Quinoline- and coumarin-based ligands and their rhenium(I) tricarbonyl complexes: synthesis, spectral characterization and antiproliferative activity on T-cell lymphoma.

{"full_text": " Journal of Inorganic Biochemistry 262 (2025) 112770\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\nQuinoline- and coumarin-based ligands and their rhenium(I) tricarbonyl\ncomplexes: synthesis, spectral characterization and antiproliferative\nactivity on T-cell lymphoma\nMartina Pis\u030ckor a , Ivan C\u0301oric\u0301 b , Berislav Peric\u0301 c , Katarina Mis\u030ckovic\u0301 S\u030cpoljaric\u0301 b, Srec\u0301ko I. Kirin c ,\nLjubica Glavas\u030c-Obrovac b,*, Silvana Raic\u0301-Malic\u0301 a,*\na\n Department of Organic Chemistry, University of Zagreb, Faculty of Chemical Engineering and Technology, Marulic\u0301ev trg 19, 10000 Zagreb, Croatia\nb\n Department of Medicinal Chemistry, Josip Juraj Strossmayer University of Osijek, Faculty of Medicine, Biochemistry and Clinical Chemistry, J. Huttlera 4, 31000\nOsijek, Croatia\nc\n Laboratory for Solid State and Complex Compounds Chemistry, Ru\u0111er Bos\u030ckovic\u0301 Institute, Division of Materials Chemistry, Bijenic\u030cka cesta 54, 10 000 Zagreb, Croatia\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: Novel 6-substituted 2-(trifluoromethyl)quinoline 5a\u20135e and coumarin 6a\u20136d ligands with aldoxime ether linked\nQuinolines pyridine moiety were synthesized by O-alkylation of quinoline and coumarin with (E)-picolinaldehyde oxime and\nCoumarins subsequently with [Re(CO)5Cl] gave rhenium(I) tricarbonyl complexes 5aRe\u20135eRe and 6aRe\u20136dRe that were fully\nRhenium(I) complexes\n characterized by NMR, single-crystal X-ray diffraction, IR and UV\u2013Vis spectroscopy. The results of anti\u00ad\nAntiproliferative activity\nROS\n proliferative evaluation of quinoline and coumarin ligands and their rhenium(I) tricarbonyl complexes on\nMitochondrial membrane potential various human tumor cell lines, including acute lymphoblastic leukemia (CCRF-CEM), acute monocytic leukemia\n (THP1), cervical adenocarcinoma (HeLa), colon adenocarcinoma (CaCo-2), T-cell lymphoma (HuT78), and non-\n tumor human fibroblasts (BJ) showed that the quinoline complexes 5aRe\u20135eRe had higher inhibitory activity\n than coumarin complexes 6aRe\u20136dRe, particularly against T-cell lymphoma (HuT78) cells. 6-Methoxy-2-(trifluor\u00ad\n omethyl)quinoline 5e and 6-methylcoumarin 6d, and their rhenium(I) tricarbonyl complexes 5eRe and 6dRe\n were found to arrest the cell cycle of HuT78 cells by causing a significant accumulation of cells in the G0/G1\n phase and a marked decrease in the number of cells in the G2/M phase. These rhenium(I) tricarbonyl complexes\n also slightly increased ROS production and significantly decreased the mitochondrial membrane potential by 50\n % (5eRe) and 45 % (6dRe) compared to untreated cells and cells treated with 5e and 6d. These results suggest\n that the cytotoxic effects of these compounds are mediated by their effects on mitochondrial membrane potential\n and the subsequent increase in ROS production.\n\n\n\n\n1. Introduction multidrug resistance and significant side effects are the main contribu\u00ad\n tors to cancer-related mortality, causing the urgent need for new drugs\n Cancer is a major public health problem worldwide and the second with improved anticancer efficacy and reduced adverse effects [4,5].\nleading cause of death with 20 million new cancer cases and 9.7 million Quinoline and cumarin derivatives have been found in many biologi\u00ad\ndeaths in 2022 [1]. According to the World Health Organization (WHO), cally active natural and synthetic compounds, which particularly exhibit\nabout 1 in 5 people will develop cancer in their lifetime and about 1 in 9 anticancer activity [6\u20139]. These heterocycles have been also used in\nmen and 1 in 12 women will die from the disease [2]. The incidence of combination with other pharmacophores by the molecular hybridization\nlymphoma, which is the most common lymphoid malignancy, has strategy that can lead to new candidates with greater safety profiles and\ngradually increased over previous decades, and it ranks among the ten improved anti-cancer activity against drug-sensitive and drug-resistant\nmost prevalent cancers worldwide. No effective chemotherapy for adult cancers [10]. Quinolines have been recently examined for their modes\nT-cell leukemia-lymphoma has yet been established, and the prognosis of action as inhibitors of tyrosine kinases, topoisomerase, proteasome,\nfor patients with this disease is very poor [3]. The development of tubulin polymerization, and DNA repair [11,12]. Some quinoline-\n\n\n\n * Corresponding authors.\n E-mail addresses: lgobrovac@mefos.hr (L. Glavas\u030c-Obrovac), sraic@fkit.unizg.hr (S. Raic\u0301-Malic\u0301).\n\nhttps://doi.org/10.1016/j.jinorgbio.2024.112770\nReceived 18 July 2024; Received in revised form 23 October 2024; Accepted 28 October 2024\nAvailable online 29 October 2024\n0162-0134/\u00a9 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.\n\fM. Pis\u030ckor et al. Journal of Inorganic Biochemistry 262 (2025) 112770\n\n\nbearing compounds have been used as drugs for various cancer treat\u00ad chromen-2-one 4d) were purchased from Aldrich (St. Louis, MO) and\nments (Fig. 1). Acros (Geel, Belgium). Melting points were determined on a Kofler\n Over the past two decades, the anticancer potential of coumarin micro hot-stage (Wien, Austria) and were reported uncorrected. TLC on\nderivatives, their mechanism of action and SAR studies were investi\u00ad silica gel 60F-254 plates (Darmstadt, Germany) was used for purity\ngated [10,13\u201320]. On the other hand, organometallic compounds offer control and reaction monitoring, and the spots were detected under UV\nnew opportunities in the design of novel anticancer drug candidates due light (254 nm). The IR spectra of all compounds were recorded with a\nto their unique electronic and stereochemical properties and ability to PerkinElmer Spectrum ONE FT-IR equipped with a Universal UATR\ninteract with biomolecules [21\u201324]. Among the various transition metal Sampling Accessory covering the range 3500\u2013500 cm\u2212 1, while the UV/\ncomplexes used in biological applications, quinoline-based complexes Vis spectra were measured in acetonitrile (HPLC grade) with a Varian\nhave emerged as a promising compounds with significant anticancer Cary 50 spectrophotometer at 25 \u25e6 C. Proton (1H NMR) and carbon (13C\nactivitiy [25\u201338]. These quinoline metal complexes showed different NMR) magnetic resonance spectra were recorded using a Bruker (Bruker\nmode of action including proteasome-independent NF\u03baB signaling Biospin, Rheinstetten, Germany) 300 and 600 MHz NMR spectrometer\npathway [39], binding to DNA via intercalation mode [40\u201342], or and a Varian INOVA 400 instrument (Palo Alto, SAD) using tetrame\u00ad\ninducing apoptosis in cancer cells via mitochondrial dysfunction thylsilane (TMS) as the internal standard in DMSO\u2011d6 at 298 K. Chemical\n[43\u201346]. Additionally, coumarin\u2011palladium(II) complex exhibited shifts were referenced to the residual solvent signal of DMSO\u2011d6 at \u03b4\nremarkable reduction in pancreatic carcinoma cells (PANC-1) growth 2.50 ppm for 1H and \u03b4 39.50 ppm for 13C. Elemental composition ana\u00ad\nboth in vitro and in vivo [47]. Bi-functional platinum(IV) complex with 7- lyses of all new compounds were within 0.5 % of the calculated values.