New rhodium(III)-triphenylphosphine complexes with 5-halogenate-8-hydroxyquinoline as ligands: synthesis, characterization, cytotoxicity, and mechanism of action.

{"full_text": " Bioorganic Chemistry 163 (2025) 108789\n\n\n Contents lists available at ScienceDirect\n\n\n Bioorganic Chemistry\n journal homepage: www.elsevier.com/locate/bioorg\n\n\n\n\nNew rhodium(III)-triphenylphosphine complexes with 5-halogenate-8-hy\u00ad\ndroxyquinoline as ligands: synthesis, characterization, cytotoxicity, and\nmechanism of action\nZhen-Feng Wang a,b, Xiao-Qiong Huang c , Run-Chun Wu c , Shu-Hua Zhang a,b,* ,\nGuangzhao Li a,**\na\n College of Chemistry, Guangdong University of Petrochemical Technology, Maoming, Guangdong, PR China\nb\n Guangxi Key Laboratory of Electrochemical and Magnetochemical Functional Materials, Guilin University of Technology, Guilin, PR China\nc\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\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 incorporation of triphenylphosphine (PPh3) can enhance the antiproliferative activity of complexes. Herein,\nRhodium(III) complexes four Rh(III) complexes GUPT1-GUPT4 were synthesized. GUPT4 exhibited stronger anticancer activity than\n5-halogenate-8-hydroxyquinoline HGU, cisplatin, and GUPT1\u2013GUPT3 against human non-small cell lung A549 and its cisplatin-resistant A549 cell\nTriphenylphosphine\n line (CR-A549), with IC50 values of 6.73 \u00b1 0.41 and 5.11 \u00b1 0.16 \u03bcM, respectively. The antiproliferative activity\nMitophagy\nApoptosis\n of the four RhIII complexes increased with different 5-substituted ligands in the following order: \u2013H (GUPT1) <\n \u2013Br (GUPT2) < \u2013Cl (GUPT3) < \u2013F (GUPT4). GUPT3 and GUPT4 induce CR-A549 mitochondrial autophagy\n and ATP blockade, leading to apoptosis. In addition, the inhibition rate of GUPT4 on A549 was 39.1 %, showing\n potential antitumor efficacy. Thus, GUPT3 and GUPT4 can be considered as promising non-Pt drug candidates\n for lung cancer treatment.\n\n\n\n\n1. Introduction ligand [11], triazolopyrimidines [12], pyrazolopyrimidine derivatives\n [13], and sulfonated iminopyridine ligands [14] have been explored for\n Platinum-based drugs, such as cisplatin and its clinically successful their anticancer and anti-inflammatory activities. However, the anti\u00ad\nderivatives, have been widely used to treat various types of cancers, with proliferative mechanisms of rhodium(III) derivatives remain poorly\ntheir success driving the development of new Pt(II/IV) and non-Pt(II/IV) understood, limiting their application in clinical chemotherapy.\nchemotherapeutics that can overcome drug resistance with minimal side A series of 8-hydroxyquinoline (HGU) metal derivatives have been\neffects [1\u20134]. Meanwhile, Rhodium complexes are a class of metal developed as antiproliferative agents and extensively studied by several\ncompounds with unique and diverse biological activities, especially in research groups [15\u201325]. In particular, rhodium(III) complexes [26]\nthe field of anti-cancer (including overcoming drug resistance and light featuring various ligands, such as 8-hydroxyquinoline or 5-bromo-8-\nactivation strategies) show great potential. Its light response charac\u00ad hydroxyquinoline [27], 8-hydroxyquinoline-5-sulfonate or 7-(1-piper\u00ad\nteristics (photodynamic therapy and photoactivated chemotherapy) are idinylmethyl)-8-hydroxyquinoline [28], (S)-5-chloro-7-((proline-1-yl)\nthe most concerned and characteristic research directions[5\u201314]. In line methyl)8-hydroxyquinoline derivatives [29], and 8-hydroxy-2-methyl\u00ad\nwith this, various rhodium(II/III) complexes with different organic li\u00ad quinoline [30], have demonstrated remarkable anticancer activity.