Polypyridyl coordinated rhenium(I) tricarbonyl complexes as model devices for cancer diagnosis and treatment

{"full_text": " Polyhedron 228 (2022) 116178\n\n\n Contents lists available at ScienceDirect\n\n\n Polyhedron\n journal homepage: www.elsevier.com/locate/poly\n\n\n\n\nPolypyridyl coordinated rhenium(I) tricarbonyl complexes as model\ndevices for cancer diagnosis and treatment\nLehlohonolo Moherane a, Orbett T. Alexander b, Marietjie Schutte-Smith b, Robin E. Kroon c,\nPenny P. Mokolokolo b, Supratim Biswas d, Sharon Prince d, Hendrik G. Visser b, Amanda-Lee\nE. Manicum a, *\na\n Department of Chemistry, Tshwane University of Technology, PO Box X680, Pretoria 0001, South Africa\nb\n Department of Chemistry, University of the Free State, PO Box 339, Bloemfontein 9300, South Africa\nc\n Department of Physics, University of the Free State, PO Box 339, Bloemfontein 9300, South Africa\nd\n Department of Human Biology, University of Cape Town, Anzio Road Observatory, 7925 Cape Town, South Africa\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: This study reports on the solid-state structures, solution-state photoluminescence and in vitro biological appli\u00ad\nRhenium(I) tricarbonyl cations of fac-[Re(CO)3(N,N\u2032 -Bid)(X)]n where N,N\u2032 -Bid = 4,4\u2032 -dimethyl-2,2\u2032 -bipyridine, 5,5\u2032 -dimethyl-2,2\u2032 -\nN,N\u2032 -bidentate bipyridine and 4,4\u2032 -dimethoxy-2,2\u2032 -bipyridine; X = triphenylphosphine, dicyclohexylphenylphosphine, cyclo\u00ad\nPhosphines\n hexyldiphenylphosphine, 1,3,5 triaza-7-phosphaadamantane, OH2 and Br, and n = 0, +1. All the synthesised\nPhotoluminescence\nCytotoxicity\n complexes (1\u201318) were spectroscopically characterized using infrared, nuclear magnetic resonance (1H, 13C and\n 31\n P) and ultraviolet/visible techniques, and single crystal X-ray diffraction. An increasing trend was noted in the\n IR CO stretching frequencies, fac-[Re(CO)3(N,N\u2032 -Bid)(Br)] > fac-[Re(CO)3(N,N\u2032 -Bid)(H2O)]+ > fac-[Re(CO)3(N,\n N\u2032 -Bid)(P)]+. The study reports three new crystal structures: fac-[Re(CO)3(5,5\u2032 -DiMBpy)(NO3)] (2a), fac-[Re\n (CO)3(4,4\u2032 -DiMoxBpy)(NO3)][(CH3)2CO] (3a) and fac-[Re(CO)3(4,4\u2032 -DiMBpy)(Br)] (4). The ligand bite angles\n (N-Re-N) are 74.8(2)\u25e6 for 2a, 74.57(13)\u25e6 for 3a and 74.80(2)\u25e6 for 4. All eighteen complexes displayed excellent\n luminescent properties, with an emission range between 505 and 609 nm, and the most significant Stokes shift of\n 270 nm is noted for 3. In vitro biological screening against breast cancers revealed two viable complexes, fac-[Re\n (CO)3(4,4\u2032 -DiMoxBpy)(Br)] (6) with IC50 = 10.92 \u00b1 2.3 \u00b5M against MDA-MB-231 cells (SI = 1.49) and IC50 =\n 16.25 \u00b1 1.9 \u00b5M against MRC-5 cells; fac-[Re(CO)3(5,5\u2032 -DiMBpy)(CyPh2P]+ (13) with IC50 = 5.74 \u00b1 2.5 \u00b5M\n against MCF-7 cells (SI = 2.62) and IC50 = 15.04 \u00b1 2.6 \u00b5M against MRC-5 cells.