\nhydroxycoumarin ligands reduced tumor-associated inflammation by The quinoline precursors, 2-(trifluoromethyl)quinolin-4-ol 3a, 6-\ninhibiting cyclooxygenase (COX) [48,49]. Ruthenium(III), copper(II) chloro-2-(trifluoromethyl)quinolin-4-ol 3b, 6-bromo-2-(trifluoro\u00ad\nand cobalt(II) complexes of coumarins, exhibited cytotoxic effect against methyl)quinolin-4-ol 3c, 6-methyl-2-(trifluoromethyl)quinolin-4-ol 3d\ncervical cancer cells (HeLa) that may be result of groove binding inter\u00ad and 6-methoxy-2-(trifluoromethyl)quinolin-4-ol 3e are known com\u00ad\naction with DNA [50,51] or generation of reactive oxygen species (ROS) pounds which were synthesized according to the method shown in\n[52]. In particular, Re-based complexes have recently drawn interest, Scheme S1 (Supplementary Material) [64,66,67].\nmainly due to their ability to modulate the redox status of cancer cells\n[53\u201357], thus offering different mechanisms of action such as photo\u00ad 2.2. Synthesis of the (E)-picolinaldehyde-O-(2-bromoethyl)oxime (2)\nactivity, redox activity, ligand exchange and catalytic activity.\n Motivated by the diverse bioactivity of coumarins and quinolones in syn-Pyridine-2-aldoxime (5.0 g, 0.041 mol) was dissolved in 100 mL\nour previous research [58\u201365], we present here the synthesis and anti\u00ad DMF, and NaH (1.5 eq, 2.5 g, 0.062 mol, 60 % suspension in mineral oil)\nproliferative activity of novel quinoline 5a\u20135e and coumarin 6a\u20136d was added in small portions at 0 \u25e6 C. After 60 min, 1,2-dibromoethane\nderivatives with aldoxime ether linked pyridine moiety and their Re (1.2 eq, 9.2 g, 0.049 mol) was added and the mixture was stirred\n[(CO)3]+ complexes 5aRe\u20135eRe and 6aRe\u20136dRe (Fig. 2). overnight in the dark. The solvent was removed under reduced pressure\n and the residue was purified by column chromatography on silica gel\n2. Experimental Part (CH2Cl2:CH3OH = 50:1) to give a yellow oil (5.3 g, 56.4 %). 1H NMR\n (300 MHz, DMSO) \u03b4 8.62 (d, J = 4.7 Hz, 1H, H-6\u2032), 8.24 (s, 1H, CH-N),\n2.1. Materials and methods 7.87\u20137.82 (m, 2H, H-3\u2032, H-4\u2032), 7.44 (ddd, J = 6.7, 4.9, 1.5 Hz, 1H, H-5\u2032),\n 4.46 (t, J = 5.7 Hz, 2H, CH2), 3.76 (t, J = 5.7 Hz, 2H, CH2); 13C NMR (75\n All solvents and chemicals (syn-pyridine-2-aldoxime 1, 4-hydroxy- MHz, DMSO) \u03b4 150.64, 150.14, 149.67, 136.98, 124.67, 120.80, 73.61,\n2H-chromen-2-one 4a, 6-chloro-4-hydroxy-2H-chromen-2-one 4b, 6- 31.26.\nbromo-4-hydroxy-2H-chromen-2-one 4c, 4-hydroxy-6-methyl-2H-\n\n\n\n\n Fig. 1. The quinolone-based compounds in clinical treatment as anticancer drugs.\n\n 2\n\fM. Pis\u030ckor et al. Journal of Inorganic Biochemistry 262 (2025) 112770\n\n\n\n\nFig. 2. Rational behind the design of novel quinoline 5a\u20135e and coumarin-based 6a\u20136d ligands and rhenium(I) tricarbonyl complexes 5aRe\u20135eRe and 6aRe\u20136dRe.\n\n\n2.3. General procedure for synthesis of ligands 5a\u20135e and 6a\u20136d Hz, 1H, H-7), 7.81 (dt, J = 15.2, 4.5 Hz, 2H, H-3\u2032, H-4\u2032), 7.54 (s, 1H, H-3),\n 7.45\u20137.39 (m, 1H, H-5\u2032), 4.74 (d, J = 4.7 Hz, 2H, CH2), 4.70 (d, J = 4.7\n The corresponding quinoline (3a\u20133e) or coumarin derivative Hz, 2H, CH2); 13C NMR (151 MHz, DMSO) \u03b4 162.02, 150.71, 149.90,\n(4a\u20134d) and K2CO3 (1.5 eq) were dissolved in DMF and the mixture was 149.65, 148.38 (q, J = 33.9 Hz), 145.83, 136.89, 132.76, 131.97,\nstirred for 1 h. After this period, (E)-picolinaldehyde O-(2-bromoethyl) 131.37, 124.56, 121.96, 121.32 (q, J = 275.7 Hz), 120.71, 120.54,\noxime 2 (1.2 eq) was added, and the reaction mixture was stirred 98.81, 72.13, 68.59; IR (ATR) /cm\u2212 1: 3079, 2981, 2885, 2027, 1918,\novernight at 80 \u25e6 C. After completion, the reaction mixture was dissolved 1717, 1588, 1459, 1392, 1356, 1274, 1177, 1131, 1086, 977, 851, 781,\nin CH2Cl2 (20 mL) and washed with distilled water (3 \u00d7 20 mL). The 728; Calc. for C18H13ClF3N3O2 (Mr = 395.8) C, 54.63; H, 3.31; Cl, 8.96;\norganic layer was dried over anhydrous MgSO4, and the solvent was F, 14.40; N, 10.62; found: C, 54.69; H, 3.38; Cl, 8.92; F, 14.46; N, 10.63\nremoved under vacuum. The residue was isolated by column chroma\u00ad %.\ntography or recrystallized from CH3OH to afford the pure O-alkylated\nproducts 5a\u20135e and 6a\u20136d. 2.3.3. Synthesis of (E)-picolinaldehyde O-(2-((6-bromo-2-\n (trifluoromethyl)quinolin-4-yl)oxy)ethyl) oxime (5c)\n2.3.1. Synthesis of (E)-picolinaldehyde O-(2-((2-(trifluoromethyl) Compound 5c was prepared according to the general procedure from\nquinolin-4-yl)oxy)ethyl) oxime (5a) 6-bromo-2-(trifluoromethyl)quinolin-4-ol 3c (200.0 mg, 0.685 mmol),\n Compound 5a was prepared according to the general procedure from K2CO3 (142.0 mg, 1.028 mmol) and (E)-picolinaldehyde O-(2-bro\u00ad\n2-(trifluoromethyl)quinolin-4-ol 3a (100.0 mg, 0.469 mmol), K2CO3 moethyl) oxime 2 (188.3 mg, 0.822 mmol). Compound 5c was isolated\n(97.3 mg, 0.704 mmol) and (E)-picolinaldehyde O-(2-bromoethyl) as a white powder (185.1 mg, 61.4 %, m.p. = 153\u2013155 \u25e6 C). 1H NMR\noxime 2 (128.9 mg, 0.563 mmol). Compound 5a was isolated as a white (300 MHz, DMSO) \u03b4 8.60 (d, J = 4.5 Hz, 1H, H-6\u2032), 8.37 (d, J = 1.4 Hz,\npowder (102.2 mg, 60.3 %, m.p. = 91\u201393 \u25e6 C). 1H NMR (300 MHz, 1H, H-5), 8.23 (s, 1H, CH-N), 8.02 (dd, J = 7.7, 5.4 Hz, 2H, H-7, H-8),\nDMSO) \u03b4 8.60 (d, J = 4.6 Hz, 1H, H-6\u2032), 8.30\u20138.20 (m, 2H, CH-N, H-5), 7.93\u20137.75 (m, 2H, H-4\u2032, H-3\u2032), 7.55 (s, 1H, H-3), 7.47\u20137.38 (m, 1H, H-5\u2032),\n8.08 (d, J = 8.4 Hz, 1H, H-8), 7.91\u20137.77 (m, 3H, H-7, H-6, H-4\u2032), 7.68 (t, 4.75 (d, J = 4.7 Hz, 2H, CH2), 4.70 (d, J = 4.7 Hz, 2H, CH2); 13C NMR\nJ = 7.5 Hz, 1H, H-3\u2032), 7.47 (s, 1H, H-3), 7.45\u20137.38 (m, 1H, H-5\u2032), 4.73 (d, (75 MHz, DMSO) \u03b4 161.89, 150.70, 149.92, 149.66, 148.37 (q, J = 33.8\nJ = 4.6 Hz, 2H, CH2), 4.69 (d, J = 4.5 Hz, 2H, CH2); 13C NMR (75 MHz, Hz), 146.00, 136.92, 134.53, 131.37, 124.57, 123.96, 122.37, 120.89\nDMSO) \u03b4 162.72, 150.73, 149.91, 149.63, 148.57, 147.90 (q, J = 33.6 (q, J = 275.7 Hz), 120.53, 120.35, 98.80, 72.13, 68.61; IR (ATR) /cm\u2212 1:\nHz), 136.86, 131.38, 129.06, 127.97, 124.56, 121.81, 121.47 (q, J = 3035, 2962, 2026, 1926, 1720, 1588, 1457, 1391, 1355, 1272, 1176,\n275.7 Hz), 121.10, 120.61, 97.79, 72.25, 68.08; IR (ATR) /cm\u2212 1: 3073, 1087, 979, 941, 937, 830, 782, 757, 620; Calc. for C18H13BrF3N3O2 (Mr\n2946, 2988, 2030, 1592, 1575, 1512, 1470, 1387, 1352, 1279, 1254, = 440.2) C, 49.11; H, 2.98; Br, 18.15; F, 12.95; N, 9.55; found: C, 49.07;\n1181, 1089, 1086, 1041, 1181, 1086, 1041, 969, 944, 831, 775, 724, H, 2.83; Br, 18.19; F, 12.91; N, 9.61 %.\n620; Calc. for C18H14F3N3O2 (Mr = 361.3) C, 59.83; H, 3.91; F, 15.77; N,\n11.63; found: C, 59.89; H, 3.87; F, 15.70; N, 11.71 %. 2.3.4. Synthesis of (E)-picolinaldehyde O-(2-((6-methyl-2-\n (trifluoromethyl)quinolin-4-yl)oxy)ethyl) oxime (5d)\n2.3.2. Synthesis of (E)-picolinaldehyde O-(2-((6-chloro-2- Compound 5d was prepared according to the general procedure from\n(trifluoromethyl)quinolin-4-yl)oxy)ethyl) oxime (5b) 6-methyl-2-(trifluoromethyl)quinolin-4-ol 3d (150.0 mg, 0.660 mmol),\n Compound 5b was prepared according to the general procedure from K2CO3 (136.8 mg, 0.990 mmol) and (E)-picolinaldehyde O-(2-bro\u00ad\n6-chloro-2-(trifluoromethyl)quinolin-4-ol 3b (100.0 mg, 0.404 mmol), moethyl) oxime 2 (181.4 mg, 0.792 mmol). Compound 5d was isolated\nK2CO3 (83.7 mg, 0.606 mmol) and (E)-picolinaldehyde O-(2-bro\u00ad as a white powder (101.8 mg, 41.1 %, m.p. = 122\u2013123 \u25e6 C). 1H NMR\nmoethyl) oxime 2 (111.1 mg, 0.485 mmol). Compound 5b was isolated (300 MHz, DMSO) \u03b4 8.60 (d, J = 4.6 Hz, 1H, H-6\u2032), 8.23 (s, 1H, CH-N),\nas a white powder (130.7 mg, 81.6 %, m.p. = 91\u201393 \u25e6 C). 1H NMR (300 7.97 (d, J = 9.0 Hz, 2H, H-8/H-5), 7.88\u20137.77 (m, 2H, H-3\u2032, H-4\u2032), 7.70\nMHz, DMSO) \u03b4 8.59 (d, J = 4.5 Hz, 1H, H-6\u2032), 8.22 (s, 1H, CH-N), 8.19 (d, (dd, J = 8.6, 1.7 Hz, 1H, H-7), 7.46\u20137.40 (m, 2H, H-3, H-5\u2032), 4.70 (d, J =\nJ = 2.3 Hz, 1H, H-5), 8.10 (d, J = 9.0 Hz, 1H, H-8), 7.88 (dd, J = 9.0, 2.3 2.1 Hz, 4H, CH2), 2.46 (s, 3H, CH3); 13C NMR (151 MHz, DMSO) \u03b4\n\n 3\n\fM. Pis\u030ckor et al. Journal of Inorganic Biochemistry 262 (2025) 112770\n\n\n162.09, 150.76, 149.85, 149.65, 146.97 (q, J = 33.4 Hz), 145.93, bromoethyl) oxime 2 (228.2 mg, 0.996 mmol). Compound 6c was iso\u00ad\n137.93, 136.88, 133.44, 128.87, 124.57, 121.57 (q, J = 275.5 Hz), lated as white powder (155.0 mg, 48.0 %, m.p. = 188\u2013190 \u25e6 C). 