\ngands such as thiabendazole\u2212 /benzimidazole-based derivatives [5a], Highlights PPh3 is a ligand with strong \u03c3-donating, moderate\nbenzo[i]dipyrido[3,2-a,2\u2032,3\u2032-c]phenazine [6], 1,3-dimethylbenzimida\u00ad \u03c0-accepting and large steric hindrance. Its bonding to metals involves\nzolium iodide or 1,3-dibenzylbenzimidazolium bromide [7], N-(3- the synergy of \u03c3-giving and feedback \u03c0-bonding. Strong \u03c3-giving affects\nhalogen-phenyl)picolinamide ligands [8], 2-phenylpyridinate de\u00ad the electron density of the metal, which in turn affects its redox, reac\u00ad\nrivatives [9], 1,2,4-triazole [10], 2-pyridinecarbothioamide (PCA) tivity, and ligand exchange rate.[31\u201335] at the same time, \u03c0-acceptance\n\n\n * Corresponding author at: College of Chemistry, Guangdong University of Petrochemical Technology, Maoming, Guangdong, PR China.\n ** Corresponding author.\n E-mail addresses: zhangshuhua@gdupt.edu.cn (S.-H. Zhang), gzli666@gdupt.edu.cn (G. Li).\n\nhttps://doi.org/10.1016/j.bioorg.2025.108789\nReceived 22 May 2025; Received in revised form 17 July 2025; Accepted 21 July 2025\nAvailable online 25 July 2025\n0045-2068/\u00a9 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.\n\fZ.-F. Wang et al. Bioorganic Chemistry 163 (2025) 108789\n\n\nhelps stabilize metal centers in low oxidation states. On the other hand,\nhuge steric hindrance is its most prominent feature, which protects the\nmetal center (improves kinetic inertness), controls coordination geom\u00ad\netry and ligand dissociation, and profoundly affects the binding mode\nand efficiency of complexes with biological targets (such as DNA).\n[31\u201335] meanwhile, hydrophobic phenyl groups significantly increase\nlipid solubility and promote cellular uptake. Therefore, when designing\nmetal complexes with specific biological activities, choosing PPh3 or\nmodifying their structure (such as introducing different substituents to\nchange electronic effects and steric hindrance) is a key strategy for\nregulating the physical and chemical properties of drugs (solubility,\nstability), pharmacokinetics (absorption, distribution) and pharmaco\u00ad\ndynamics (target binding, reactivity).[31\u201335] the balance between its\nelectronic and spatial properties is critical to the final biological activity.\nAdditionally, the antiproliferative activity of several metal complexes\nincreased with the introduction of triphenylphosphine (\u2013PPh3) and\nhalogen (\u2013X) co-ligands [15e,36\u201338]; however, their water solubility\nwas not significantly improved [15e,36\u201338]. In this context, the high\nantiproliferative activity of GUPT1\u2013GUPT4, which combine\nHGU1\u2013HGU4 with PPh3, has yet to be reported and remains largely\nunexplored [20e,36\u201338]\n Thus, we designed and synthesized four rhodium(III)-\ntriphenylphosphine complexes GUPT1\u2013GUPT4 with high anticancer\nactivity. These compounds, namely [Rh(GU1)(PPh3)2Cl2] (GUPT1), [Rh\n Fig. 1. Crystal structures of GUPT1 and GUPT2 with the H atoms were omitted\n(GU2)(PPh3)2Cl2] (GUPT2), [Rh(GU3)2(PPh3)Cl] (GUPT3), and [Rh\n for clarity. Displacement ellipsoids are drawn at the 30 % probability level.\n(GU4)2(PPh3)Cl] (GUPT4), (HGU = 5-R-8-hydroxyquinoline, R = H,\nHGU1; R = Br, HGU2; R = Cl, HUG3, R = F, HGU4), were derived from\n8-hydroxyquinoline derivates (HGU1\u2013HGU4) and tris(triphenylphos\u00ad\nphine)rhodium(I) chloride ((PPh3)3RhCl). In addition, the cytotoxicity\nand antitumor mechanisms of GUPT1\u2013GUPT4 against A549 and CR-\nA549 tumor cells were evaluated.\n\n2. Results and discussion\n\n2.1. Synthesis and characterization\n\n The reactions of the precursor ((PPh3)3RhCl, CAS number:\n14694\u201395-2) with the HGU1\u2013HGU4 ligands in a mixture of methanol,\ndichloromethane, and triethylamine at 65 \u25e6 C for 1.0 day and subse\u00ad\nquently at 80 \u25e6 C for 3.0 days in a 15-mL high-temperature resistant tube\nafforded the target compounds GUPT1\u2013GUPT4 in isolated yields of\n40.8\u201360.5 % (Scheme 1). In addition, GUPT1\u2013GUPT4 were character\u00ad\nized by electrospray ionization mass spectrometry (Figs. S1 and S2), 1H\nNMR (Figs. S3\u2013S5), elemental analysis, and X-ray diffraction analysis Fig. 2. Crystal structure of GUPT3 with the H atoms were omitted for clarity.