\n\n\n\n\n1. Introduction applied. For example, polypyridyl complexes involving metals such as\n Re [7\u20139] and Ru [10,11] have shown practical applications in molecular\n Photodynamic therapy (PDT) and molecular imaging (MI) have imaging, with Ir [12,13] showing practical applications in cellular im\u00ad\ndisplayed potential as effective complementary or alternative cancer aging studies. This is, therefore, the justification behind this study, in\ndiagnostic and treatment methods [1\u20133], following Raab\u2019s work on the which polypyridyl ligands are coordinated to the Re(I) tricarbonyl metal\neffects of visible light and acridine dye [4]. The PDT process begins with core, because previous studies indicated the rich photophysical and\nadministering a photosensitizer (PS); this is usually a photoactivatable biochemical properties of these complexes as possible agents for PDT\nmolecule that can be activated by irradiation with light at a specific [14,15]. Furthermore, as potential MI probes, Re(I) complexes have\nwavelength. There are, however, weaknesses that exist with the current displayed optimal polarized emission, increased photostability, large\nPS molecules for PDT due to insolubility issues and conglomeration Stokes shifts, excellent biocompatibility and cytotoxic potential towards\nwithin physiological environments [5,6], which indicates the need for cancer cells [16\u201319].\nnew PDT agents. Molecular imaging, on the other hand, involves the Therefore, this work was aimed at investigating the solution state\nimaging of molecules with medical significance within living organisms luminescence and biological applications of polypyridyl coordinated Re\nand it is a critical area in which late-transition metal complexes can be (I) complexes for cancer therapy. Different functionalized 2,2\u2032 -\n\n\n * Corresponding author.\n E-mail address: ManicumAE@tut.ac.za (A.-L.E. Manicum).\n\nhttps://doi.org/10.1016/j.poly.2022.116178\nReceived 26 July 2022; Accepted 11 October 2022\nAvailable online 21 October 2022\n0277-5387/\u00a9 2022 Elsevier Ltd. All rights reserved.\n\fL. Moherane et al. Polyhedron 228 (2022) 116178\n\n\nbipyridine N,N\u2032 -donor bidentate ligands were used, namely 5,5\u2032 - (tetramethylsilane) as the internal standard for 1H NMR and phosphoric\ndimethyl-2,2\u2032 -bipyridine (5,5\u2032 -DiMBpy), 4,4\u2032 -dimethyl-2,2\u2032 -bipyridine acid as an external reference for 31P NMR. Coupling constants, J, are\n(4,4\u2032 -DiMBpy) and 4,4\u2032 -dimethoxy-2,2\u2032 -bipyridine (4,4\u2032 -DiMoxBpy). reported in Hertz (Hz). For the in vitro biological study, the complexes\nThe monodentate ligands used were four P-donor ligands, triphenyl\u00ad were soluble in DMSO after heating and no precipitates were observed in\nphosphine (PPh3), dicyclohexylphenylphosphine (Cy2PhP), cyclo\u00ad the cell medium after adding them to the cells. Furthermore, for the\nhexyldiphenylphosphine (CyPh2P) and 1,3,5 triaza-7- stability determination of complexes 1\u201318 in DMSO, their solution UV/\nphosphaadamantane (PTA). The crystallographic study and photo\u00ad Vis spectra were regularly recorded over several days.