1H NMR\n121.05, 120.62, 120.40, 97.75, 72.26, 68.08, 21.24; IR (ATR) /cm\u2212 1: (600 MHz, DMSO) \u03b4 8.61 (ddd, J = 4.8, 1.7, 1.0 Hz, 1H, H-6\u2032), 8.25 (s,\n3076, 2980, 1687, 1455, 1371, 1247, 1105, 981, 825; Calc. for 1H, CH-N), 7.89 (d, J = 2.4 Hz, 1H, H-5), 7.86 (td, J = 7.6, 1.5 Hz, 1H, H-\nC19H16F3N3O2 (Mr = 375.4) C, 60.80; H, 4.30; F, 15.18; N, 11.20; found: 4\u2032), 7.82\u20137.78 (m, 2H, H-3\u2032, H-7), 7.42 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H, H-\nC, 60.78; H, 4.37; F, 15.24; N, 11.24 %. 5\u2032), 7.39 (d, J = 8.8 Hz, 1H, H-8), 6.05 (s, 1H, H-3), 4.65\u20134.62 (m, 2H,\n CH2), 4.56\u20134.53 (m, 2H, CH2).; 13C NMR (75 MHz, DMSO) \u03b4 163.46,\n2.3.5. Synthesis of (E)-picolinaldehyde O-(2-((6-methoxy-2- 161.01, 151.79, 150.70, 149.94, 149.67, 136.94, 135.22, 124.90,\n(trifluoromethyl)quinolin-4-yl)oxy)ethyl) oxime (5e) 124.58, 120.55, 118.87, 117.00, 115.92, 91.71, 71.72, 68.68; IR (ATR)\n Compound 5e was prepared according to the general procedure from /cm\u2212 1: 2982, 2882, 1727, 1708, 1619, 1560, 1434, 1349, 1242, 1180,\n6-methoxy-2-(trifluoromethyl)quinolin-4-ol 3e (150.0 mg, 0.617 1086, 968, 882, 778, 705, 516; Calc. for C17H13BrN2O4 (Mr = 389.2) C,\nmmol), K2CO3 (127.9 mg, 0.926 mmol) and (E)-picolinaldehyde O-(2- 52.46; H, 3.37; Br, 20.53; N, 7.20; found: C, 52.53; H, 3.28; Br, 20.57; N,\nbromoethyl) oxime 2 (169.6 mg, 0.740 mmol). Compound 5e was iso\u00ad 7.25 %.\nlated as white powder (134.9 mg, 55.9 %, m.p. = 119\u2013122 \u25e6 C). 1H NMR\n(300 MHz, DMSO) \u03b4 8.60 (d, J = 4.6 Hz, 1H, H-6\u2032), 8.23 (s, 1H, CH-N), 2.3.9. Synthesis of (E)-picolinaldehyde O-(2-((6-methyl-2-oxo-2H-\n8.00 (d, J = 9.1 Hz, 1H, H-5), 7.85\u20137.73 (m, 2H, H-3\u2032, H-4\u2032), 7.52\u20137.40 chromen-4-yl)oxy)ethyl) oxime (6d)\n(m, 4H, H-3, H-7, H-8, H-5\u2032), 4.71 (d, J = 5.5 Hz, 4H, CH2), 3.82 (s, 3H, Compound 6d was prepared according to the general procedure from\nCH3); 13C NMR (151 MHz, DMSO) \u03b4 162.09, 150.76, 149.84, 149.65, 4-hydroxy-6-methyl-2H-chromen-2-one 4d (200.0 mg, 1.135 mmol),\n146.96 (q, J = 33.3 Hz), 137.92, 136.87, 133.43, 128.87, 124.56, K2CO3 (235.4 mg, 1.703 mmol) and (E)-picolinaldehyde O-(2-bro\u00ad\n121.44 (q, J = 275.5 Hz), 121.04, 120.65, 120.58, 120.40, 97.74, 72.26, moethyl) oxime 2 (312.0 mg, 1.362 mmol). Compound 6d was isolated\n68.08, 21.24; IR (ATR) /cm\u2212 1: 2982, 2024, 1916, 1481, 1283, 1178, as white powder (155.0 mg, 42.1 %, m.p. = 171\u2013173 \u25e6 C). 1H NMR (300\n1099, 951, 853, 777; Calc. for C19H16F3N3O3 (Mr = 391.4) C, 58.31; H, MHz, DMSO) \u03b4 8.61 (d, J = 4.7 Hz, 1H, H-6\u2032), 8.25 (s, 1H, CH-N), 7.84\n4.12; F, 14.56; N, 10.74; found: C, 58.26; H, 4.17; F, 14.62; N, 10.79 %. (m, 2H, H-3\u2032, H-4\u2032), 7.57 (s, 1H, H-5), 7.45 (dd, J = 5.9, 3.9 Hz, 2H, H-7,\n H-5\u2032), 7.28 (d, J = 8.4 Hz, 1H, H-8), 5.95 (s, 1H, H-3), 4.67\u20134.58 (m, 2H,\n2.3.6. Synthesis of (E)-picolinaldehyde O-(2-((2-oxo-2H-chromen-4-yl) CH2), 4.53 (d, J = 3.8 Hz, 2H, CH2), 2.28 (s, 3H CH3); 13C NMR (75 MHz,\noxy)ethyl) oxime (6a) DMSO) \u03b4 164.74, 161.71, 150.92, 150.77, 149.90, 149.69, 136.94,\n Compound 6a was prepared according to the general procedure from 133.59, 133.44, 124.62, 122.33, 120.64, 116.25, 114.80, 90.81, 71.86,\n4-hydroxy-2H-chromen-2-one 4a (250.0 mg, 1.542 mmol), K2CO3 68.30, 20.26; IR (ATR) /cm\u2212 1:2971, 2956, 2936, 1571, 1391, 1355,\n(319.7 mg, 2.313 mmol) and (E)-picolinaldehyde O-(2-bromoethyl) 1273, 1254, 1174, 1130, 1085, 979, 945, 820, 781, 737, 620, 514; Calc.\noxime 2 (423.9 mg, 1.850 mmol). Compound 6a was isolated as white for C18H16N2O (Mr = 324.3) C, 66.66; H, 4.97; N, 8.64; found: C, 66.62;\npowder (279.6 mg, 58.4 %, m.p. = 123\u2013125 \u25e6 C)\u22c51H NMR (300 MHz, H, 4.99; N, 8.69 %.\nDMSO) \u03b4 8.61 (d, J = 4.6 Hz, 1H, H-6\u2032), 8.24 (s, 1H, CH-N), 7.89\u20137.78\n(m, 3H, H-3\u2032, H-4\u2032, H-5), 7.68\u20137.61 (m, 1H, H-7), 7.45\u20137.37 (m, 2H, H-8, 2.4. General procedure for the synthesis of metal complexes 5aRe\u20135eRe\nH-5\u2032), 7.31 (t, J = 7.6 Hz, 1H, H-6), 5.99 (s, 1H, H-3), 4.62 (d, J = 4.9 Hz, and 6aRe\u20136dRe\n2H, CH2), 4.56 (d, J = 4.9 Hz, 2H, CH2); 13C NMR (75 MHz, DMSO) \u03b4\n164.70, 161.52, 152.73, 150.72, 149.93, 149.64, 136.89, 132.74, A solution of Re(CO)5Cl (1 eq) and corresponding ligand (1 eq) in\n124.58, 124.08, 122.85, 120.64, 116.39, 115.08, 90.86, 71.83, 68.19; IR chloroform (5 mL) was refluxed for 10 h in the dark. The resulting clear\n(ATR) /cm\u2212 1: 3080, 2982, 2938, 1714, 1699, 1622, 1566, 1411, 1383, yellow solution was cooled to room temperature and its volume was\n1274, 1249, 1191, 1143, 1078, 1067, 930, 855, 765; Calc. for reduced to give a fine yellow precipitate, which was collected by fila\u00ad\nC17H14N2O4 (Mr = 310.3) C, 65.80; H, 4.55; N, 9.03; found: C, 65.76; H, tration and dried.\n4.56; N, 9.07 %.\n 2.4.1. Synthesis of complex 5aRe\n2.3.7. Synthesis of (E)-picolinaldehyde O-(2-((6-chloro-2-oxo-2H- Compound 5aRe was prepared according to the general procedure\nchromen-4-yl)oxy)ethyl) oxime (6b) from ligand 5a (30.0 mg, 0.083 mmol) and Re(CO)5Cl (30.0 mg, 0.083\n Compound 6b was prepared according to the general procedure from mmol). Complex 5aRe was isolated as a yellow powder (26.0 mg, 46.9 %,\n6-chloro-4-hydroxy-2H-chromen-2-one 4b (100.0 mg, 0.509 mmol), m.p. = 132\u2013134 \u25e6 C). 1H NMR (300 MHz, DMSO) \u03b4 9.46 (s, 1H, CH-N),\nK2CO3 (105.5 mg, 0.763 mmol) and (E)-picolinaldehyde O-(2-bro\u00ad 9.03 (d, J = 5.4 Hz, 1H, H-6\u2032), 8.31 (m, 1H, H-5), 8.23 (d, J = 8.3 Hz, 1H,\nmoethyl) oxime 2 (139.9 mg, 0.611 mmol). Compound 6b was isolated H-8), 8.12 (dd, J = 11.3, 7.9 Hz, 2H, H-4\u2032, H-7), 7.88 (t, J = 7.7 Hz, 1H,\nas white powder (87.7 mg, 50.0 %, m.p. = 187\u2013189 \u25e6 C). 1H NMR (600 H-3\u2032), 7.82\u20137.76 (m, 1H, H-6), 7.64 (t, J = 7.6 Hz, 1H, H-5\u2032), 7.50 (s, 1H,\nMHz, DMSO) \u03b4 8.61\u20138.60 (m, 1H, H-6\u2032), 8.25 (s, 1H, CH-N), 7.86\u20137.83 H-3), 4.89 (dd, J = 13.0, 6.3 Hz, 4H, CH2); 13C NMR (151 MHz, DMSO) \u03b4\n(m, 1H, H-4\u2032), 7.80 (dd, J = 6.7, 1.3 Hz, 1H, 3\u2032), 7.75 (d, J = 2.5 Hz, 1H, 196.49, 196.25, 186.87, 162.46, 160.81, 153.26, 151.91, 147.89 (q, J =\nH-5), 7.68 (dt, J = 8.2, 1.4 Hz, 1H, H-7), 7.45 (d, J = 8.9 Hz, 1H, H-8), 33.7 Hz), 147.37, 140.58, 131.46, 129.08 (d, J = 3.6 Hz), 128.97,\n7.44\u20137.41 (m, 1H, H-5\u2032), 6.06 (s, 1H, H-3), 4.65\u20134.62 (m, 2H, CH2), 4.54 127.91, 121.81, 121.46 (q, J = 275.7 Hz), 121.03, 97.86, 79.14, 73.74,\n(dd, J = 5.1, 3.6 Hz, 2H, CH2); 13C NMR (151 MHz, DMSO) \u03b4 163.57, 66.77; IR max/cm\u2212 1 3006, 2981, 2019 (M\u2013C=O sym. stretch), 1922\n161.12, 151.40, 150.72, 149.95, 149.70, 136.96, 132.48, 128.23, (M\u2013C\u2261O asym. stretch), 1884 (M\u2013C\u2261O asym. stretch), 1576, 1515,\n124.62, 122.00, 120.61, 118.66, 116.61, 91.77, 71.74, 68.69; IR (ATR) 1475, 1413, 1382, 1348, 1275, 1183, 1182, 1135, 1098, 1044, 991, 942,\n/cm\u2212 1 3078, 2978, 2940, 1702, 1622, 1559, 1443, 1368, 1185, 1147, 769; Calc. for C21H14ClF3N3O5Re (Mr = 667.0) C, 37.82; H, 2.12; Cl,\n1111, 1079, 984, 940, 860, 824, 705, 531; Calc. for C17H13ClN2O4 5.31; F, 8.54; N, 6.30; Re, 27.92; found: C, 37.86; H, 2.18; Cl, 5.26; F,\n(344.7) C, 59.23; H, 3.80; Cl, 10.28; N, 8.13; found: C, 59.28; H, 3.86; Cl, 8.59; N, 6.26; Re, 27.88 %.\n10.27; N, 8.08 %.\n 2.4.2. Synthesis of complex 5bRe\n2.3.8. Synthesis of (E)-picolinaldehyde O-(2-((6-bromo-2-oxo-2H- Compound 5bRe was prepared according to the general procedure\nchromen-4-yl)oxy)ethyl) oxime (6c) from ligand 5b (30.0 mg, 0.076 mmol) and Re(CO)5Cl (27.4 mg, 0.076\n Compound 6c was prepared according to the general procedure from mmol). Complex 5bRe was isolated as a yellow powder (33.2 mg, 62.5\n6-bromo-4-hydroxy-2H-chromen-2-one 4c (200.0 mg, 0.830 mmol), %, m.p. = 131\u2013133 \u25e6 C). 