n emissive rhodium(III) metallointercalator, Chem. Sci. 14 (2023) 6890\u20136903.\n Xiao-Qiong Huang: Validation, Methodology, Data curation, [14] X. Hu, L. Guo, M. Liu, Q. Zhang, Y. Gong, M. Sun, S. Feng, Y. Xu, Y. Liu, Z. Liu,\nConceptualization. Run-Chun Wu: Validation, Methodology, Formal Increasing anticancer activity with phosphine ligation in zwitterionic half-\nanalysis, Data curation. Jian-Min Liang: Formal analysis, Data cura\u00ad sandwich iridium(III), rhodium(III), and ruthenium(II) complexes, Inorg. Chem. 61\n (2022) 20008\u201320025.\ntion. Zhen Zhou: Writing \u2013 original draft, Resources, Funding acquisi\u00ad [15] L. Guo, X. Hu, Y. Yang, W. An, J. Gao, Q. Liu, Z. Liu, Synthesis and biological\ntion. Qi-Pin Qin: Writing \u2013 review & editing, Writing \u2013 original draft, evaluation of zwitterionic half-sandwich rhodium(III) and ruthenium(II)\nSupervision, Formal analysis, Data curation, Conceptualization. Hong organometallic complexes, Bioorg. Chem. 116 (2021) 105311.\n [16] X. Hu, L. Guo, M. Liu, M. Sun, Q. Zhang, H. Peng, F. Zhang, Z. Liu, Formation of\nLiang: Supervision, Resources, Project administration, Formal analysis. iridium(III) and rhodium(III) amine, imine, and amido complexes based on\n pyridine-amine ligands: structural diversity arising from reaction conditions,\nDeclaration of competing interest substituent variation, and metal centers, Inorg. Chem. 61 (2022) 10051\u201310065.\n [17] E. Vitaku, D.T. Smith, J.T. Njardarson, Analysis of the structural diversity,\n substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA\n The authors declare that they have no known competing financial approved pharmaceuticals, J. Med. Chem. 57 (2014) 10257\u201310274.\ninterests or personal relationships that could have appeared to influence [18] V.F.S. Pape, R. Palko\u0301, S. To\u0301th, M.J. Szabo\u0301, J. Sessler, G. Dorma\u0301n, E\u0301.A. Enyedy,\n T. Soo\u0301s, I. Szatma\u0301ri, G. Szaka\u0301cs, Structure-activity relationships of 8-hydroxyqui\u00ad\nthe work reported in this paper. noline-derived mannich bases with tertiary amines targeting multidrug-resistant\n cancer, J. Med. Chem. 65 (2022) 7729\u20137745.\nData availability [19] X. Zhou, Insights of metal 8-hydroxylquinolinol complexes as the potential\n anticancer drugs, J. Inorg. Biochem. 238 (2023) 112051.\n [20] R. Gupta, V. Luxami, K. Paul, Insights of 8-hydroxyquinolines: a novel target in\n The data presented in this study are available upon request from the medicinal chemistry, Bioorg. Chem. 108 (2021) 104633.\ncorresponding author. The data are not publicly available because of [21] M. Huang, Y. Zhang, Y. Gong, Z. Liang, X. Chen, Y. Ni, X. Pan, W. Wu, J. Chen,\n Z. Huang, J. Sun, 8-Hydroxyquinoline ruthenium(II) complexes induce ferroptosis\nproject confidentiality.\n in HeLa cells by down-regulating GPX4 and ferritin, J. Inorg. Biochem. 248 (2023)\n 112365.