\nluminescence investigations provided insight into the synthesized\ncomplexes\u2019 solid-state molecular structures and MI potential. The in vitro\nbiological study shed light on applying three synthesized complexes to 2.2. Synthesis of the complexes\nfemale-related cancers, i.e. triple negative MDA-MB-231 and MCF-7\nbreast cancers. The synthesis of the starting synthon, fac-[NEt4]2[Re(CO)3(Br)3],\n was strictly performed under Schlenk conditions. The reported com\u00ad\n2. Experimental plexes were synthesized according to published procedures [22,23], and\n Scheme 1 summarizes the synthetic routes.\n2.1. Materials and methods fac-[NEt4]2[Re(CO)3(Br)3] (251 mg, 0.325 mmol) was stirred in 15\n ml of water at pH 2.2 for 30 min until it dissolved. Next, AgNO3 (163 mg,\n All the chemicals used for the synthesis and characterization were 0.962 mmol) was added to the solution and stirred for 24 h at room\nreagent grade and used without further purification. Chemicals were temperature. The formed precipitate, AgBr (183 mg, 0.975 mmol), was\npurchased from Sigma-Aldrich, South Africa unless stated otherwise. All filtered off and weighed. This was followed by adding the respective\nsolvents used were purified and dried by following the procedure pre\u00ad polypyridyl ligands 4,4\u2032 -dimethyl-2,2-bipyridyl (120 mg, 0.649 mmol),\nscribed by Perrin et al. (1966) for dry conditions [20]. Schlenk line 5,5\u2032 -dimethyl-2,2-bipyridyl (119 mg, 0.648 mmol) and 4,4\u2032 -dimethoxy-\nmethods were used for all reactions that were either moisture or air 2,2-bipyridyl (112 mg, 0.519 mmol) to the filtrate and stirring for 36 h at\nsensitive. Rhenium pentacarbonyl bromide was bought from Strem room temperature. The light-yellow precipitates (product) that formed\nChemicals, Newburyport (USA). The precursor, fac-[NEt4]2[Re were filtered off, dried, recrystallized and weighed to yield complexes\n(CO)3(Br)3], used for the aqua complexes, was synthesized according to 1\u20133, 2a and 3a.\nthe procedure provided by Roger Alberto et al. (1994) [21]. All the li\u00ad The bromide coordinated complexes (4\u20136) were synthesised as fol\u00ad\ngands were bought from Sigma-Aldrich and will be abbreviated. Nitric lows: fac-[NEt4]2[Re(CO)3(Br)3] (~200 mg, 0.260 mmol) was dissolved\nacid (HNO3) was used to adjust the pH during the synthesis of the aqua in water (20 ml) and respectively added to 4,4\u2032 -dimethyl-2,2\u2032 -bipyridine\ncomplexes. The UV/Vis analysis was performed on a Varian Cary 50 (96 mg, 0.518 mmol), 5,5\u2032 -dimethyl-2,2\u2032 -bipyridine (95 mg, 0.518\nConc UV/Visible spectrophotometer equipped with a Julabo F12mV mmol) and 4,4\u2032 -dimethoxy-2.2-bipyridyl dissolved in ethanol (6 ml).