1H NMR (300 MHz, DMSO) \u03b4 9.47 (s, 1H, CH-N),\nK2CO3 (172.0 mg, 1.245 mmol) and (E)-picolinaldehyde O-(2- 9.03 (d, J = 5.2 Hz, 1H, H-6\u2032), 8.31 (dd, J = 8.4, 7.2 Hz, 1H, H-4\u2032),\n\n 4\n\fM. Pis\u030ckor et al. Journal of Inorganic Biochemistry 262 (2025) 112770\n\n\n8.16\u20138.10 (m, 3H, H-5, H-8, H-3\u2032), 7.88 (dd, J = 9.0, 2.4 Hz, 1H, H-7), H, 2.31; Cl, 5.09; F, 8.18; N, 6.03; Re, 26.71; found: C, 37.98; H, 2.26; Cl,\n7.80 (dd, J = 5.3, 3.5 Hz, 1H, H-5\u2032), 7.57 (s, 1H, H-3), 4.95\u20134.90 (m, 2H, 5.13; F, 8.22; N, 6.01; Re, 26.66 %.\nCH2), 4.91\u20134.86 (m, 2H, CH2); 13C NMR (151 MHz, DMSO) \u03b4 196.52,\n196.24, 186.85, 161.76, 151.88, 148.34 (q, J = 33.9 Hz), 145.82, 2.4.6. Synthesis of complex 6aRe\n140.62, 132.82, 132.01, 131.32, 129.14, 128.98, 121.84, 121.32 (d, J = Compound 6aRe was prepared according to the general procedure\n275.7 Hz), 120.81, 98.81, 73.47, 72.46, 67.46, 63.05; IR (ATR) /cm\u2212 1: from ligand 6a (50.0 mg, 0.161 mmol) and Re(CO)5Cl (58.2 mg, 0.161\n2981, 2988, 2020 (M\u2013C\u2261O sym. stretch), 1940 (M\u2013C\u2261O asym. stretch), mmol). Complex 6aRe was isolated as a yellow powder (87.7 mg, 88.4 %,\n1893 (M\u2013C\u2261O asym. stretch), 1723, 1577, 1573, 1465, 1463, 1388, m.p. > 250 \u25e6 C). 1H NMR (300 MHz, DMSO) \u03b4 9.46 (s, 1H, CH-N), 9.02 (d,\n1354, 1276, 1252, 1186, 1127, 1098, 982, 830,779, 728; Calc. for J = 5.1 Hz, 1H, H-6\u2032), 8.31 (t, J = 7.6 Hz, 1H, H-4\u2032), 8.15 (d, J = 7.6 Hz,\nC21H13Cl2F3N3O5Re (Mr = 701.5) C, 35.96; H, 1.87; Cl, 10.11; F, 8.13; 1H, H-3\u2032), 7.80 (d, J = 7.7 Hz, 2H, H-5, H-5\u2032), 7.64 (t, J = 7.6 Hz, 1H, H-\nN, 5.99; Re, 26.55; found: C, 35.99; H, 1.91; Cl, 10.16; F, 8.19; N, 5.96; 7), 7.40 (d, J = 8.2 Hz, 1H, H-8), 7.26 (t, J = 7.6 Hz, 1H, H-6), 5.99 (s,\nRe, 26.60 %. 1H, H-3), 4.83 (s, 2H, CH2), 4.69 (s, 2H, CH2);13C NMR (75 MHz, DMSO)\n \u03b4 196.48, 196.24, 186.85, 164.48, 161.46, 160.97, 153.25, 152.74,\n2.4.3. Synthesis of complex 5cRe 151.87, 140.58, 132.82, 129.09, 129.00, 123.98, 122.86, 116.44,\n Compound 5cRe was prepared according to the general procedure 114.98, 91.09, 73.40, 66.82; IR (ATR) /cm\u2212 1: 2997, 2982, 2026\nfrom ligand 5c (20.0 mg, 0.046 mmol) and Re(CO)5Cl (16.4 mg, 0.046 (M\u2013C\u2261O sym. stretch), 1912 (M\u2013C\u2261O asym. stretch), 1726, 1625, 1411,\nmmol). Complex 5cRe was isolated as a yellow powder (23.0 mg, 67.0 %, 1237, 1178, 1049, 1047, 931, 805, 772, 640; Calc. for C20H14ClN2O7Re\nm.p. = 143\u2013145 \u25e6 C). 1H NMR (600 MHz, DMSO) \u03b4 9.47 (s, 1H, CH-N), (Mr = 616.0) C, 39.00; H, 2.29; Cl, 5.75; N, 4.55; Re, 30.23; found: C,\n9.03 (d, J = 5.3 Hz, 1H, H-6\u2032), 8.31 (ddd, J = 9.2, 6.0, 1.9 Hz, 2H, H-5, H- 39.06; H, 2.35; Cl, 5.80; N, 4.59 Re, 30.27 %.\n4\u2032), 8.12 (d, J = 7.6 Hz, 1H, H-3\u2032), 8.00 (dt, J = 9.0, 5.6 Hz, 2H, H-8, H-7),\n7.79 (ddd, J = 7.7, 5.4, 1.4 Hz, 1H, H-5\u2032), 7.56 (s, 1H, H-3), 4.97\u20134.90 2.4.7. Synthesis of complex 6bRe\n(m, 2H, CH2), 4.87 (dd, J = 7.2, 3.3 Hz, 2H, CH2); 13C NMR (151 MHz, Compound 6bRe was prepared according to the general procedure\nDMSO) \u03b4 196.56, 196.26, 186.86, 161.65, 161.18, 153.37, 151.88, from ligand 6b (30.0 mg, 0.087 mmol) and Re(CO)5Cl (31.4 mg, 0.087\n148.41 (q, J = 33.7 Hz), 122.26, 146.01, 140.64, 134.61, 131.33, mmol). Complex 6bRe was isolated as a yellow powder (31.9 mg, 56.4\n129.20, 129.01, 124.06, 121.84, 121.85 (q, J = 124.1 Hz), 98.84, 73.47, %, m.p. = 115\u2013117 \u25e6 C). 1H NMR (300 MHz, DMSO) \u03b4 9.48 (s, 1H, CH-N),\n67.50; IR (ATR) /cm\u2212 1: 2981, 2936, 2024 (M\u2013C\u2261O sym. stretch), 1893 9.02 (d, J = 5.2 Hz, 1H, H-6\u2032), 8.31 (t, J = 7.2 Hz, 1H, H-4\u2032), 8.13 (d, J =\n(M\u2013C\u2261O asym. stretch), 1588, 1458, 1391, 1356, 1275, 1135, 1088, 7.7 Hz, 1H, H-3\u2032), 7.85 (d, J = 2.3 Hz, 1H, H-5), 7.82\u20137.75 (m, 2H, H-5\u2032,\n980, 945, 884, 851, 781; Calc. for C21H13Cl2BrF3N3O5Re (Mr = 744.9) H-7), 7.38 (d, J = 8.8 Hz, 1H, H-8), 6.06 (s, 1H, H-3), 4.85 (m, 2H, CH2),\nC, 33.82; H, 1.76; Br, 10.71; Cl, 4.75; F, 7.64; N, 5.63; Re, 24.96; found: 4.69 (m, 2H, CH2); 13C NMR (151 MHz, DMSO) \u03b4 198.52, 198.21,\nC, 33.89; H, 1.82; Br, 10.79; Cl, 4.81; F, 7.61; N, 5.60; Re, 24.99 %. 188.82, 165.27, 163.30, 162.96, 155.33, 153.79, 142.61, 137.27,\n 131.19, 131.01, 134.01, 127.03, 120.80, 118.84, 117.95, 93.92, 75.14,\n2.4.4. Synthesis of complex 5dRe 69.51; IR (ATR) /cm\u2212 1: 3034, 2017 (M\u2013C\u2261O sym. stretch), 1918\n Compound 5dRe was prepared according to the general procedure (M\u2013C\u2261O asym. stretch), 1882 (M\u2013C\u2261O asym. stretch), 159, 1057, 1501,\nfrom ligand 5d (30.0 mg, 0.079 mmol) and Re(CO)5Cl (28.9 mg, 0.079 1458, 1389, 1350, 1277, 1192, 1136, 947, 846, 772, 643. Calc. for\nmmol). Complex 5dRe was isolated as a yellow powder (28.5 mg, 53.0 C20H13Cl2N2O7Re (Mr = 650.4) C, 36.93; H, 2.01; Cl, 10.90; N, 4.31; Re,\n%, m.p. = 122\u2013123 \u25e6 C). 1H NMR (300 MHz, DMSO) \u03b4 9.46 (s, 1H, CH-N), 28.63; found: 36.99; H, 2.07; Cl, 10.96; N, 4.35; Re, 28.58 %.\n9.04 (d, J = 5.1 Hz, 1H, H-6\u2032), 8.31 (dd, J = 7.7, 6.6 Hz, 1H, H-4\u2032), 8.11\n(d, J = 7.6 Hz, 1H, H-3\u2032), 7.98 (d, J = 8.2 Hz, 2H, H-8, H-5), 7.86\u20137.75 2.4.8. Synthesis of complex 6cRe\n(m, 1H, H-5\u2032), 7.70 (dd, J = 8.7, 1.6 Hz, 1H, H-7), 7.44 (s, 1H, H-3), Compound 6cRe was prepared according to the general procedure\n4.99\u20134.88 (m, 2H, CH2), 4.88\u20134.79 (m, 2H, CH2), 2.38 (s, 3H, CH3); 13C from ligand 6c (50.0 mg, 0.128 mmol) and Re(CO)5Cl (46.4 mg, 0.128\nNMR (151 MHz, DMSO) \u03b4 196.53, 196.24, 186.89, 161.82, 160.87, mmol). Complex 6cRe was isolated as a yellow powder (36.2 mg, 40.7 %,\n153.30, 151.96, 146.95 (q, J = 33.5 Hz), 145.93, 140.62, 137.89, m.p. = 247\u2013249 \u25e6 C). 1H NMR (300 MHz, DMSO) \u03b4 9.48 (s, 1H, CH-N),\n133.44, 129.10, 128.94, 128.82, 120.95, 120.53, 119.46 (q, J = 33.5 9.03 (d, J = 5.2 Hz, 1H, H-6\u2032), 8.31 (t, J = 7.2 Hz, 1H, H-4\u2032), 8.14 (d, J =\nHz), 97.76, 73.66, 66.97, 21.20; IR (ATR) /cm\u2212 1: 3074, 2982, 2930, 7.7 Hz, 1H, H-3\u2032), 7.85 (d, J = 2.3 Hz, 1H, H-5), 7.82\u20137.75 (m, 2H, H-7,\n2024 (M\u2013C\u2261O sym. stretch), 1908 (M\u2013C\u2261O asym. stretch), 187 (M\u2013C\u2261O H-5\u2032), 7.38 (d, J = 8.8 Hz, 1H, H-8), 6.06 (s, 1H, H-3), 4.86 (s, 2H, CH2),\nasym. stretch), 1357, 1282, 1233, 1178, 1100, 1099, 951, 835, 735, 714; 4.69 (s, 2H, CH2); 13C NMR (151 MHz, DMSO) \u03b4 196.52, 196.21, 186.82,\nCalc. for C22H16ClF3N3O5Re (Mr = 681.0) C, 38.80; H, 2.37; Cl, 5.21; F, 163.27, 161.30, 160.96, 153.33, 151.28, 151.75, 140.61, 135.27,\n8.37; N, 6.17; Re, 27.34; found: C, 38.84; H, 2.40; Cl, 5.25; F, 8.41; N, 129.19, 129.01, 125.03, 118.80, 116.84, 115.95, 91.92, 73.14, 67.51; IR\n6.14; Re, 27.38 %. (ATR) /cm\u2212 1: 3008, 2981, 2884, 2028 (M\u2013C\u2261O sym. stretch), 1907\n (M\u2013C\u2261O asym. stretch), 1728, 1709, 1561, 1434, 1350, 1243, 1186,\n2.4.5. Synthesis of complex 5eRe 1081, 968, 822, 705, 657; Calc. for C20H13BrClN2O7Re (Mr = 694.9) C,\n Compound 5eRe was prepared according to the general procedure 34.57; H, 1.89; Br, 11.50; Cl, 5.10; N, 4.03; Re, 26.80; found: C, 34.61; H,\nfrom ligand 5e (20.0 mg, 0.051 mmol) and Re(CO)5Cl (18.5 mg, 0.051 1.84; Br, 11.54; Cl, 5.16; N, 4.09; Re, 26.86 %.\nmmol). Complex 5eRe was isolated as a yellow powder (32.0 mg, 89.8 %,\nm.p. = 122\u2013123 \u25e6 C)\u22c51H NMR (600 MHz, DMSO) \u03b4 9.46 (s, 1H, CH-N), 2.4.9. Synthesis of complex 6dRe\n9.04 (dd, J = 5.4, 1.5 Hz, 1H, H-6\u2032), 8.30 (td, J = 7.8, 1.7 Hz, 1H, H- Compound 6dRe was prepared according to the general procedure\n4\u2032), 8.11 (dd, J = 7.7, 1.2 Hz, 1H, H-3\u2032), 7.97 (m, 2H, H-5, H-8), from ligand 6d (20.0 mg, 0.062 mmol) and Re(CO)5Cl (22.3 mg, 0.062\n7.81\u20137.77 (m, 1H, H-5\u2032), 7.70 (dd, J = 8.5, 2.1 Hz, 1H, H-7), 7.44 (s, 1H, mmol). Complex 6dRe was isolated as a yellow powder (20.9 mg, 53.5\nH\u2013Ar), 4.95\u20134.89 (m, 2H, CH2), 4.89\u20134.71 (m, 2H, CH2), 2.37 (s, 3H, %, m.p. = 247\u2013249 \u25e6 C). 