\n(Figs. 1,2 Fig. S6 and Tables 1\u20132). The structures of GUPT1-GUPT4 are Displacement ellipsoids are drawn at the 30 % probability level.\nstriking similar except that they have different amounts of GU, PPh3\n\n\n\n\n Scheme 1. Synthesis of GUPT1\u2013GUPT4.\n\n 2\n\fZ.-F. Wang et al. Bioorganic Chemistry 163 (2025) 108789\n\n\nTable 1\nCrystallographic data for GUPT1\u2013GUPT4.\n Complexes GUPT1 GUPT2 GUPT3 GUPT4\n\n Formula C45H36Cl2NOP2Rh C45H35BrCl2NOP2Rh C36H25Cl3N2O2PRh C36H25ClF2N2O2PRh\n Mr 842.50 921.40 757.81 724.91\n Crystal size(mm) 0.39 \u00d7 0.21 \u00d7 0.12 0.22 \u00d7 0.21 \u00d7 0.18 0.26 \u00d7 0.25 \u00d7 0.19 0.23 \u00d7 0.20 \u00d7 0.18\n Crystal system Monoclinic Monoclinic Triclinic Monoclinic\n Space group P21/c C2/c P-1 P21/n\n a/\u00c5 15.471(1) 24.7490(4) 11.517(1) 12.345(1)\n b/\u00c5 20.319(1) 12.2019(2) 11.612(1) 15.913(8)\n c/\u00c5 24.651(1) 26.4634(3) 13.389(1) 16.713(1)\n \u03b1/\u25e6 90 90 76.915(1) 90\n \u03b2/\u25e6 101.800(2) 106.366(1) 66.095(1) 104.625(6)\n \u03b3/\u25e6 90 90 77.051(1) 90\n Volume/\u00c53 7585.0(6) 7667.7(2) 1576.69(10) 3176.6(3)\n Z 8 8 2 4\n F(000) 3440 3712 764 1464\n DC(g/cm3) 1.476 1.596 1.596 1.516\n \u03bc/mm\u2212 1 0.713 7.187 0.884 0.720\n 2\u03b8 range (\u25e6 ) 4.95\u2013121.79 6.96\u2013151.65 4.10\u201350.20 4.72\u201350.20\n Ref. Meas./indep. 101,842/17384 25,857/7357 35,688/5541 11,254/5645\n Obs.Ref.[I \u2265 2\u03c3 (I)] 14,890 6654 4902 4110\n Rint 0.0624 0.0436 0.0293 0.0552\n R1 [I \u2265 2\u03c3 (I)]a 0.0467 0.0316 0.0356 0.0521\n \u03c9R2 (all data)b 0.1180 0.0864 0.0818 0.1650\n Goof 1.002 1.006 1.000 1.138\n \u0394\u03c1(max, min) (e\u00c5\u2212 3) 1.027, \u2212 1.459 0.516,-0.653 1.558, \u2212 0.482 0.906,-1.064\n a\n R1 = \u03a3||Fo| \u2212 |Fc||/\u03a3|Fo|.\n b\n wR2 = [\u03a3w(|F2o| \u2212 |F2c |)2/\u03a3w(|F2o|)2]1/2.\n\n\n (Br1\u22efBr1a, 3.858(2) \u00c5, symmetry code: (a) 1 \u2212 x, 2 \u2212 y, 1 \u2212 z.) and\nTable 2 C\u2013H\u22efCl hydrogen bonds (C43\u2013H43\u22efCl1b, 3.520(2) \u00c5; symmetry\nSelected bond lengths (\u00c5) and angles (\u25e6 ) for GUPT1\u2013GUPT4.\n code: (b) 1 \u2212 x, y, 0.5 \u2212 z. Fig. S7). Furthermore, the CCDC deposition\n Complexes GUPT1 GUPT2 GUPT3 GUPT4 numbers for GUPT1\u2013GUPT4 are 2,325,993\u20132,325,996, respectively.\n Rh1\u2013O1 2.025(2) 2.038(2) 2.039(2) 2.030(4)\n Rh1\u2013N1 2.037(3) 2.057(2) 2.012(3) 2.084(4) 2.2. Cytotoxicity against cancer cells\n Rh1\u2013X2 2.3554(9) 2.3629(6) 2.022(2) 2.027(3)\n Rh1\u2013Cl1 2.3613(8) 2.3550(6) 2.3923(9) 2.355(1)\n Rh1\u2013P1 2.3942(9) 2.4022(7) 2.3071(9) 2.292(1)\n The cytotoxic activity of GUPT1\u2013GUPT4 was evaluated against non-\n Rh1\u2013Y2 2.3867(8) 2.3919(7) 2.019(3) 2.011(4) malignant Human Embryonic Kidney (HEK293), cancerous human non-\n O1\u2013Rh1\u2013N1 82.66(10) 81.61(7) 82.06(10) 81.19(17) small cell lung A549, and cisplatin-resistant CR-A549 human cell lines\n O1\u2013Rh1\u2013X2 87.71(7) 173.90(5) 176.18(10) 170.47(15) using CCK-8 assays [15e,41,42]. In CR-A549 cells, GUPT4 exhibited the\n N1\u2013Rh1\u2013X2 170.35(8) 92.40(6) 96.63(10) 92.35(16)\n highest antitumor potency (IC50 = 5.11 \u00b1 0.16 \u03bcM), significantly out\u00ad\n O1\u2013Rh1\u2013Cl1 175.96(7) 89.82(5) 89.12(7) 93.19(12)\n N1\u2013Rh1\u2013Cl1 93.30(8) 171.40(6) 89.14(8) 88.15(13) performing HGU1\u2013HGU4 ligands (>50 \u03bcM), (PPh3)3RhCl (>50 \u03bcM),\n X2\u2013Rh1\u2013Cl1 96.32(3) 96.18(2) 87.27(8) 93.60(11) cisplatin (>50 \u03bcM), GUPT1 (14.59 \u00b1 0.26 \u03bcM), GUPT2 (12.07 \u00b1 0.44\n O1\u2013Rh1\u2013Y2 89.06(7) 92.10(6) 98.98(10) 90.09(17) \u03bcM), and GUPT3 (8.74 \u00b1 1.02 \u03bcM) (Table 3). The antiproliferative ac\u00ad\n N1\u2013Rh1\u2013Y2 89.29(8) 92.40(6) 176.02(11) 90.21(17) tivities of the