\ntemperature cell regulator (accurate to within 0.1 \u25e6 C) in a 1.000 \u00b1 The solution was stirred for 48 h, then the solvent was filtered off. The\n0.001 cm quartz cuvette cell. The infrared spectra of the complexes were yellow solid obtained was washed with water, cold ethanol and petro\u00ad\nrecorded on a Bruker Tensor 27 Standard System spectrophotometer leum ether, then allowed to air-dry. 7, 11 and 15 were synthesized by\nwith a laser range of 4000\u2013370 cm\u2212 1, which was coupled to a computer. respectively dissolving 1 (25 mg; 0.0528 mmol), 2 (26 mg; 0.0555\nThe IR spectrometer was equipped with a temperature cell regulator, mmol) and 3 (31 mg; 0.0603 mmol) in methanol (10 ml) and adding\naccurate to within 0.3 \u25e6 C. KBr pellets were used for solid samples. All PPh3 (14 mg; 0.0545 mmol) dissolved in methanol (5 ml). The solution\nNuclear Magnetic Resonance (NMR) spectra were recorded on a Bruker was stirred at 80 \u25e6 C for 48 h and the dark brown solution obtained was\n300 MHz NMR spectrometer operating at 300 MHz, using deuterated concentrated by evaporation of the solvent. The precipitate obtained\nsolvents or samples spiked with deuterated solvent. All the chemical from solvent evaporation was washed with methanol to dissolve the\nshifts, \u03b4, are reported in ppm (part per million) using TMS excess PPh3. The product was dried and weighed. 8, 12 and 16 were\n separately synthesized by dissolving 1 (25 mg; 0.053 mmol), 2 (25 mg;\n\n\n\n\n Scheme 1. A schematic presentation of the synthetic approach for complexes 1\u201318.\n\n 2\n\fL. Moherane et al. Polyhedron 228 (2022) 116178\n\n\n0.053 mmol) and 3 (50 mg; 0.099 mmol) in methanol (10 ml) and 33.52; H, 2.81; N, 5.21; Found: C, 33.49; H, 2.79; N, 5.23 %.\nadding one equivalent of PTA dissolved in methanol. The solution was fac-[Re(CO)3(4,4\u2032 -DiMoxBpy)(Br)] (6). Yield: 70 mg, 62.85 %; 1H\nstirred at 80 \u25e6 C for 48 h and the yellow solution that was obtained was NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.87\u20138.84 (dd, J = 5 Hz, J = 6 Hz, 2H,\nconcentrated by evaporation of the solvent. The precipitate obtained H6/6\u2032 ), 7.57\u20137.56 (d, J = 2 Hz, 2H, H3/3\u2032 ), 7.02\u20136.99 (m, 2H, H5/5\u2032 ),\nfrom solvent evaporation was washed with methanol to dissolve the 4.04 (s, 6H, 4,4\u2032 -2xOCH3); 13C NMR (151 MHz, CDCl3), \u03b4 (ppm): 167.5,\nexcess PTA and the product was dried and weighed. 9, 13 and 17 were 157.2, 154.6, 154.4, 112.1, 110.3, 56.5; IR (KBr, cm\u2212 1), vCO : 2021,\nsynthesized by dissolving 1 (25 mg; 0.053 mmol), 2 (25 mg; 0.053 1876; UV/Vis, \u03bbmax, nm (\u03b5, M\u2212 1 cm\u2212 1): 365 (4720); Anal. Calc. for\nmmol) and 3 (30 mg; 0.059 mmol) in methanol and adding CyPh2P (14 C15H15BrN2O5Re: C, 31.64; H, 2.66; N, 4.92; Found: C, 31.60; H, 2.64; N,\nmg; 0.054 mmol) dissolved in methanol (5 ml). The solution was stirred 4.90 %.\nat 80 \u25e6 C for 48 h and the dark orange solution was concentrated by fac-[Re(CO)3(4,4\u2032 -DiMBpy)(PPh3)][NO3] (7). Yield: 30 mg, 81.35 %;\n 1\nevaporation of the solvent. The precipitate obtained from solvent H NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.96\u20138.94 (d, J = 8 Hz, 2H, H6/6\u2032 ),\nevaporation was washed with methanol to dissolve the excess CyPh2P. 7.99 (s, 2H, H3/3\u2032 ), 7.72\u20137.66 (m, 6H, -PPh3), 7.59\u20137.55 (t, J = 7 Hz,\n10, 14 and 18 were synthesized by dissolving 1 (25 mg; 0.053 mmol), 2 3H, -PPh3), 7.51\u20137.46 (ddd, J = 3 Hz, J = 