1H NMR (600 MHz, DMSO) \u03b4 9.48 (s, 1H, CH-N),\nCH3);13C NMR (151 MHz, DMSO) \u03b4 196.54, 196.25, 186.91, 161.84, 9.07\u20138.96 (m, 1H, H-6\u2032), 8.31 (td, J = 7.8, 1.4 Hz, 1H, H\u2013Ar, H-4\u2032), 8.13\n160.89, 153.32, 151.97, 146.96 (q, J = 33.5 Hz), 145.94, 140.63, (d, J = 7.5 Hz, 1H, H-3\u2032), 7.79 (ddd, J = 7.7, 5.4, 1.4 Hz, 1H, H-5\u2032), 7.56\n137.91, 133.46, 129.12, 128.95, 128.84, 121.58 (q, J = 275.4 Hz), (d, J = 1.2 Hz, 1H, H-5), 7.44 (dd, J = 8.6, 1.9 Hz, 1H, H-7), 7.29 (d, J =\n120.96, 120.55, 97.78, 73.66, 66.99, 21.21; IR (ATR) /cm\u2212 1: 3072, 8.4 Hz, 1H, H-8), 5.95 (s, 1H, H-3), 4.85 (dd, J = 8.1, 3.7 Hz, 2H, CH2),\n2981, 2929, 2022 (M\u2013C\u2261O sym. stretch), 1914 (M\u2013C\u2261O asym. stretch), 4.72\u20134.59 (m, 2H, CH2), 2.20 (s, 3H, CH3); 13C NMR (151 MHz, DMSO) \u03b4\n1896 (M\u2013C\u2261O asym. stretch), 1358, 1282, 1233, 1178, 1100, 1099, 196.52, 196.22, 186.89, 164.51, 161.64, 161.07, 153.32, 151.93,\n951, 835, 735, 715; Calc. for C22H16ClF3N3O6Re (Mr = 697.0) C, 37.91; 150.90, 140.63, 133.59, 133.35, 129.14, 128.98, 122.48, 116.20,\n\n 5\n\fM. Pis\u030ckor et al. Journal of Inorganic Biochemistry 262 (2025) 112770\n\n\n114.66, 90.98, 73.31, 67.12, 20.18; IR (ATR) /cm\u2212 1: 3077, 2958, 2023 The cells were cultured in two different types of media: DMEM and\n(M\u2013C\u2261O sym. stretch), 1912 (M\u2013C\u2261O asym. stretch), 1717, 1575, 1391, RPMI 1640. Both media were supplemented with 2 mM glutamine, fetal\n1356, 1275, 1255, 1175, 1131, 1087, 979, 946, 829, 737, 620; Calc. for bovine serum (10 % inactivated by heat), and antibiotics (100 U of\nC21H16ClN2O7Re (Mr = 630.0) C, 40.04; H, 2.56; Cl, 5.63; N, 4.45; Re, penicillin and 0.1 mg of streptomycin). The RPMI 1640 was further\n29.56; Found:C, 40.10; H, 2.61; Cl, 5.67; N, 4.49; Re, 29.48 %. supplemented with 10 mM HEPES and 1 mM sodium pyruvate. The cells\n growing in a monolayer were cultured in the DMEM, while the cells\n2.5. X-Ray crystallography growing in suspension were cultured in the RPMI 1640. The cells were\n grown in a CO2 incubator (IGO 150 CELLlife\u2122, JOUAN) under 37 \u25e6 C in a\n The X-ray intensity data for 5dRe, 6aRe and 6cRe were collected on humidified atmosphere with 5 % CO2.\nXtaLAB Synergy (Dualflex) CCD diffractometer using monochromatic\nCu-K\u03b1 (\u03bb = 1.54184 \u00c5) radiation at room temperature. Basic experi\u00ad 2.6.2. Proliferation assay\nmental data are given in Table S1. The data were processed with the Growth-inhibitory activity was evaluated using a slightly modified\nCrysAlisPro program [68], used for unit cell determination and data procedure based on the National Cancer Institute\u2019s protocol [75]. In\nreduction. Structures were solved by direct methods using the SHELXT brief, the cells were seeded in 96-well microtiter plates and incubated\nprogram [69] and refined against F2 on all data by a full-matrix least for 24 h, and then were treated for an additional 72 h with 10\u2212 7 to 10\u2212 4\nsquares procedure with the SHELXL program [70]. All non\u2011hydrogen M concentrations of tested compounds. After treatment period, effects of\natoms were refined in an anisotropic model of atomic displacement tested compounds on the cell growth rate were evaluated using the MTT\nparameters (ADPs). In the structure of 5dRe two Re complexes with assay [76]. The absorbance was measured at 595 nm with a microplate\nidentical chemical composition and different conformation form the reader. The IC50 values, which represent a 50 % inhibition of cell\nasymmetric unit of the structure. Carbonyl groups coordinated to Re growth, and QC calculation were carried out using the GraphPadPrism\natom in trans-position with respect to Cl- anion, showed unusually small and Excel software. The effect of single concentrations was analysed by\nC\u2013\u2013O bonds, due the disorder of these groups with Cl- anions [71\u201373]. charting the logarithm of the evaluated compound\u2019s concentration\nThus, in final structural model used in the refinement, disorder between against its corresponding percent inhibition value using the least squares\nCl- anions and trans C\u2013 \u2013O groups is accounted with constraint that the fit.\nsum of occupations of individual C\u2013 \u2013O and Cl- position is full (occupa\u00ad\ntion 1). In one independent complex molecule in 5dRe, Cl1A, C3CA and 2.7. Cell cycle analysis\nO3CA were refined to occupancy of 0.774(9) and positions Cl1B, C3CB\nand O3CB to occupancy of 0.226(9). For the second independent com\u00ad The HuT78 cells were plated in 24-well plates at a concentration of 1\nplex molecule, analogue position occupancies were refined to values of \u00d7 105 cells per well and treated for 24 h with the selected compounds 5e\n0.949(5) and 0.051(5), respectively. In order to keep the refinement and 6d at a concentration of 50 \u03bcM), 5eRe at a concentration of 10 \u03bcM\nconvergent, for disordered carbonyl groups and Cl- anions, additional and 6dRe at a concentration of 2 \u03bcM. After drug treatment, the cells were\nADP restraints were used (SIMU, DELU and ISOR), as well as bond dis\u00ad fixed with ice-cold 70 % ethanol in phosphate-buffered saline (PBS) and\ntance restraints to carbonyl groups (1.2 \u00c5). Similarly, the difference incubated with 0.3 \u03bcg/mL propidium iodide for 30 min at room tem\u00ad\nelectron density in the vicinity of one -CF3 group in one complex suggest perature. Prior to analysis by flow cytometry (BD FACSLyric, Becton\nan orientation disordered, so the final refinement model used the anal\u00ad Dickinson, San Jose, CA, SAD), samples were treated with 0.4 \u03bcg/mL\nogous disorder model, in which orientations are refined to the values of RNase A for 5 min at room temperature. The resulting DNA histograms\n0.707(13) and 0.293(13), respectively. Restraint that ADPs for these were generated and analysed using FlowJo 10.10. software (Treestar,\ndisorderly oriented F atoms have more isotropic character is also used. Inc., Ashland, OR, USA).\nStructures 6aRe and 6cRe contained only one complex molecule in\nasymmetric unit of the structure. In both structures, highest difference 2.8. Measurement of mitochondrial membrane potential (\u0394\u03a8 m)\nelectron density peaks are located around Re atoms, although for\nstructure 6cRe these peaks are significant, suggesting higher disorder of The changes in (\u0394\u03a8m) were measured with the dye 75 nM TMRE\nthe Re atoms. Namely, it is common feature of the structures with (tetramethylrhodamine, ethyl ester, perchlorate). In brief, the tested\nrhenium that significant peaks of difference electron density peaks are cells (HuT78) were plated in 96-well plates at a concentration of 1.5 \u00d7\nlocated in the vicinity of Re atoms, sometimes these peaks are treated as 105 cells per well and treated with 50 \u03bcM 5e and 6d, 10 \u03bcM 5eRe and 2\nadditional disordered positions of the Re atoms and their occupancies \u03bcM 6dRe. After 24 h of treatment, cells were harvested, centrifuged at\nare refined [61,74], however such treatment does not improve signifi\u00ad 1100 rpm for 6 min and stained with 200 nM TMRE dye according to the\ncantly the structural model of the complex, especially for the highest kit protocol (TMRE Mitochondrial Membrane Potential Assay Kit,\noccupied position of the Re atom. Positions of hydrogen atoms were abcam, UK). Positive control cells were treated with 20 \u03bcM FCCP\ntreated in the riding model, i.e. they were calculated according to the (carbonyl cyanide-p-trifluoromethoxyphenylhydrazone) for 10 min.