\nAcknowledgments [22] X. Ma, J. Lu, P. Yang, Z. Zhang, B. Huang, R. Li, R. Ye, 8-Hydroxyquinoline-\n modified ruthenium(II) polypyridyl complexes for JMJD inhibition and\n photodynamic antitumor therapy, Dalton Trans. 51 (2022) 13902\u201313909.\n We thank the National Natural Science Foundation of China (China, [23] X. He, J. Chen, L. Wei, M. Kandawa-Shultz, G. Shao, Y. Wang, Antitumor activity of\nGrant No. 22267020), Natural Science Foundation of Guangxi (Grant iridium/ruthenium complexes containing Nitro -substituted quinoline ligands in\nNo. 2020GXNSFAA297077), and Talent Project of Yulin Normal Uni\u00ad vivo and in vitro, Dyes Pigments 213 (2023) 111146.\n [24] P.K. Anuja, N. Roy, U. Das, S. Varddhan, S.K. Sahoo, P. Paira, [Ru(\u03b76-p-cymene)\nversity (China, Grant Nos. G2023ZK05, G2023ZK19, G2022ZK24, and (N^O 8-hydroxyquinoline)(PTA)] complexes as rising stars in medicinal chemistry:\nG2022ZK25). synthesis, properties, biomolecular interactions, in vitro anti-tumor activity toward\n human brain carcinomas, and in vivo biodistribution and toxicity in a zebrafish\n model, Dalton Trans. 51 (2022) 8497\u20138509.\nAppendix A. Supplementary data [25] A. Kotian, V. Kamat, K. Naik, D.G. Kokare, K. Kumara, K.L. Neratur, V. Kumbar,\n K. Bhat, V.K. Revankar, 8-Hydroxyquinoline derived p-halo N4-phenyl substituted\n Supplementary data to this article can be found online at https://doi. thiosemicarbazones: crystal structures, spectral characterization and in vitro\n cytotoxic studies of their Co(III), Ni(II) and Cu(II) complexes, Bioorg. Chem. 112\norg/10.1016/j.ejmech.2024.116478. (2021) 104962.\n [26] L. Co\u0302rte-Real, V. Po\u0301sa, M. Martins, R. Colucas, N.V. May, X. Fontrodona, I. Romero,\nReferences F. Mendes, C. Pinto Reis, M.M. Gaspar, J.C. Pessoa, E\u0301.A. Enyedy, I. Correia, Cu(II)\n and Zn(II) complexes of new 8-hydroxyquinoline schiff bases: investigating their\n structure, solution speciation, and anticancer potential, Inorg. Chem. 62 (2023)\n [1] S.H. van Rijt, P.J. Sadler, Current applications and future potential for bioinorganic\n 11466\u201311486.\n chemistry in the development of anticancer drugs, Drug Discov. Today 14 (2009)\n [27] A. Ali, S. Mishra, S. Kamaal, A. Alarifi, M. Afzal, K.D. Saha, M. Ahmad, Evaluation\n 1089\u20131097.\n of catacholase mimicking activity and apoptosis in human colorectal carcinoma\n [2] M. Sohrabi, M. Saeedi, B. Larijani, M. Mahdavi, Recent advances in biological\n cell line by activating mitochondrial pathway of copper(II) complex coupled with\n activities of rhodium complexes: their applications in drug discovery research, Eur.\n 2-(quinolin-8-yloxy)(methyl)benzonitrile and 8-hydroxyquinoline, Bioorg. Chem.\n J. Med. Chem. 216 (2021) 113308.\n 106 (2021) 104479.\n [3] U. Das, B. Kar, S. Pete, P. Paira, Ru(II), Ir(III), Re(I) and Rh(III) based complexes as\n [28] Y.-F. Wang, J.-X. Tang, Z.-Y. Mo, J. Li, F.-P. Liang, H.-H. Zou, The strong in vitro\n next generation anticancer metallopharmaceuticals, Dalton Trans. 50 (2021)\n and vivo cytotoxicity of three new cobalt(II) complexes with 8-methoxyquinoline,\n 11259\u201311290.