rhodium(III)\u2013triphenylphosphine complexes against A549\n X2\u2013Rh1\u2013Y2 89.80(3) 87.10(2) 82.08(10) 82.89(16)\n Cl1\u2013Rh1\u2013Y2 90.80(3) 87.28(2) 87.04(8) 176.06(13)\n cancer cells also followed the order: GUPT4 > GUPT3 > GUPT2 >\n O1\u2013Rh1\u2013P1 91.83(7) 91.29(6) 86.53(7) 95.39(12) GUPT1 > cisplatin \u2248 HGU1\u2013HGU4 ligands \u2248 (PPh3)3RhCl. GUPT4\n N1\u2013Rh1\u2013P1 89.73(8) 92.40(6) 91.65(8) 175.40(13) demonstrated greater potency than previously reported rhodium(III)\u20138-\n X2\u2013Rh1\u2013P1 91.34(3) 90.15(2) 97.11(8) 91.40(11) hydroxyquinoline derivatives [26\u201330] in CR-A549 cancer cells\n Cl1\u2013Rh1\u2013P1 88.24(3) 86.81(2) 175.42(4) 88.97(5)\n (Table 3). Interestingly, GUPT1\u2013GUPT4 showed promising selectivity\n Y2\u2013Rh1\u2013P1 178.58(3) 173.17(2) 92.25(8) 92.89(12)\n toward CR-A549 cells (Table 3), exhibiting a 3.4\u20139.8-fold lower cyto\u00ad\nGUPT1: X = Cl, Y = P, GUPT2:X = Cl, Y = P; GUPT3: X = O, Y = N, GUPT3: X = toxicity against HEK293 noncancerous cells than cisplatin. This suggests\nO, Y = N. that their antiproliferative effects may involve a cell death/apoptosis\n mechanism different from that of cisplatin. Among the rhodium(III)-8-\nligands, Cl ions or different directions of extension of the ligands in the\nspace. Therefore, only GUPT2 is analyzed here. Table 3\n Single-crystal X-ray diffraction analysis reveals that GUPT2 belongs Cytotoxicity (IC50, \u03bcM) of GUPT1\u2013GUPT4 in HEK293, A549, and CR-A549 cell\nto the monoclinic space group C2/c, and it consists of one RhIII atom, lines after 48 h treatment (CCK-8 assay).\ntwo PPh3 ligands, one GU2 ligand and two counter-anion Cl\u2212 ions. The\n CR-A549 A549 HEK293\nRh1 atom in GUPT2 is six-coordinated to P atom (P1, P2) in two PPh3\n HGU1\nligands (Rh1\u2013P1 = 2.3942(9) \u00c5; Rh1\u2013P2 = 2.3867(8) \u00c5), and to one N, >50 >50 >50\n GUPT1 14.59 \u00b1 0.26 25.09 \u00b1 0.94 >50\none O atom belonging to one GU2 ligand (Rh1\u2013O1, 2.025(2) \u00c5; HGU2 >50 >50 >50\nRh1\u2013N1, 2.037(3) \u00c5), and to two Cl ions (Rh1\u2013Cl1, 2.3613(8) \u00c5; GUPT2 12.07 \u00b1 0.44 19.35 \u00b1 0.88 >50\nRh1\u2013Cl2, 2.3554(9) \u00c5), in line with the results obtained for previously HGU3 >50 >50 >50\nreported rhodium compounds [26\u201330,39,40], resulting in a slightly GUPT3 8.74 \u00b1 1.02 10.36 \u00b1 0.11 >50\n HGU4\ndistorted octahedron geometry (Fig. 1, Table 2). The GUPT2 molecule\n >50 >50 >50\n GUPT4 5.11 \u00b1 0.16 6.73 \u00b1 0.41 >50\nexists intramolecular hydrogen bond (C29\u2013H29\u22efO1, 3.111(1) \u00c5) (PPh3)3RhCl >50 >50 >50\nwhich further formed 3D network through abundant Br\u22efBr interaction Cisplatin >50 12.07 \u00b1 0.77 16.11 \u00b1 0.89\n\n\n 3\n\fZ.-F. Wang et al. Bioorganic Chemistry 163 (2025) 108789\n\n\nhydroxyquinoline metal derivatives, GUPT4, containing\u2013PPh3 and \u2013F (Fig. 4), the green fluorescence intensity for GUPT4 (5.11 \u03bcM) and\nligands, was the most effective metal complex. Under the same condi\u00ad GUPT3 (8.74 \u03bcM) reached approximately 65.50 % and 37.33 %,\ntions, the cytotoxic activity of GUPT1\u2013GUPT4 in CR-A549 cells followed respectively, according to the FCM data. The results indicate that The\nthe order: GUPT4 > GUPT3 > GUPT2 > GUPT1 > HGU1\u2013HGU4 li\u00ad greater the electronegativity of the substituent on the ligand, the greater\ngands \u2248 (PPh3)3RhCl \u2248 cisplatin. Thus, GUPT4 and GUPT3 were chosen the loss of the membrane potential \u0394\u03c8mp of the cell caused by the metal\nas the model rhodium(III)-8-hydroxyquinoline derivatives to elucidate complex.