\npositions of the carbon atoms to which they are bonded. C\u2013H distances Cells were analysed with multimode microplate reader Tecan Spark\nfor aromatic, methylene and methyl H-atoms were constrained to 0.93, (Tecan, Mannedorf, Switzerland) fusing fluorescence filter setting (Ex/\n0.97 and 0.96 \u00c5, respectively, with isotropic ADP parameter Uiso(H) = Em = 490/595 nm) and the Sparkcontrol method editor software.\n1.2xUiso(C) for aromatic and methylene H-atoms and Uiso(H) = 1.5xUi\u00ad\nso(C) for methyl H-atoms. Torsion angles of the methyl groups were 2.9. Determination of intracellular free oxygen radicals (ROS) and\nrefined. The CCDC 2370977\u20132,370,979 contain the supplementary superoxide production\ncrystallographic data for this paper.\n HuT78 cells were resuspended at a concentration of 1 \u00d7 105 cells/mL\n2.6. Evaluation of the antiproliferative activity in PBS and incubated for 1 h in an incubator at 37 \u25e6 C/5 % CO2 with with\n 50 \u03bcM 5e and 6d, 10 \u03bcM 5eRe and 2 \u03bcM 6dRe. At the end of the incu\u00ad\n2.6.1. Cell lines and cell culturing bation period, reagents were added to the cells according to the manu\u00ad\n The impact of new synthesized compounds was tested on on human facturer\u2019s instructions from the Fluorometric Intracellular Ros Kit\ntumor cell lines, including T-lymphoblasts (acute lymphoblastic leuke\u00ad (Sigma-Aldrich, St. Louis, USA) and the cells were then incubated in an\nmia) (CCRF-CEM), monocytic (acute monocytic leukemia) (THP1), incubator at 37 \u25e6 C/5 % CO2 for 30 min. Cell analysis was performed with\ncervical adenocarcinoma (HeLa), colon adenocarcinoma (CaCo-2), T- Tecan Spark Multimode Microplate Reader (Tecan, Mannedorf,\ncell lymphoma (HuT78), and non-tumor human fibroblasts (BJ). Switzerland) using the Sparkcontrol Method Editor software.\n\n 6\n\fM. Pis\u030ckor et al. Journal of Inorganic Biochemistry 262 (2025) 112770\n\n\nIntracellular free oxygen radicals are detected with a green fluorescence complexes. Fig. 3 illustrates the observed trends of the chemical shift in\nfilter setting (Ex/Em = 490/595 nm), while superoxide production was the coordination of 6c with the Re(I) ion. The 13C NMR spectra of the\ndetected by an orange fluorescence signal (Ex/Em = 550/620 nm). metal complexes show three signals in the range of 197\u2013189 ppm, which\nExperiments were performed in triplicate and quantitative data are correspond to the carbon atoms of the carbonyl group and indicate the\nexpressed as mean \u00b1 standard deviation. STATISTICA 14.0.1.8. (TIBCO presence of [Re(CO)3Cl] in the structures of the metal complexes. IR\nSoftware Inc., Tulsa, USA) was used to statistically analyse the results. spectroscopy further confirmed the complexation due to the appearance\nStudent\u2019s t-test was used to analyse the data. A P-value of less than 0.05 of strong \u03bd(CO) symmetric and asymmetric stretching modes expected\nwas considered statistically significant. for fac-[Re(CO)3Cl] groups in the range of 2026\u20131884 cm\u2212 1 (Figs. S48-\n S74, Table S3, Supplementary Material).\n3. Results and discussion The stability of quinoline 5eRe and coumarin 6dRe derivatives in\n aqueous solution was further investigated by UV\u2013Vis and 1H NMR\n3.1. Chemistry and spectroscopic characterization spectroscopy. The complexes 5eRe and 6dRe were dissolved in an\n acetonitrile and water mixture (1,1) and their UV\u2013Vis spectra were\n Novel quinoline and coumarin ligands were synthesized as shown in recorded over 24 h and demonstrated a blue shift (\u0394\u03bbmax \u2248 40 nm) of the\nScheme 1. First, 2-(trifluoromethyl)quinolin-4-ol derivatives substituted band around 390 nm, what is consistent with the aquated forms of 5eRe\nat C-6 position were obtained by a Knoevenagel condensation of various and 6dRe (Figs. S84 and S85, Supplementary Material) [77,78].\np-substituted aniline derivatives and ethyl 4,4,4-trifluoroacetoactate in Furthermore, the 1H NMR spectra of 5eRe and 6dRe in CD3CN and\nthe presence of polyphosphoric acid (PPA) at 150 \u25e6 C (Scheme S1, Sup\u00ad D\u2082O indicated deshielding effect of the aldoxime proton and a change in\nplementary Material). O-Alkylated (E)-picolinaldehyde oxime 2 was multiplicity of the methylene protons at 5 ppm, which can be attributed\nsynthesized by base-promoted alkylation of syn-2-pyridinealdoxime to aquation (Figs. S86 and S87, Supplementary Material).\nwith 1,2-dibromoethane. Finally, reaction of corresponding quinoline\n3a\u20133e or coumarin 4a\u20134d and O-alkylated (E)-picolinaldehyde oxime 2\nwith NaH afforded targeted quinoline 5a\u20135e and coumarin 6a\u20136d li\u00ad 3.2. Solid state characterization\ngands in moderate yield (41\u201381 %).\n Ligands 5a\u20135e and 6a\u20136d subsequently reacted with [Re(CO)5Cl] to The crystals of the quinoline complex 5dRe and the coumarin com\u00ad\nobtain the corresponding rhenium(I) tricarbonyl complexes 5aRe\u20135eRe plexes 6aRe and 6cRe were obtained by slow evaporation from\nand 6aRe\u20136dRe in good yield (40\u201389 %). Interestingly, all the prepared dichloromethane: methanol solutions. The structures are shown in\ncomplexes are chiral at the metal centre. However, since no other chiral Fig. 4, while the parameters of crystallographic refinement and data\ninformation is present, racemic mixtures were obtained in the synthesis. acquisition as well as the relevant interatomic distances and angles are\nLigands and complexes were fully characterized by 1H and 13C NMR, as listed in Tables S1 and S2. In all complexes, the ligands coordinate with\nwell as IR and UV\u2013Vis spectroscopy (Figs. S7-S83, Table S3, Supple\u00ad the metal ion in a bidentate manner, resulting in an octahedral geometry\nmentary Material). The purity of both the ligands and the complexes was with an N2C3Cl coordination sphere around Re(I). The crystal structures\nconfirmed by elemental analysis. The difference between the 1H NMR of the complexes show the expected fac-stereochemistry, which is due to\nspectra of the ligands and their rhenium(I) tricarbonyl complexes is the the influence of back-bonding of the CO ligands. All three complexes\ndeshielding of pyridine, aldoxime and methylene protons due to the crystallize in centrosymmetric space groups confirming that both en\u00ad\nelectron-withdrawing inductive effects of the transition metal. Signifi\u00ad antiomers are present. In all complexes, the metal centre is coordinated\ncant shifts are observed for the aldoxime proton and the pyridine proton by Npyridine and Naldoxime, with the chloride ion in these complexes is\nin ortho position to the N-donor atom. Both the aldoxime protons (\u0394\u03b4 \u2248 covalently bonded to the metal. The bond lengths and bond angles\n1.2 ppm) and pyridine protons (\u0394\u03b4 \u2248 0.4 ppm) experience strong observed in all complexes are consistent with the typical structural\ndeshielding effects, which are observed in both coumarin and quinoline features identified in previous studies of rhenium tricarbonyl complexes\n with bidentate ligands (fac-[Re(X)(CO)3(N\u2227N)]) [78\u201381]. For example,\n\n\n\n\nScheme 1. Synthesis of quinoline and coumarin derivatives with aldoxime ether linked pyridine moieties and corresponding Re[(CO)3]+ metal complexes. Reagents\nand conditions: (i) 1,1-dibromoethane, NaH, DMF, r.t, 24 h; (ii) K2CO3, DMF, 80 \u25e6 C, 24 h (iii) [Re(CO)5Cl], CHCl3, reflux, 24 h.\n\n 7\n\fM. Pis\u030ckor et al. Journal of Inorganic Biochemistry 262 (2025) 112770\n\n\n\n\n Fig. 3. Comparison of the proton NMR spectra of ligand 6c and rhenium(I) tricarbonyl complex 6cRe in DMSO\u2011d6.\n\n\nthe average length of the Re\u2011carbonyl bond is 1.94(4) \u00c5, with the all tested compounds (6a\u20136d) exhibited moderate inhibitory activity on\nOC\u2013Re\u2013CO angles forming an almost regular trigonal pyramid with HuT78 cells with IC50 values ranging from 43.8 to 49.2 \u03bcM.