\n Dalton Trans. 51 (2022) 8840\u20138847.\n [4] T. Storr, K.H. Thompson, C. Orvig, Design of targeting ligands in medicinal\n [29] Z.-F. Wang, Q.-C. Wei, J.-X. Li, Z. Zhou, S.-H. Zhang, A new class of nickel(II)\n inorganic chemistry, Chem. Soc. Rev. 35 (2006) 534\u2013544.\n oxyquinoline-bipyridine complexes as potent anticancer agents induces apoptosis\n [5] B. Rosenberg, L. Van Camp, T. Krigas, Inhibition of cell division in escherichia coli\n and autophagy in A549/DDP tumor cells through mitophagy pathways, Dalton\n by electrolysis products from a platinum electrode, Nature 205 (1965) 698\u2013699.\n Trans. 51 (2022) 7154\u20137163.\n [6] Y.-Q. Gu, K. Yang, Q.-Y. Yang, H.-Q. Li, M.-Q. Hu, M.-X. Ma, N.-F. Chen, Y.-H. Liu,\n [30] L.-Q. Du, T.-Y. Zhang, X.-M. Huang, Y. Xu, M.-X. Tan, Y. Huang, Y. Chen, Q.-P. Qin,\n H. Liang, Z.-F. Chen, Rhodium(III)-picolinamide complexes act as anticancer and\n Synthesis and anticancer mechanisms of zinc(II)-8-hydroxyquinoline complexes\n antimetastasis agents via inducing apoptosis and autophagy, J. Med. Chem. 66\n with 1,10-phenanthroline ancillary ligands, Dalton Trans. 52 (2023) 4737\u20134751.\n (2023) 9592\u20139606.\n [31] Y. Yang, Z. Zhou, Z.-Z. Wei, Q.-P. Qin, L. Yang, H. Liang, High anticancer activity\n [7] T.-M. Khan, N.S. Gul, X. Lu, R. Kumar, M.I. Choudhary, H. Liang, Z.-F. Chen,\n and apoptosis- and autophagy-inducing properties of novel lanthanide(III)\n Rhodium(iii) complexes with isoquinoline derivatives as potential anticancer\n complexes bearing 8-hydroxyquinoline-N-oxide and 1,10-phenanthroline, Dalton\n agents: in vitro and in vivo activity studies, Dalton Trans. 48 (2019) 11469\u201311479.\n Trans. 50 (2021) 5828\u20135834.\n [8] Z.-F. Wang, X.-L. Nai, Y. Xu, F.-H. Pan, F.-S. Tang, Q.-P. Qin, L. Yang, S.-H. Zhang,\n [32] V. Ferretti, C.P. Matos, C. Canelas, J.C. Pessoa, A.I. Tomaz, R. Starosta, I. Correia, I.\n Cell nucleus localization and high anticancer activity of quinoline-benzopyran\n E. Leo\u0301n, New ternary Fe(III)-8-hydroxyquinoline-reduced Schiff base complexes as\n rhodium(III) metal complexes as therapeutic and fluorescence imaging agents,\n selective anticancer drug candidates, J. Inorg. Biochem. 236 (2022) 111961.\n Dalton Trans. 51 (2022) 12866\u201312875.\n [33] Y. Yang, L.-Q. Du, Y. Huang, C.-J. Liang, Q.-P. Qin, H. Liang, Platinum(II) 5-\n [9] Y.-B. Peng, W. He, Q. Niu, C. Tao, X.-L. Zhong, C.-P. Tan, P. Zhao, Mitochondria-\n substituted-8-hydroxyquinoline coordination compounds induces mitophagy-\n targeted cyclometalated rhodium(III) complexes: synthesis, characterization and\n mediated apoptosis in A549/DDP cancer cells, J. Inorg. Biochem. 241 (2023)\n anticancer research, Dalton Trans. 50 (2021) 9068\u20139075.\n 112152.\n[10] Y.-B. Peng, C. Tao, C.-P. Tan, P. Zhao, Mitochondrial targeted rhodium(III)\n [34] N. Ribeiro, I. Bulut, V. Po\u0301sa, B. Sergi, G. Sciortino, J.C. Pessoa, L.B. Maia, V. Ugone,\n complexes: synthesis, characterized and antitumor mechanism investigation,\n E. Garribba, E\u0301.A. Enyedy, C. Acilan, I. Correia, Solution chemical properties and\n J. Inorg. Biochem. 