\nthe antineoplastic mechanism. Comparing complexes GUPT1 and\nGUPT2, we found that the IC50 of the rhodium complex decreased in the 2.5. Analysis of reactive oxygen species (ROS) and [Ca2+] levels\npresence of an electron-withdrawing substituent on the 8-hydroxyqui\u00ad\nnoline ligand. Comparing complexes GUPT3 and GUPT4, we found The destruction of \u0394\u03c8mp could also influence [Ca2+] and intracel\u00ad\nthat a greater electronegativity of the substituent on the 8-hydroxyqui\u00ad lular ROS levels [46,47]. Thus, to evaluate the involvement of intra\u00ad\nnoline ligand correlated with a lower IC50 of the rhodium complex. cellular [Ca2+] and ROS in CR-A549 cells, their levels following\nThat is to say, the greater the electronegativity of the substituent on the treatment with GUPT4 (5.11 \u03bcM) and GUPT3 (8.74 \u03bcM) were measured\nligand, the better the anticancer activity of the metal complex. This using Fluo-3AM and DCFH-DA assays, respectively. As illustrated in\nprovides theoretical guidance for the synthesis of metal complexes with Figs. 5 and 6, compared with untreated cells, GUPT4 and GUPT3\ngood anticancer activity. significantly increased [Ca2+] and ROS levels by 65.16 % and 66.92 %\n (GUPT4) and 37.42 % and 39.57 % (GUPT3), respectively. These results\n2.3. Apoptosis suggest that the elevation of [Ca2+] and ROS levels contributed to the\n induction of apoptosis in CR-A549 cancer cells.\n To study the model of cell apoptosis induced by GUPT4 (5.11 \u03bcM)\nand GUPT3 (8.74 \u03bcM), we assessed their pro-apoptotic effects on CR- 2.6. Evaluation of cellular respiration, ATP, and mitochondrial\nA549 cells using flow cytometry (FCM) with Annexin V-APC and 7- dysfunction\nAAD staining [43]. As depicted in Fig. 3, the treatment of CR-A549\ncells with GUPT4 (5.11 \u03bcM) and GUPT3 (8.74 \u03bcM) resulted in Mitochondrial dysfunction, characterized by the loss of \u0394\u03c8mp,\napoptosis rates of 58.95 % and 37.60 %, respectively, indicating that modulation of apoptosis-inducing factors/proteins, and reductions in\nboth complexes induce apoptosis, with GUPT4 being more effective mitochondrial state I/IV respiration and ATP production [48\u201350], is\n(GUPT4 > GUPT3). The results also indicated that the greater the involved in apoptotic cell death. Western blot analysis was performed to\nelectronegativity of the ligand substituent, the greater the ability of the study the apoptosis-inducing factors/proteins in apoptosis induced by\ncomplex to induce apoptosis. To be emphasized, the proportion of early GUPT4 (5.11 \u03bcM) and GUPT3 (8.74 \u03bcM) treatment. The ratios of\nand late apoptotic cells in the GUPT4 treatment group was 52.93 % and cleaved-caspase-3/GAPDH, caspase-9/GAPDH, and cytochrome c/\n6.02 %, respectively, while 29.34 % in the early apoptotic and 8.26 % in GAPDH increased in CR-A549 cells after treatment with GUPT4 (5.11\nthe late apoptotic for GUPT3, indicating that GUPT4 and GUPT3 mainly \u03bcM) and GUPT3 (8.74 \u03bcM), indicating that the apoptosis-inducing fac\u00ad\ninduced cell death through early apoptosis. In addition, the proportion tors, cleaved-caspase-3, caspase-9, and cytochrome c, were released into\nof necrotic cells in the GUPT4 and GUPT3 groups was only 6.45 % and the cytosol (Fig. 7). Additionally, we further tested whether GUPT4\n2.34 %, respectively. The cell necrosis rate were very low, indicating (5.11 \u03bcM) and GUPT3 (8.74 \u03bcM) would inhibit state I/IV respiration and\nthat the type of cell death in the GUPT4 and GUPT3 groups was ATP production in CR-A549 cells using state I/IV respiration and ATP\napoptosis rather than necrosis. production kits [15e,48\u201350]. In GUPT4-and GUPT3-treated cells, a\n significant decrease in state I/IV respiration was observed (Tables 4 and\n2.4. Loss of the mitochondrial membrane potential (\u0394\u03c8 mp) S1\u2013S3), and ATP synthase activity was inhibited. According to the re\u00ad\n sults, both GUPT4 and GUPT3 can decrease state I/IV respiration and\n After stimulation, various coordination metal derivatives can ATP production by targeting mitochondrial dysfunction.