\nangles between 87.3(3) and 92.1(3) degrees. In addition, the average Rhenium(I) tricarbonyl complexes of both quinolines 5aRe\u20135eRe and\nlengths of the Re\u2013Cl bonds are between 2.430(2) and 2.470(2) \u00c5. It is coumarins 6aRe\u20136dRe exhibited better growth-inhibitory effect on can\u00ad\ninteresting to mention that 6aRe and 6cRe show intermolecular aromatic cer cell lines than their ligands (Fig. 5). Thus, antiproliferative activity of\nstacking between coumarin groups of neighbouring complex molecules quinoline-based complexes 5aRe\u20135eRe on HuT78 cells increased from 2-\n(see packing diagrams in Figs. S5 and S6, Supplementary Material). fold to 5-fold relative to corresponding ligands 5a\u20135e. However, some\n rhenium organometallic complexes were also cytotoxic to non-tumor BJ\n cells. Their cytotoxicity was comparable or lower than that of 5-FU. In\n3.3. Biological evaluation the group of quinoline-based complexes, 6-methoxy-2-(trifluoromethyl)\n quinoline complex 5eRe showed the best activity (IC50 = 9.4 \u03bcM) and\n3.3.1. Antiproliferative evaluation selectivity (SI = 5.8) on HuT78 cells. 6-Unsubstituted 2-(tri\u00ad\n The results of antiproliferative evaluation of novel quinoline and fluoromethyl)quinoline 5aRe showed moderate activity on all evaluated\ncoumarin ligands 5a\u20135e and 6a\u20136f and their rhenium(I) tricarbonyl cell lines with IC50 values in the range from 11.5 to 29 \u03bcM.\ncomplexes 5aRe\u20135eRe and 6aRe\u20136dRe on human tumor cell lines, Among the coumarin-based complexes, 6-methylcoumarin complex\nincluding T-lymphoblasts (acute lymphoblastic leukemia) (CCRF-CEM), 6dRe showed a marked and selective antiproliferative effect (IC50 = 2.4\nmonocytic (acute monocytic leukemia) (THP1), cervical adenocarci\u00ad \u03bcM, SI = 8.7) on HuT78 cells. Both the bromo-substituted quinoline 5cRe\nnoma (HeLa), colon adenocarcinoma (CaCo-2), T-cell lymphoma and coumarin 6cRe complexes showed an inhibitory activity on T-lym\u00ad\n(HuT78), and non-tumor human fibroblasts (BJ) are presented in phoblasts (CCRF-CEM) (5cRe, IC50 = 6.3 \u03bcM, 6cRe, IC50 = 9.5 \u03bcM) and\nTable 1. 5-Fluorouracil (5-FU) is included as a reference drug. monocytic leukemia (THP1) (5cRe, IC50 = 10.6 \u03bcM, 6cRe, IC50 = 15.4\n A comparison of the antiproliferative activity of quinoline and \u03bcM) and moderate activity on cervical adenocarcinoma (HeLa) and\ncoumarin derivatives with pyridine aldoxime moiety showed that colon adenocarcinoma (CaCo-2). Their activities were greater than those\nquinolines 5a\u20135e have a higher activity than corresponding coumarins of 5-FU, with the exception of inhibition of HeLa and CaCo-2 cells. The\n6a\u20136d. As shown in Table 1, 6-chloro-2-(trifluoromethyl)quinoline metal coordination of quinoline increased the activity of complex 5cRe\nligand 5b and 6-bromo-2-(trifluoromethyl)quinoline ligand 5c showed over ligand 5c on CCRF-CEM cells by 7-fold. The 6-chloro-2-(trifluoro\u00ad\na good (5b, IC50 = 24.9 \u03bcM, 5c, IC50 = 33.2 \u03bcM) and selective inhibitory methyl)quinilone complex 5bRe was also 5-fold more active (IC50 =\nactivity on T-cell lymphoma (HuT78). Compounds were non-toxic (IC50 2.7 \u03bcM) than its ligand 5b (Table 1). The observed results of pronounced\n> 100 \u03bcM) to non-tumor human fibroblasts (BJ). 6-Methyl-2-(trifluoro\u00ad antiproliferative activity of the metal complexes compared to their\nmethyl)quinoline 5d and 6-methoxy-2-(trifluoromethyl)quinoline 5e coumarin and quinoline ligands are in agreement with the results of\nligands showed slightly less activity (5d, IC50 = 41.2 \u03bcM, 5e, IC50 = 48.7 previously published studies [82\u201384]. Based on the results of\n\u03bcM) on HuT78 cells relative to 5b and 5c. Among the coumarin ligands,\n\n 8\n\fM. Pis\u030ckor et al. Journal of Inorganic Biochemistry 262 (2025) 112770\n\n\n\n\nFig. 4. Crystal structure of the complexes 5dRe, 6aRe and 6cRe. Only metal and coordinating atoms are labelled. For 5dRe only higher occupied positions of\ndisordered groups are shown (Cl\u2212 anions, two carbonyl groups and one CF3 group). The comprehensive labelling schemes are shown in Figs. S1, S2, and S3\n(Supplementary Material).\n\n\n\nTable 1\nThe growth-inhibition effects in vitro of compounds 5a\u2013e and 6a\u2013f and their rhenium(I) tricarbonyl complexes 5aRe\u20135eRe and 6aRe\u20136dRe on selected tumor cell lines.\n\n\n\n\n IC50a (\u03bcM) SI (HuT78)b\n R1 Compd CCRF-CEM HeLa CaCo-2 THP-1 HuT78 BJ\n 5a 94.9 \u00b1 40 >100 >100 86.4 \u00b1 11.4 43.4 \u00b1 1.6 >100 2.3\n H\n 5aRe 11.5 \u00b1 7.9 20.2 \u00b1 1.2 28.4 \u00b1 2.4 16.1 \u00b1 0.7 29.0 \u00b1 1.6 64.0 \u00b1 3.4 2.2\n 5b >100 >100 >100 64.6 \u00b1 5.9 24.9 \u00b1 0.2 >100 4.1\n Cl\n 5bRe 22.1 \u00b1 1.1 20.7 \u00b1 0.7 28.9 \u00b1 5.6 26.7 \u00b1 8.7 10.4 \u00b1 0.2 30.1 \u00b1 2.3 2.9\n 5c 42.1 \u00b1 0.9 >100 >100 49.1 \u00b1 11.4 33.2 \u00b1 5.9 >100 4.3\n Br\n 5cRe 6.3 \u00b1 1.7 21.8 \u00b1 1.5 30.6 \u00b1 1.5 10.6 \u00b1 1.7 11.0 \u00b1 1.2 21.0 \u00b1 5.2 1.9\n 5d 81.1 \u00b1 11.0 >100 <100 55.2 \u00b1 7.01 41.2 \u00b1 1.7 >100 2.4\n CH3\n 5dRe 15.9 \u00b1 2.2 39.3 \u00b1 20.9 56.4 \u00b1 25.1 17.8 \u00b1 3.0 10.2 \u00b1 2.3 31.5 \u00b1 6.2 3.1\n 5e >100 >100 >100 76.4 \u00b1 7.5 48.7 \u00b1 3.3 >100 2.1\n OCH3\n 5eRe 17.2 \u00b1 6.6 27.9 \u00b1 11.7 29.4 \u00b1 7.4 36.1 \u00b1 3.7 9.4 \u00b1 0.1 54.5 \u00b1 2.7 5.8\n 6a 46.5 \u00b1 7.1 >100 >100 46.2 \u00b1 5.1 49.2 \u00b1 5.5 >100 2.2\n H\n 6aRe 26.0 \u00b1 10.5 >100 >100 71.0 \u00b1 5.7 40.5 \u00b1 7.1 >100 2.5\n 6b 89.5 \u00b1 33.4 >100 >100 56.2 \u00b1 5.9 44.8 \u00b1 37.3 >100 2.2\n Cl\n 6bRe 24.4 \u00b1 0.8 >100 >100 25.8 \u00b1 1.6 34.9 \u00b1 1.4 78.1 \u00b1 2.5 2.2\n 6c 94.0 \u00b1 11.1 >100 >100 39.6 \u00b1 7.2 44.7 \u00b1 0.3 >100 2.3\n Br\n 6cRe 9.5 \u00b1 2.7 19.1 \u00b1 2.3 33.2 \u00b1 6.2 15.4 \u00b1 2.1 10.6 \u00b1 1.0 59.1 \u00b1 5.9 5.6\n 6d 78.2 \u00b1 19.7 >100 >100 37.9 \u00b1 8.2 43.8 \u00b1 5.4 >100 2.3\n CH3\n 6dRe 13.0 \u00b1 2.9 22.5 \u00b1 0.7 32.0 \u00b1 3.0 16.5 \u00b1 1.9 2.4 \u00b1 0.8 20.9 \u00b1 1.8 8.7\n 5Fu 52.2 \u00b1 0.8 8.2 \u00b1 1.9 5.9 \u00b1 0.7 76.4 \u00b1 0.5 >100 16.8 \u00b1 7.0 /\n a\n 50 % inhibitory concentration or compound concentration required to inhibit tumor cell proliferation by 50 %.\n b\n SI, selectivity index, SI = IC50 for normal cell line/IC50 for cancer cell line (HuT78).\n\n\n 9\n\fM. Pis\u030ckor et al. Journal of Inorganic Biochemistry 262 (2025) 112770\n\n\n\n\n Fig. 5. Insight into structure-activity relationship of the ligands 5a\u20135e and 6a\u20136d and their Re(I) complexes on antiproliferative activity.\n\n\nantiproliferative activity and selectivity, four compounds (5e, 5eRe, 6d caused a significant accumulation of cells in the G0/G1 phase of the cell\nand 6dRewere chosen for further biological evaluations) as representa\u00ad cycle and a significant decrease in the number of cells in the G2/M phase\ntives of quinolones and coumarins. of the cell cycle. The population of HuT78 cells in the G0/G1 phase\n increased from 30.9 % (control group) to 60.5 % (5e), 50.1 % (5eRe),\n3.3.2. Cell cycle modification 57.1 % (6d) and 47.3 % (6dRe), while the percentage of cells in the G2/\n One of the possible mechanisms involved in the treatment of cancer M phase decreased significantly compared to the non-treated cells\nis the interruption of the cell cycle [49,85]. The cell cycle distribution in (Fig. 6). These compounds affect the same phases of the cell cycle and\nHuT78 cells was analysed to determine whether ligands 5e and 6d and lead to changes in cell proliferation and growth. The ability of tri\u00ad\ntheir complexes 5eRe and 6dRe inhibit the proliferation of these cells by carbonyl rhenium complexes to stop the passage of cells in the M/G2\ncell cycle arrest. These compounds were selected because the metal phase of the cell cycle was also observed in the study by Simpson et al.