3 Hz, J = 2.8 Hz, 6H, -PPh3),\n(50 mg; 0.087 mmol) and 3 (31 mg; 0.060 mmol) in methanol (10 ml) 7.39\u20137.37 (d, J = 5 Hz, 2H, H5/5\u2032 ), 2.60 (s, 6H, 4,4\u2032 -2xCH3); 13C NMR\nand one equivalent of Cy2PhP (15 mg; 0.0530 mmol) dissolved in (151 MHz, CDCl3), \u03b4 (ppm): 155.7, 153.5, 152.6, 152.2, 132.7, 132.2,\nmethanol was added. The solution was stirred at 80 \u25e6 C for 48 h and the 132.1, 132.0, 128.6, 128.5, 128.2, 123.9, 22.0, 21.8; 31P NMR (400\ndark orange solution was concentrated by evaporation of the solvent. MHz, CDCl3), \u03b4 (ppm): 29.1; IR (KBr, cm\u2212 1), vCO : 2025, 1909, UV/Vis,\nThe precipitate obtained from solvent evaporation was washed with \u03bbmax, nm (\u03b5, M\u2212 1 cm\u2212 1): 347 (3860); Anal. Calc. for C33H30N3O6Re: C,\nmethanol to dissolve the excess Cy2PhP. The product was dried and 50.70; H, 3.87; N, 5.37; Found: C, 50.69; H, 3.85; N, 5.35 %.\nweighed. fac-[Re(CO)3(4,4\u2032 -DiMBpy)(PTA)][NO3] (8). Yield: 25 mg, 78.01 %;\n 1\n fac-[Re(CO)3(4,4\u2032 -DiMBpy)(H2O)][NO3] (1). Yield: 120 mg, 77.88 H NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.78\u20138.76 (d, J = 8 Hz, 2H, H6/6\u2032 ),\n 1\n%; H NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.93\u20138.91 (d, J = 6 Hz, H6/6\u2032 ), 8.68 (s, 2H, H3/3\u2032 ), 8.12 (d, J = 8 Hz, 2H, H5/5\u2032 ), 4.45 (s, 6H, -PTA),\n8.00 (s, 2H, H3/3\u2032 ), 7.35\u20137.34 (d, J = 6 Hz, 2H, H5/5\u2032 ), 2.61 (s, 6H, 4,4\u2032 - 3.83 (s, 6H, -PTA), 2.56 (s, 6H, 4,4\u2032 -2xCH3); 13C NMR (151 MHz, CDCl3),\n2xCH3); 13C NMR (151 MHz, CD2Cl2), \u03b4 (ppm): 155.5, 153.2, 153.7, \u03b4 (ppm): 193.0, 187.4,155.5, 154.2, 152.22, 129.2, 127.3, 73.6, 73.5,\n128.1, 123.9, 21.5; IR (KBr, cm\u2212 1), vCO : 2023, 1914, 1868; UV/Vis, \u03bbmax, 72.8, 72.7, 56.3, 55.9, 50.5, 50.3, 49.7, 49.6, 21.9; 31P NMR (400 MHz,\nnm (\u03b5, M\u2212 1 cm\u2212 1): 360 (3680); Anal. Calc. for C15H17N3O7Re: C, 33.52; CDCl3), \u03b4 (ppm): \u2212 79.3; IR (KBr, cm\u2212 1), vCO : 2029, 1914; UV/Vis, \u03bbmax,\nH, 3.19; N, 7.82; Found: C, 33.50; H, 3.21; N, 7.77 %. nm (\u03b5, M\u2212 1 cm\u2212 1): 361 (2810); Anal. Calc. for C21H27N6O6PRe: C, 37.28;\n fac-[Re(CO)3(5,5\u2032 -DiMBpy)(H2O)][NO3] (2) and (2a). From the H, 4.02; N, 12.42; Found: C, 37.25; H, 4.00; N, 12.40 %.\nfiltrate of 2, crystals suitable for single-crystal X-ray diffraction char\u00ad fac-[Re(CO)3(4,4\u2032 -DiMBpy)(CyPh2P)][NO3] (9). Yield: 30 mg, 77.83\n 1\nacterization were obtained and collected. The molecular structure of fac- %; H NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.96\u20138.95 (d, J = 6 Hz, 2H, H6/\n[Re(CO)3(5,5\u2032 -DiMBpy)(NO3)] (2a) was confirmed with XRD and the 6\u2032 ), 7.99 (s, 2H, H3/3\u2032 ), 7.54\u20137.469 (m, 10H, -Ph2P), 7.39\u20137.37 (dd, J =\ndata is reported in the crystallography section. Yield: 128 mg, 82.82 %; 1 Hz, J = 6 Hz, 2H, H5/5\u2032 ), 2.60 (s, 6H, 4,4\u2032 -2xCH3), 2.30\u20132.19 (m, 1H,\n1\n H NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.92 (s, 2H, H6/6\u2032 ), 8.11\u20138.09 (d, J -CyP), 1.83\u20131.73 (m, 5H, -CyP), 1.34\u20131.24 (m, 5H, -CyP); 13C NMR (151\n= 8 Hz, 2H, H3/3\u2032 ), 7.97\u20137.95 (dd, J = 2 Hz, J = 8 Hz, 2H, H4/4\u2032 ), 2.55 MHz, CDCl3), \u03b4 (ppm): 196.7, 193.6, 155.7, 155.5, 153.5, 152.6, 152.2,\n(s, 6H, 5,5\u2032 -2xCH3); 13C NMR (151 MHz, CD2Cl2), \u03b4 (ppm): 186.7, 153.8, 151.3, 131.1, 131.1, 128.6, 128.5, 124.1, 37.5, 37.0, 29.7, 29.3, 26.4,\n140.4, 138.3, 122.3, 18.3; IR (KBr, cm\u2212 1), vCO : 2017, 1888; UV/Vis, 26.4, 25.8, 24.8, 24.8, 22.1, 21.9; 31P NMR (400 MHz, CDCl3), \u03b4 (ppm):\n\u03bbmax, nm (\u03b5, M\u2212 1 cm\u2212 1): 355 (3235); Anal. Calc. for C15H17N3O7Re: C, 34.3; IR (KBr, cm\u2212 1), vCO : 2022, 1981; UV/Vis, \u03bbmax, nm (\u03b5, M\u2212 1 cm\u2212 1):\n33.52; H, 3.19; N, 7.82; Found: C, 33.48; H, 3.16; N, 7.79 %. 355 (4572); Anal. Calc. for C33H36N3O6PRe: C, 50.31; H, 4.61; N, 5.33;\n fac-[Re(CO)3(4,4\u2032 -DiMoxBpy)(H2O)][NO3] (3) and (3a). From the Found: C, 50.28; H, 4.59; N, 5.31 %.\nfiltrate of 3, crystals suitable for single-crystal X-ray diffraction char\u00ad fac-[Re(CO)3(4,4\u2032 -DiMBpy)(Cy2PhP)][NO3] (10). Yield: 31 mg,\nacterization were obtained and collected. The molecular structure of fac- 80.75 %; 1H NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.96\u20138.94 (d, J = 6 Hz,\n[Re(CO)3(4,4\u2032 -DiMoxBpy)(NO3)][(CH3)2CO] (3a) was confirmed with 2H, H6/6\u2032 ), 7.99 (s 2H, H3/3\u2032 ), 7.69\u20137.64 (m, 3H, -PhP), 7.57\u20137.52 (m,\nXRD and the data is reported in the crystallography section. Yield: 189 2H, -PhP), 7.39\u20137.37 (dd, J = 1 Hz, J = 6 Hz, 2H, H5/5\u2032 ), 2.60 (s, 6H,\nmg, 71.80 %; 1H NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.99\u20138.88 (d, J = 6 4,4\u2032 -2xCH3), 2.19\u20132.12 (m, 2H, -Cy2P), 1.86\u20131.64 (m, 10H, -Cy2P),\nHz, 2H, H6/6\u2032 ), 7.56\u20137.55 (d, J = 3 Hz, 2H, H3/3\u2032 ), 7.02\u20136.99 (dd, J = 3 1.38\u20131.15 (m, 10H, -Cy2P); 13C NMR (151 MHz, CDCl3), \u03b4 (ppm): 152.6,\nHz, J = 6 Hz, 2H, H5/5\u2032 ), 4.04 (s, 6H, 4,4\u2032 -2xOCH3); 13C NMR (151 MHz, 151.3, 131.6, 131.5, 131.4, 128.5, 128.4, 128.2, 128.0, 124.1, 35.2,\nCDCl3), \u03b4 (ppm): 162.4, 156.4, 125.4, 124.8, 105.7, 104.4, 59.4; IR (KBr, 34.5, 26.5, 26.3, 26.2, 25.8, 25.4, 24.5, 21.9; 31P NMR (400 MHz,\ncm\u2212 1), vCO : 2024, 1886; UV/Vis, \u03bbmax, nm (\u03b5, M\u2212 1 cm\u2212 1): 350 (3995); CDCl3), \u03b4 (ppm): 60.5; IR (KBr, cm\u2212 1), vCO : 2026, 1900; UV/Vis, \u03bbmax,\nAnal. Calc. for C15H17N3O9Re: C, 31.63; H, 3.01; N, 7.38; Found: C, nm (\u03b5, M\u2212 1 cm\u2212 1): 354 (4147); Anal. Calc. for C33H42N3O6PRe: C, 49.93;\n31.60; H, 2.99; N, 7.36 %. H, 3.21; N, 5.29; Found: C, 49.96; H, 5.30; N, 5.27 %.