\ndecrease \u0394\u03c8mp, an initiator of apoptosis [44,45]. To confirm this idea,\nthe loss of \u0394\u03c8mp induced by GUPT4 and GUPT3 was assessed by the 2.7. Mitophagy determination\nincrease in green-to-red fluorescence ratio. As rhodium(III)-8-\nhydroxyquinoline derivatives can penetrate CR-A549 cells within 48 h Mitophagy is a key mechanism for controlling mitochondrial damage\n\n\n\n\n Fig. 3. Cell apoptosis induced by GUPT4 (5.11 \u03bcM) and GUPT3 (8.74 \u03bcM) after 48 h treatment in CR-A549 cells.\n\n 4\n\fZ.-F. Wang et al. Bioorganic Chemistry 163 (2025) 108789\n\n\n\n\n Fig. 4. Loss of \u0394\u03c8mp in CR-A549 cells induced by GUPT4 (5.11 \u03bcM) and GUPT3 (8.74 \u03bcM) after 48 h incubation.\n\n\n\n\n Fig. 5. Analysis of [Ca2+] in CR-A549 cells upon treatment with GUPT4 (5.11 \u03bcM) and GUPT3 (8.74 \u03bcM) for 48 h.\n\n\n\n\n Fig. 6. Generation of ROS in CR-A549 cells were incubated with GUPT4 (5.11 \u03bcM) and GUPT3 (8.74 \u03bcM) for 48 h.\n\n\n[15e,51\u201353]. Because rhodium(III)-8-hydroxyquinoline metal de\u00ad (Fig. 7). After 48 h of treatment, most key mitophagy-related markers\nrivatives disrupt mitochondrial function, reduce state I/IV respiration, were upregulated in GUPT4-and GUPT3-treated CR-A549 cells, while\nand decrease ATP production, they may induce mitophagy, which can the levels of P62/GAPDH and FUNDC1/GAPDH were downregulated\nsubsequently trigger autophagy or cell apoptosis [15e,51\u201353]. To (Fig. 7), suggesting that mitochondrial mitophagy persisted for 48 h or\nanalyze the mitophagy process, the protein expressions of six known longer. The results confirmed that GUPT4 and GUPT3 induced\nmitophagy markers, LC3B II/LC3B I, Beclin-1, P62, FUNDC1, PINK1, apoptosis in CR-A549 cells by triggering mitophagy and mitochondrial\nand Parkin, were evaluated in CR-A549 cells after treatment with dysfunction, as well as by reducing state I/IV respiration and ATP\nGUPT4 (5.11 \u03bcM) and GUPT3 (8.74 \u03bcM) using Western blot analysis production.\n\n 5\n\fZ.-F. Wang et al. Bioorganic Chemistry 163 (2025) 108789\n\n\n\n\nFig. 7. Expression levels of mitophagy-and apoptosis-inducing factors/proteins in CR-A549 cells after GUPT4 (5.11 \u03bcM) and GUPT3 (8.74 \u03bcM) treatment for 48 h.\nGAPDH was used as the loading control for untreated (control) cells.\n\n\n 3. Conclusion\nTable 4\nCellular state I/IV respiration and ATP production in CR-A549 cells treated with\n Four 5-halogenate-8-hydroxyquinoline rhodium(III)-triphenylphosp\nGUPT4 (5.11 \u03bcM) and GUPT3 (8.74 \u03bcM) for 48 h, as determined using state I/IV\nrespiration and ATP production kits. hine complexes GUPT1\u2013GUPT4 have been presented. The anticancer\n activities of GUPT1\u2013GUPT4 against A549 and CR-A549 cells were\n Groups Complexes Values\n investigated. GUPT3 and GUPT4 showed better anticancer activity than\n Control 95.59 \u00b1 4.04 U/mg prot HGU1\u2013HGU4, cisplatin, GUPT1, and GUPT2. Our investigation\n State I respiration GUPT3 40.83 \u00b1 2.15 U/mg prot\n revealed that GUPT3 and GUPT4 induced oxidative stress (ROS) inside\n GUPT4 26.29 \u00b1 1.52 U/mg prot\n Control 83.69 \u00b1 4.03 U/mg prot mitochondria, leading to mitophagy-mediated apoptosis in CR-A549\n State IV respiration GUPT3 37.27 \u00b1 1.25 U/mg prot cells, with effectiveness in the following order: GUPT3 < GUPT4. This\n GUPT4 24.64 \u00b1 1.37 U/mg prot mechanism highlights their potential as promising chemotherapeutic\n Control 6.26 \u00b1 0.34 \u03bcM agents for apoptosis-resistant CR-A549 cell tumors. Moreover, the\n ATP GUPT3 2.68 \u00b1 0.14 \u03bcM\n increased electronegativity of the ligand substituent correlates with the\n GUPT4 1.52 \u00b1 0.13 \u03bcM\n stronger anticancer activity of the rhodium complexes. In addition,\n GUPT4 demonstrated significant anticancer activity (~39.1 % inhibi\u00ad\n tion) and safety in A549 tumor-bearing mice. These findings provide\n2.8. In vivo antiproliferative activity theoretical guidance for the synthesis of rhodium complexes with high\n anticancer activity.