\ncomplex 5eRe showed the most pronounced and most selective inhibi\u00ad [86]. Numerous studies have shown that quinoline- and coumarin-based\ntory effect in the group of quinoline derivatives, and the metal complex compounds and their hybrids significantly affect the growth of tumor\n6dRe showed the strongest and most selective inhibition of HuT78 cell cells in different phases of the cell cycle, most frequently in the G0/G1\ngrowth among the coumarin derivatives compared to their effect on the phase [87\u201389]. These data suggest that the observed cell cycle arrest\ngrowth of non-tumor BJ cells. HuT78 cells were exposed to the com\u00ad contributes to the proliferation inhibitory effects of the tested com\u00ad\npounds for 24 h at the concentration required to inhibit tumor cell pounds on HuT78 cells.\nproliferation by 50 % (IC50). As shown in Fig. 6, all tested compounds\n\n\n\n\nFig. 6. Flow cytometric analysis of the cell cycle distribution of HuT78 cells exposed to compounds 5e and 6d (50 \u03bcM), 5eRe (10 \u03bcM), and 6dRe (2 \u03bcmol dm\u2212 3) for 24\nh. (a) DNA histograms show changes in the cell cycle. (b) Data are presented as percentage (%) of cells in the cell cycle phase.\n\n 10\n\fM. Pis\u030ckor et al. Journal of Inorganic Biochemistry 262 (2025) 112770\n\n\n3.3.2. Reactive oxygen species ROS production in treated tumor cells form of the complexes, which could have an effect on mitochondrial\n membrane potential. These results suggest that the cytotoxic effects of\n Tumor cells contain higher concentrations of ROS than normal cells, these compounds are mediated, at least in part, by their effects on\nbut when intracellular ROS concentrations increase drastically to toxic mitochondrial membrane potential and the subsequent slight increase in\nlevels, oxidative stress causes irreversible damage and can eventually ROS production. Understanding these mechanisms is critical for the\nlead to cancer cell death [90,91]. ROS can be generated by various development of effective cancer therapies that target mitochondrial\ncellular processes or chemical reactions [92]. The most important ROS function and oxidative stress pathways.\nfor physiological and cancer processes are singlet oxygen, superoxide\nanions, hydroxyl radicals and hydrogen peroxide. Metal complexes are 4. Conclusions\nwell-known to generate ROS due to the presence of easily accessible\nmultiple oxidation states [91,93,94]. Quinolines, obtained by Knoevenagel condensation, and coumarins\n Total ROS and superoxide production in HuT78 cells were investi\u00ad were synthesized by base-promoted O-alkylation with (E)-picolinalde\u00ad\ngated to better understand the observed cytotoxic and cell cycle effects hyde oxime to afford quinolines 5a\u20135e and coumarins 6a\u20136d with\nof the novel quinoline (5e) and coumarin (6d) ligands and their com\u00ad aldoxime ether linked pyridine moiety. Quinoline and coumarin ligands\nplexes with rhenium(I) (5eRe and 6dRe) (Fig. 7). Our aim was to deter\u00ad subsequently reacted with [Re(CO)5Cl] to obtain the corresponding\nmine whether our novel quinoline and coumarin rhenium(I) tricarbonyl rhenium(I) tricarbonyl complexes 5aRe\u20135eRe and 6aRe\u2013 6dRe.\ncomplexes behave as ROS generators in tumor cells. The results of the antiproliferative evaluations showed that Re(I)\n As can be seen in Fig. 7a, complexes 5eRe and 6dRe slightly, but not coordination of quinoline and coumarin ligands enhanced the activity of\nsignificantly, increased the production of total ROS, while compounds these complexes up to 18-fold compared to the corresponding ligands\n5e and 6d slightly decreased the production of total ROS compared to alone. Notably, quinoline complexes 5aRe\u20135eRe were more active than\nROS production in untreated HuT78 cells. Results obtained in this study coumarin complexes 6aRe\u20136dRe, showing pronounced activity against\non the novel quinoline and coumarin rhenium(I) tricarbonyl complexes T-cell lymphoma (HuT78). Among the quinoline rhenium-complexes, 6-\nare in agreement with the results of the studies by Enslin et al. [83] and methoxy-2-(trifluoromethyl)quinoline complex 5eRe showed the best\nKnopf et al. [95]. Since the formation of superoxide radicals is a growth-inhibition effect on HuT78 cells (IC50 = 9.4 \u03bcM) with a selec\u00ad\nconsequence of the incomplete redox reaction of oxygen molecules or tivity index of 5.8. Within the group of coumarin rhenium(I) tricarbonyl\nduring the production of adenosine triphosphate, we measured them complexes, 6dRe showed the most significant effect on the growth of\nseparately. Compounds 5e, 6d and 5eRe slightly decreased the synthesis HuT78 cells with an IC50 of 2.4 \u03bcM and a selectivity index of 8.7.\nof superoxide anions, while compound 6dRe increased their concentra\u00ad Ligands 5e and 6d and their complexes 5eRe, and 6dRe were found to\ntion by about 20 % compared to non-treated (control) cells (Fig. 7b). arrest the cell cycle of HuT78 cells, causing a significant accumulation of\nAlthough an increase in superoxide and other reactive oxygen species cells in the G0/G1 phase and a marked decrease in the number of cells in\nwas expected when tumor cell lines were treated with antitumor agents, the G2/M phase. The rhenium(I) tricarbonyl complexes slightly\na reduction in their levels may mean that the pathway for ROS pro\u00ad increased ROS production and significantly reduced mitochondrial\nduction in the cells is inhibited and the processes necessary for cell membrane potential by 50 % (5eRe) and by 45 % (6dRe) compared to\nsurvival are disrupted. untreated cells and cells treated with 5e and 6d. These results suggest\n The overproduction of ROS in the mitochondria occurs in tumor cells that the cytotoxic effects of these compounds are mediated, at least in\ndue to an increased metabolic rate, a gene mutation and relative hyp\u00ad part, by their effects on mitochondrial membrane potential and the\noxia. Cytotoxic compounds often reduce mitochondrial membrane po\u00ad subsequent slight increase in ROS production. Further chemical and\ntential [96,97]. A decrease in mitochondrial membrane potential can pharmacological optimization is warranted to obtain structurally related\nincrease ROS production and trigger treated cell death [97,98]. As quinoline- and coumarin-based lead compounds as pronounced and\nshown in Fig. 7c, compounds 5e and 6d showed no significant effect on selective agents for T-cell lymphoma.\nmitochondrial membrane potential. Their rhenium(I) tricarbonyl com\u00ad\nplexes reduced the mitochondrial membrane potential by 50 % (5eRe) CRediT authorship contribution statement\nand by 45 % (6dRe) compared to untreated cells and compared to cells\ntreated with 5e and 6d, respectively. Investigation of the stability of Martina Pis\u030ckor: Writing \u2013 original draft, Formal analysis. Ivan\n5eRe and 6dRe in aqueous solution indicated the formation of an aquated C\u0301oric\u0301: Investigation. Berislav Peric\u0301: Writing \u2013 original draft, Formal\n\n\n\n\nFig. 7. Evaluation of changes in: a) ROS production; b) superoxide production and c) mitohondrial membrane potential after exposure of HuT78 cells to 5e, 6d (50\n\u03bcM), 5eRe (10 \u03bcM) and 6dRe (2 \u03bcM) for 24 h. Data are presented as mean and standard deviation of three independent measurements in triplicate. A statistically\nsignificant p value is defined as p < 0.05 (*, #).\n\n 11\n\fM. Pis\u030ckor et al. Journal of Inorganic Biochemistry 262 (2025) 112770\n\n\nanalysis. Katarina Mis\u030ckovic\u0301 S\u030cpoljaric\u0301: Investigation. Srec\u0301ko I. Kirin: [16] F. Hersi, H.A. Omar, R.A. Al-Qawasmeh, Z. Ahmad, A.M. Jaber, D.M. Zaher, T.\n H. Al-Tel, Design and synthesis of new energy restriction mimetic agents: potent\nWriting \u2013 original draft. Ljubica Glavas\u030c-Obrovac: Writing \u2013 original\n anti-tumor activities of hybrid motifs of aminothiazoles and coumarins, Sci. Rep.\ndraft. 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