\n fac-[Re(CO)3(4,4\u2032 -DiMBpy)(Br)] (4). The precipitate was recrystal\u00ad fac-[Re(CO)3(5,5\u2032 -DiMBpy)(PPh3)][NO3] (11). Yield: 31 mg, 83.33\nlized from hexane and dichloromethane in a 1:1 ratio to yield 4 and this %; 1H NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.93\u20138.91 (d, J = 7 Hz, 2H, H6/\nwas confirmed with single-crystal X-ray diffraction. Yield: 112 mg, 6\u2032 ), 7.99 (s, 2H, H3/3\u2032 ), 7.72\u20137.66 (m, 6H, -PPh3), 7.59\u20137.55 (t, J = 7\n79.91 %; 1H NMR (300 MHz, CDCl3), \u03b4 (ppm): 8.92\u20138.90 (d, J = 6 Hz, Hz, 3H, -PPh3), 7.51\u20137.46 (ddd, J = 3 Hz, J = 3 Hz, J = 3 Hz, 6H, -PPh3),\n2H, H6/6\u2032 ), 7.99 (s, 2H, H3/3\u2032 ), 7.35\u20137.33 (d, J = 4 Hz, 2H, H5/5\u2032 ), 2.60 7.40\u20137.40 (d, J = 5 Hz, 2H, H4/4\u2032 ), 2.19 (s, 6H, 5,5\u2032 -2xCH3); 13C NMR\n(s, 6H, 4,4\u2032 -2xCH3); 13C NMR (151 MHz, CD2Cl2), \u03b4 (ppm): 155.3, 152.5, (151 MHz, CDCl3), \u03b4 (ppm): 153.2, 152.3, 139.5, 137.7, 132.9, 132.8,\n151.7, 148.8, 127.9, 123.9, 21.4; IR (KBr, cm\u2212 1), vCO : 2013, 1881, 1864; 132.8, 131.8, 130.9, 129.4, 129.3, 122.3, 18.7, 18.6; 31P NMR (400\nUV/Vis, \u03bbmax, nm (\u03b5, M\u2212 1 cm\u2212 1): 380 (3685); Anal. Calc. for MHz, CDCl3), \u03b4 (ppm): 29.1; IR (KBr, cm\u2212 1), vCO : 2022, 1902; UV/Vis,\nC15H15BrN2O3Re: C, 33.52; H, 2.81; N, 5.21; Found: C, 33.51; H, 2.83; N, \u03bbmax, nm (\u03b5, M\u2212 1 cm\u2212 1): 350 (3873); Anal. Calc. for C33H30N3O6PRe: C,\n5.19 %. 50.70; H, 3.87; N, 5.37; Found: C, 50.68; H, 3.88; N, 5.39 %.\n fac-[Re(CO)3(5,5\u2032 -DiMBpy)(Br)] (5). Yield: 101 mg, 72.01 %; 1H fac-[Re(CO)3(5,5\u2032 -DiMBpy)(PTA)][NO3] (12). Yield: 25 mg, 77.21\nNMR (300 MHz, CDCl3), \u03b4 (ppm): 8.88 (s, 2H, H6/6\u2032 ), 8.05\u20138.02 (d, J = %; 1H NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.82 (s, 2H, H6/6\u2032 ), 8.71\u20138.69\n8 Hz, 2H, H3/3\u2032 ), 7.86\u20137.82 (dd, J = 2 Hz, J = 8 Hz, 2H, H4/4\u2032 ), 2.52 (s, (d, J = 6 Hz, 2H, H3/3\u2032 ), 7.44\u20137.42 (d, J = 6 Hz, 2H, H4/4\u2032 ), 4.48\u20134.39\n6H, 5,5\u2032 -2xCH3); 13C NMR (151 MHz, CD2Cl2), \u03b4 (ppm): 153.1, 139.6, (q, J = 11 Hz, 6H, -PTA), 3.81 (s, 6H, -PTA), 2.73 (s, 6H, 5,5\u2032 -2xCH3); 13C\n137.8, 122.3, 18.3; IR (KBr, cm\u2212 1), vCO : 2018, 1934, 1897; UV/Vis, \u03bbmax, NMR (151 MHz, CDCl3), \u03b4 (ppm): 153.8, 153.6, 152.2, 149.5, 141.6,\nnm (\u03b5, M\u2212 1 cm\u2212 1): 375 (2925); Anal. Calc. for C15H15BrN2O3Re: C, 138.9, 137.4, 133.0, 125.5, 120.3, 73.6, 73.6, 72.5, 72.4, 56.3, 55.8,\n\n 3\n\fL. Moherane et al. Polyhedron 228 (2022) 116178\n\n\n50.6, 50.4, 49.6, 49.4, 18.6, 18.3; 31P NMR (400 MHz, CDCl3), \u03b4 (ppm): 128.3, 128.2, 111.1, 106.2, 55.3, 35.5, 34.8, 26.4, 25.9, 25.8; 31P NMR\n\u2212 79.3; IR (KBr, cm\u2212 1), vCO : 2020, 1905; UV/Vis, \u03bbmax, nm (\u03b5, M\u2212 1 cm\u2212 1): (400 MHz, CDCl3), \u03b4 (ppm): 59.8; IR (KBr, cm\u2212 1), vCO : 2023, 1897; UV/\n355 (2874); Anal. Calc. for C21H27N6O6PRe: C, 37.28; H, 4.02; N, 12.42; Vis, \u03bbmax, nm (\u03b5, M\u2212 1 cm\u2212 1): 357 (3777); Anal. Calc. for C33H42N3O8PRe:\nFound: C, 37.29; H, 3.99; N, 12.44 %. C, 47.99; H, 5.13; N, 5.09; Found: C, 48.00; H, 5.10; N, 5.07 %.