218 (2021) 111400.\n anticancer potential of 8-hydroxyquinoline hydrazones and their oxidovanadium\n[11] C. Pe\u0301rez-Arnaiz, M.I. Acun\u0303a, N. Busto, I. Echevarr\u00eda, M. Mart\u00ednez-Alonso,\n (IV) complexes, J. Inorg. Biochem. 235 (2022) 111932.\n G. Espino, B. Garc\u00eda, F. Dom\u00ednguez, Thiabendazole-based Rh(III) and Ir(III)\n [35] J.P. Me\u0301sza\u0301ros, J.M. Poljarevic\u0301, I. Szatma\u0301ri, O. Csuvik, F. F\u00fclo\u0308p, N. Szoboszlai,\n biscyclometallated complexes with mitochondria-targeted anticancer activity and\n G. Spengler, E\u0301.A. Enyedy, An 8-hydroxyquinoline\u2013proline hybrid with multidrug\n metal-sensitive photodynamic activity, Eur. J. Med. Chem. 157 (2018) 279\u2013293.\n resistance reversal activity and the solution chemistry of its half-sandwich\n[12] L. Guo, P. Li, J. Li, Y. Gong, X. Li, Y. Liu, K. Yu, Z. Liu, Half-sandwich iridium(III),\n organometallic Ru and Rh complexes, Dalton Trans. 49 (2020) 7977\u20137992.\n rhodium(III), and ruthenium(II) complexes chelating hybrid sp2-N/sp3-N donor\n [36] T. Pivarcsik, O. Do\u0308mo\u0308to\u0308r, J.P. Me\u0301sza\u0301ros, N.V. May, G. Spengler, O. Csuvik,\n ligands to achieve improved anticancer selectivity, Inorg. Chem. 62 (2023)\n I. Szatma\u0301ri, E\u0301.A. Enyedy, 8-Hydroxyquinoline-Amino acid hybrids and their half-\n 15118\u201315137.\n\n\n 8\n\fX.-Q. Huang et al. European Journal of Medicinal Chemistry 272 (2024) 116478\n\n sandwich Rh and Ru complexes: synthesis, anticancer activities, solution chemistry relevant treatment through mitophagy to inhibit metabolic adaptations of cancer\n and interaction with biomolecules, Int. J. Mol. Sci. 22 (2021) 11281. cells, Angew. Chem. Int. Ed. 61 (2022) e202203843.\n[37] H.-R. Zhang, Y.-C. Liu, Z.-F. Chen, T. Meng, B.-Q. Zou, Y.-N. Liu, H. Liang, Studies [53] (a) M.E. Gegg, A.H.V. Schapira, PINK1-parkin-dependent mitophagy involves\n on the structures, cytotoxicity and apoptosis mechanism of 8-hydroxylquinoline ubiquitination of mitofusins 1 and 2: Implications for Parkinson disease\n rhodium(III) complexes in T-24 cells, New J. Chem. 40 (2016) 6005\u20136014. pathogenesis, Autophagy 7 (2011) 243\u2013245;\n[38] Y.-L. Zhang, Q.-P. Qin, Q.-q. Cao, H.-H. Han, Z.-L. Liu, Y.-C. Liu, H. Liang, Z.- (b) Y. Guo, S. Jin, H. Yuan, T. Yang, K. Wang, Z. Guo, X. Wang, DNA-unresponsive\n F. Chen, Synthesis, crystal structure, cytotoxicity and action mechanism of a Rh(iii) platinum(II) complex induces ERS-mediated mitophagy in cancer cells, J. Med.\n complex with 8-hydroxy-2-methylquinoline as a ligand, Med. Chem. Comm 8 Chem. 65 (2022) 520\u2013530.\n (2017) 184\u2013190. [54] K. Palikaras, E. Lionaki, N. Tavernarakis, Mechanisms of mitophagy in cellular\n[39] K. Wang, C. Zhu, Y. He, Z. Zhang, W. Zhou, N. Muhammad, Y. Guo, X. Wang, homeostasis, physiology and pathology, Nat. Cell Biol. 20 (2018) 1013\u20131022.