\n To evaluate the in vivo therapeutic efficacy of GUPT4 (5.0 mg/kg),\nan A549 tumor xenograft model was established, and the compound was 4. Experimental methods\nadministered intraperitoneally every 2 days for 21.0 days [48c,d].\nGUPT4 treatment resulted in significant tumor growth inhibition 4.1. Materials and instruments\n(~39.1 %) (Fig. 8), with no significant changes in body weight\n(Tables S4\u2013S6), suggesting that GUPT4 exhibits anticancer efficacy and 4.1.1. Materials\nsafety in A549 tumor-bearing mice. The HGU1\u2013HGU4 ligands and (Ph3P)3-RhCl were purchased from\n Energy Chemical and Aladdin. In addition, the Tris, gel loading buffer,\n\n\n\n\n 6\n\fZ.-F. Wang et al. Bioorganic Chemistry 163 (2025) 108789\n\n\n\n\n Fig. 8. Antiproliferative effect of GUPT4 (5.0 mg/kg) on mice bearing A549 xenografts.\n\n\nRNase A, Annexin V-APC, 7-AAD and propidium iodide (PI) were pur\u00ad 4.4. Synthesis of GUPT3\nchased from Sigma and BD. The antibody of cleaved-caspase-3, caspase-\n9, cytochrome c, LC3B II/LC3B I, Beclin-1, P62, FUNDC1, PINK1, Parkin, Replacing HGU1 (0.05 mmol, 7.3 mg) with HGU3 (0.10 mmol, 18.0\nP62, GAPDH and FUNDC1 were purchased from Abcam. The Kits of mg) with the procedure for GUPT1 gave rise to GUPT3. Yield: 40.8 %.\nROS, Ca2+ and JC-1 were purchased from Jiangsu Kaige Biotechnology Elemental analysis: calcd (%) for RhC36H25O2Cl3N2P: C 57.06, H 3.33, N\nCo., Ltd. The CR-A549, A549 and HEK293 cell lines were obtained from 3.70; found: C 57.07, H 3.35, N 3.73. ESI-MS (positive ion mode,\nthe Shanghai Institute for Biological Science (China). The ATP assay kit Fig. S2): m/z: 1126.56 [M-(Ph3P) + 3(H2O) + H]+.\n(United Kingdom, Abcam ab113849) and state I/IV respiration assay\nkits (Beijing Solarbio, China, BC0515 and BC0945) were obtained from 4.5. Synthesis of GUPT4\nAbcam and Beijing Solarbio Science & Technology Co., Ltd.\n Replacing HGU1 (0.05 mmol, 7.3 mg) with HGU4 (0.10 mmol, 16.3\n4.1.2. Instruments mg) with the procedure for GUPT1 gave rise to GUPT4. Yield: 56.7 %.\n Elemental analyses (C, H and N) were carried out on a PerkinElmer Elemental analysis: calcd (%) for RhC36H25O2ClF2N2P: C 59.65, H 3.48,\nseries II CHNS/O 2400 elemental analyzer. The 1H NMR spectra was N 3.86; found: C 59.66, H 3.50, N 3.85. 1H NMR (400 MHz, DMSO\u2011d6,\nrecorded on a Bruker AV-400 NMR spectrometer. ESI-MS spectra was Fig. S5): \u03b4 7.65\u20137.59 (m, 7H), 7.58\u20137.54 (m, 4H), 7.42\u20137.35 (m, 5H),\nperformed on Thermofisher Scientific Exactive LC-MS spectrometer 7.30\u20137.23 (m, 3H), 7.18 (m, 2H), 7.01\u20136.96 (m, 4H).\n(Thermal Elctronic, USA). Apoptosis assay, ROS, Ca2+ and JC-1 analysis\nwere recorded on Flow cytometer (BECKMAN COULTER CytoFLEX).\nThe absorbance of CCK-8 assay was determined by measuring the optical 4.6. Biological experiments\ndensity at 450 nm using a multifunctional enzyme marker (n = 5,\nSwitzerland, TECAN SPARK). The A549 and CR-A549 cells were cultured in six-well plates (SWP)\n at a density of 5.0 \u00d7 105 cells per well for 24 h. After incubation with\n GUPT4 (5.11 \u03bcM) and GUPT3 (8.74 \u03bcM) for 48 h, the CR-A549 cells\n4.2. Synthesis of GUPT1 were harvested from SWP, and Annexin V-APC (5.0 \u03bcL)/7-AAD (5.0 \u03bcL)\n double dyeing (for apoptosis test), Fluo-3AM (1.0 \u03bcM) fluorescence\n The ligand HGU1 (0.05 mmol, 7.3 mg) and (Ph3P)3RhCl (0.05 mmol, probe (for [Ca2+]), DCFH-DA (10.0 \u03bcM) fluorochrome (for ROS), and JC-\n46.3 mg) were dissolved in MeOH (0.6 mL), CH2Cl2 (0.1 mL) and trie\u00ad 1 (1.0 \u03bcL) staining (for \u0394\u03c8mp) were added to the CR-A549 cells and\nthylamine (0.1 mL), and then, the mixture in the HTRT (15.0 mL) was incubated for 30.0 min at 37.0 \u25e6 C. And then the fluorescence intensity\nsealed and placed in an oven at 65 \u25e6 C for 1.0 day and at 80 \u25e6 C for 3.0 for SWP sample was measured by FCM analysis. In addition, The release\ndays (Scheme 1). After 1.0 day, the reddish-brown lumpy crystals of of the state I/IV respiration and ATP in the GUPT4 (5.11 \u03bcM)-and\nGUPT1 were obtained. Yield: 60.5 %. Elemental analysis: calcd (%) for GUPT3 (8.74 \u03bcM)-treated cells were detected with state I/IV respiration\nRhC45H36OCl2NP2: C 64.15, H 4.31, N 1.66; found: C 64.16, H 4.35, N and ATP assay system bioluminescence detection kit.