\n Z. Guo, Restraining cancer cells by dual metabolic inhibition with a [55] M. Yu, J. Yang, X. Gao, W. Sun, S. Liu, Y. Han, X. Lu, C. Jin, S. Wu, Y. Cai,\n mitochondrion-targeted platinum(II) complex, Angew. Chem. Int. Ed. 58 (2019) Lanthanum chloride impairs spatial learning and memory by inducing [Ca2+]m\n 4638\u20134643. overload, mitochondrial fission-fusion disorder and excessive mitophagy in\n[40] S.E. Weinberg, N.S. Chandel, Targeting mitochondria metabolism for cancer hippocampal nerve cells of rats, Metallomics 12 (2020) 592\u2013606.\n therapy, Nat. Chem. Biol. 11 (2015) 9\u201315. [56] Z.-F. Wang, X.-Q. Huang, R.-C. Wu, Y. Xiao, S.-H. Zhang, Antitumor studies\n[41] W. Zhou, X. Wang, M. Hu, C. Zhu, Z. Guo, A mitochondrion-targeting copper evaluation of triphenylphosphine ruthenium complexes with 5,7-dihalo-\n complex exhibits potent cytotoxicity against cisplatin-resistant tumor cells through substituted-8-quinolinoline targeting mitophagy pathways, J. Inorg. Biochem. 248\n multiple mechanisms of action, Chem. Sci. 5 (2014) 2761\u20132770. (2023) 112361.\n[42] Z. Zhu, Z. Wang, C. Zhang, Y. Wang, H. Zhang, Z. Gan, Z. Guo, X. Wang, [57] Z.-F. Wang, X.-F. Zhou, Q.-C. Wei, Q.-P. Qin, J.-X. Li, M.-X. Tan, S.-H. Zhang, Novel\n Mitochondrion-targeted platinum complexes suppressing lung cancer through bifluorescent Zn(II)-cryptolepine-cyclen complexes trigger apoptosis induced by\n multiple pathways involving energy metabolism, Chem. Sci. 10 (2019) 3089\u20133095. nuclear and mitochondrial DNA damage in cisplatin-resistant lung tumor cells, Eur.\n[43] S. Kuang, F. Wei, J. Karges, L. Ke, K. Xiong, X. Liao, G. Gasser, L. Ji, H. Chao, J. Med. Chem. 238 (2022) 114418.\n Photodecaging of a mitochondria-localized iridium(III) endoperoxide complex for [58] S.-H. Zhang, Z.-F. Wang, H. Tan, Novel zinc(II)-curcumin molecular probes bearing\n two-photon photoactivated therapy under hypoxia, J. Am. Chem. Soc. 144 (2022) berberine and jatrorrhizine derivatives as potential mitochondria-targeting anti-\n 4091\u20134101. neoplastic drugs, Eur. J. Med. Chem. 243 (2022) 114736.\n[44] T. Mosmann, Rapid colorimetric assay for cellular growth and survival: application [59] W. Lv, Z. Zhang, K.Y. Zhang, H. Yang, S. Liu, A. Xu, S. Guo, Q. Zhao, W. Huang,\n to proliferation and cytotoxicity assays, J. Immunol. Methods 65 (1983) 55\u201363. A mitochondria-targeted Photosensitizer showing improved photodynamic therapy\n[45] P. Li, D. Nijhawan, I. Budihardjo, S.M. Srinivasula, M. Ahmad, E.S. Alnemri, effects under hypoxia, Angew. Chem. Int. Ed. 55 (2016) 9947\u20139951.\n X. Wang, Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 [60] Z. Lv, L. Zou, H. Wei, S. Liu, W. Huang, Q. Zhao, Phosphorescent Starburst Pt(II)\n complex initiates an apoptotic protease cascade, Cell 91 (1997) 479\u2013489. Porphyrins as Bifunctional therapeutic agents for tumor hypoxia imaging and\n[46] S. Jin, Y. Hao, Z. Zhu, N. Muhammad, Z. Zhang, K. Wang, Y. Guo, Z. Guo, X. Wang, photodynamic therapy, ACS Appl. Mater. Interfaces 10 (2018) 19523\u201319533.\n Impact of mitochondrion-targeting group on the reactivity and cytostatic pathway [61] J. Qi, Y. Zheng, B. Li, L. Wei, J. Li, X. Xu, S. Zhao, X. Zheng, Y. Wang, Mechanism of\n of platinum(IV) complexes, Inorg. Chem. 57 (2018) 11135\u201311145. vitamin B6 benzoyl hydrazone platinum(II) complexes overcomes multidrug\n[47] Q.-Y. Liu, Y.-Y. Qi, D.-H. Cai, Y.-J. Liu, L. He, X.-Y. Le, Sparfloxacin- Cu(II)- resistance in lung cancer, Eur. J. Med. Chem. 237 (2022) 114415.\n aromatic heterocyclic complexes: synthesis, characterization and in vitro [62] (a) C.-J. Liang, R.-C. Wu, X.-Q. Huang, Q.-P. Qin, H. Liang, M.-X. Tan, Synthesis\n anticancer evaluation, Dalton Trans. 51 (2022) 9878\u20139887. and anticancer mechanisms of four novel platinum(II) 4\u2032-substituted-2,2\u2032:6\u2032,2\u2032\u2032-\n[48] W.-Y. Zhang, F. Du, M. He, L. Bai, Y.-Y. Gu, L.-L. Yang, Y.-J. Liu, Studies of terpyridine complexes, Dalton Trans. 53 (2024) 2143\u20132152;\n anticancer activity in vitro and in vivo of iridium(III) polypyridyl complexes- (b) L.-Q. Du, C.-J. Zeng, D.-Y. Mo, Q.-P. Qin, M.-X. Tan, H. Liang, 8-\n loaded liposomes as drug delivery system, Eur. J. Med. Chem. 178 (2019) 390\u2013400. hydroxyquinoline-N-oxide copper(II)- and zinc(II)-phenanthroline and bipyridine\n[49] W.-Y. Zhang, Y.-J. Wang, F. Du, M. He, Y.-Y. Gu, L. Bai, L.-L. Yang, Y.-J. Liu, coordination compounds: Design, synthesis, structures, and antitumor evaluation,\n Evaluation of anticancer effect in vitro and in vivo of iridium(III) complexes on J. Inorg. Biochem. 251 (2024) 112443;\n gastric carcinoma SGC-7901 cells, Eur. J. Med. Chem. 178 (2019) 401\u2013416. (c) Z.-F. Chen, Q.-P. Qin, J.-L. Qin, Y.-C. Liu, K.-B. Huang, Y.-L. Li, T. Meng, G.-\n[50] Y. Guo, S. Jin, D. Song, T. Yang, J. Hu, X. Hu, Q. Han, J. Zhao, Z. Guo, X. Wang, H. Zhang, Y. Peng, X.-J. Luo, H. Liang, Stabilization of G-Quadruplex DNA,\n Amlexanox-modified platinum(IV) complex triggers apoptotic and autophagic Inhibition of telomerase activity, and tumor cell apoptosis by organoplatinum(II)\n bimodal death of cancer cells, Eur. J. Med. Chem. 242 (2022) 114691. complexes with oxoisoaporphine, J. Med. Chem. 58 (2015) 2159\u20132179;\n[51] Y. Huang, X. You, L. Wang, G. Zhang, S. Gui, Y. Jin, R. Zhao, D. Zhang, Pyridinium- (d) Q.-P. Qin, Z.-Z. Wei, Z.-F. Wang, X.-L. Huang, M.-X. Tan, H.-H. Zou, H. Liang,\n substituted tetraphenylethylenes functionalized with alkyl chains as autophagy Imaging and therapeutic applications of Zn(II)-cryptolepine\u2013curcumin molecular\n modulators for cancer therapy, Angew. Chem. Int. Ed. 59 (2020) 10042\u201310051. probes in cell apoptosis detection and photodynamic therapy, Chem. Commun. 56\n[52] M.-M. Wang, F.-J. Xu, Y. Su, Y. Geng, X.-T. Qian, X.-L. Xue, Y.-Q. Kong, Z.-H. Yu, (2020) 3999\u20134002.\n H.-K. Liu, Z. Su, A new strategy to fight metallodrug resistance: mitochondria-\n\n\n\n\n 9\n\f", "pages_extracted": 9, "text_length": 69845}