\n1.65. 1H NMR (400 MHz, DMSO\u2011d6, Fig. S3): \u03b4 7.66\u20137.59 (m, 8H), 7.55\n(m, 6H), 7.44\u20137.37 (m, 6H), 7.36\u20137.31 (m, 3H), 7.24 (m, 7H), 7.19\u20137.13 4.7. The other methods\n(m, 2H), 6.97 (m, 4H).\n The other methods of GUPT1\u2013GUPT4 were similar to those illus\u00ad\n trated in previous work [15e,48,54]. In addition, the detailed anti\u00ad\n4.3. Synthesis of GUPT2 proliferative activity of GUPT4 (5.0 mg/kg) in vivo as regards A549 cells\n can be found in the ESI.\n Replacing HGU1 (0.05 mmol, 7.3 mg) with HGU2 (0.05 mmol, 11.2\nmg) with the procedure for GUPT1 gave rise to GUPT2. Yield: 54.2 %. CRediT authorship contribution statement\nElemental analysis: calcd (%) for RhC45H35OBrCl2NP2: C 58.66, H 3.83,\nN 1.52; found: C 58.63, H 3.81, N 1.55. 1H NMR (400 MHz, DMSO\u2011d6, Zhen-Feng Wang: Methodology, Formal analysis, Data curation.\nFig. S4): \u03b4 7.65\u20137.59 (m, 8H), 7.58\u20137.52 (m, 6H), 7.42\u20137.38 (m, 5H), Xiao-Qiong Huang: Data curation. Run-Chun Wu: Formal analysis.\n7.36\u20137.32 (m, 3H), 7.30\u20137.23 (m, 6H), 7.20\u20137.14 (m, 3H), 6.99\u20136.94 Shu-Hua Zhang: Writing \u2013 review & editing, Writing \u2013 original draft,\n(dd, J = 8.5, 3.0 Hz, 4H). ESI-MS (positive ion mode, Fig. S1): m/z: Supervision, Project administration. Guangzhao Li: Writing \u2013 review &\n713.85 [M + 4(DMSO) + 3(H2O) + H]+. editing, Writing \u2013 original draft, Project administration.\n\n 7\n\fZ.-F. Wang et al. Bioorganic Chemistry 163 (2025) 108789\n\n\nDeclaration of competing interest [12] M. Fandzloch, A.W. Augustyniak, L. Dobrzan\u0301ska, T. J\u0119drzejewski, J. Sitkowski,\n M. Wypij, P. Golin\u0301ska, J. Inorg. Biochem. 210 (2020) 111072.\n [13] (a) S. Saha, R. Kushwaha, A. Mandal, N. Singh, S. Banerjee, Coord. Chem. Rev.\n We declare that have no financial and personal relationships with 525 (2025) 216306;\nother people or organizations that can inappropriately influence our (b) Y.-Q. Gu, M.-X. Ma, Q.-Y. Yang, K. Yang, H.-Q. Li, M.-Q. Hu, H. Liang, Z.-\nwork, there is no professional or other personal interest of any nature of F. Chen, Bioorg. Chem. 141 (2023) 106838.\n [14] L. Guo, X. Hu, Y. Yang, W. An, J. Gao, Q. Liu, Z. Liu, Bioorg. Chem. 116 (2021)\nkind in any product, service and/or company that could be constructed 105311.\nas influencing the position pressented in, or the review of, the manscript [15] (a) R. Gupta, V. Luxami, K. Paul, Bioorg. Chem. 108 (2021) 104633;\nentitled. (b) V. Oliveri, V. Lanza, D. Milardi, M. Viale, I. Maric, C. Sgarlata, G. Vecchio,\n Metallomics 9 (2017) 1439\u20131446;\n (c) T. Meng, Q.-P. Qin, Z.-L. Chen, H.-H. Zou, K. Wang, F.-P. Liang, Eur. J. Med.\nAcknowledgments Chem. 169 (2019) 103\u2013110;\n (d) V.F.S. Pape, N.V. May, G.T. Ga\u0301l, I. Szatma\u0301ri, F. Szeri, F. F\u00fclo\u0308p, G. Szaka\u0301cs, E\u0301.\n A. Enyedy, Dalton Trans. 47 (2018) 17032\u201317045;\n This work was supported by the National Natural Science Foundation (e) Z.-F. Wang, X.-Q. Huang, R.-C. Wu, Y. Xiao, S.-H. Zhang, J. Inorg. Biochem.\nof China (No. 21861014), the Talent introduction program of Guang\u00ad 248 (2023) 112361.\n [16] (a) Q.-P. Qin, Z.-F. Wang, M.-X. Tan, X.-L. Huang, H.-H. Zou, B.-Q. Zou, B.-B. Shi,\ndong Institute of Petrochemical Technology (Nos. 2020RC033, S.-H. Zhang, Metallomics 11 (2019) 1005\u20131015;\n2020RC002, 2020RC035) and the China University Students Innovative (b) Y. Yang, Z. Zhou, Z.-Z. Wei, Q.-P. Qin, L. Yang, H. Liang, Dalton Trans. 50\nProject (Nos. 202410606027 and 202410606025). (2021) 5828\u20135834;\n (c) R. Wang, B.-Q. Zou, Q.-P. Qin, Z.-F. Wang, M.-X. 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