\n fac-[Re(CO)3(5,5\u2032 -DiMBpy)(CyPh2P)][NO3] (13). Yield: 31 mg,\n79.66 %; 1H NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.50\u20138.49 (dd, J = 1 Hz, 2.3. Single-crystal X-ray crystallography\nJ = 2 Hz, 2H, H6/6\u2032 ), 8.26\u20138.24 (d, H = 8 Hz, 2H, H3/3\u2032 ), 7.63\u20137.60 (dd,\nJ = 2 Hz, J = 8 Hz, 2H, H4/4\u2032 ), 7.49\u20137.47 (m, 5H, -Ph2P), 7.33\u20137.32 (m, The crystal structure data of 2a, 3a and 4 were collected on a Bruker\n5H, -Ph2P), 2.39 (s, 6H, 5,5\u2032 -2xCH3), 2.26\u20132.18 (m, 1H, -CyP), D8 Quest Eco Chi Photon II CPAD diffractometer. All the cell re\u00ad\n1.97\u20131.55 (m, 10H, -CyP); 13C NMR (151 MHz, CDCl3), \u03b4 (ppm): 153.8, finements and data reduction were completed using SAINT-Plus and\n153.1, 153.0,149.5, 141.2, 139.6, 137.4, 133.7, 131.5, 131.1, 131.0, XPREP [24]. To correct the absorption effects, the multi-scan technique\n128.8, 128.6, 128.6, 128.5, 128.3,128.2, 125.7, 125.6, 125.3, 120.3, and software package SADABS [31] were used. All the crystal structures\n37.5, 29.7, 29.5, 24.8, 24.8, 18.6, 18.5, 18.3; 31P NMR (400 MHz, were solved using the direct method package SIR-97 [25] and refined by\nCDCl3), \u03b4 (ppm): 34.5; IR (KBr, cm\u2212 1), vCO : 2022, 1899; UV/Vis, \u03bbmax, using WinGX [26] and SHELXL-97 [27]. The crystal structures\u2019 graph\u00ad\nnm (\u03b5, M\u2212 1 cm\u2212 1): 356 (3884); Anal. Calc. for C33H36N3O6PRe: C, 50.31; ical representation was obtained with the program DIAMOND [28]. The\nH, 4.61; N, 5.33; Found: C, 50.30; H, 4.63; N, 5.30 %. structures are shown with thermal ellipsoids drawn at the 50 % proba\u00ad\n fac-[Re(CO)3(5,5\u2032 -DiMBpy)(Cy2PhP)][NO3] (14). Yield: 50 mg, bility level, unless otherwise stated. A summary of the general crystal\n78.95 %; 1H NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.51\u20138.50 (dd, J = 1 Hz, data and refinement parameters for complexes 2a, 3a and 4 are given in\nJ = 2 Hz, 2H, H6/6\u2032 ), 8.28\u20138.26 (d, J = 8 Hz, 2H, H3/3\u2032 ), 7.70\u20137.64 (m, Table SI 1 (\u2020ESI).\n2H, H4/4\u2032 ), 7.63\u20137.62 (dd, J = 1 Hz, J = 2 Hz, 5H, -PhP), 2.40 (s, 6H,\n5,5\u2032 -2xCH3), 2.06\u20132.04 (m, 1H, -Cy2P), 1.95\u20131.74 (m, 11H, -Cy2P),\n1.70\u20131.59 (m, 10H, -Cy2P); 13C NMR (151 MHz, CDCl3), \u03b4 (ppm): 153.8, 2.4. UV/Vis absorbance and photoluminescence\n149.5, 137.4, 134.8, 134.6, 133.0, 131.5, 131.4, 128.3, 128.2, 120.3,\n35.5, 34.8, 32.5, 32.4, 30.1, 30.0, 28.8, 28.8, 26.4, 18.3; 31P NMR (400 The UV/Vis absorbance measurement was conducted in a 1 cm\nMHz, CDCl3), \u03b4 (ppm): 51.1; IR (KBr, cm\u2212 1), vCO : 2023, 1901; UV/Vis, tandem quartz cuvette on a Varian Cary 50 Conc. spectrophotometer. All\n\u03bbmax, nm (\u03b5, M\u2212 1 cm\u2212 1): 352 (3915); Anal. Calc. for C33H42N3O6PRe: C,\n49.93; H, 5.33; N, 5.29; Found: C, 49.91; H, 5.31; N, 5.25 %. Table 1\n fac-[Re(CO)3(4,4\u2032 -DiMoxBpy)(PPh3)][NO3] (15). Yield: 34 mg, A summary of the IR stretching frequencies, UV/Vis and 31P NMR data of\n75.89 %; 1H NMR (300 MHz, CDCl3), \u03b4 (ppm): 8.88\u20138.86 (d, J = 6 Hz, complexes 1\u201318.\n2H, H6/6\u2032 ), 8.06\u20138.05 (d, J = 6 Hz, 2H, H3/3\u2032 ), 7.51\u20137.46 (m, 12H, Complex IR (cm\u00a11) UV/Vis \u03b5 (M\u00a11 31\n P (\u03b4,\n-PPh3), 7.41\u20137.39 (m, 3H, -PPh3), 7.02\u20136.99 (dd, J = 3 Hz, J = 3 Hz, 2H, (nm) cm\u00a11) ppm)\n\nH5/5\u2032 ), 4.29 (s, 6H, 4,4\u2032 -2xOCH3); 13C NMR (151 MHz, CDCl3), \u03b4 (ppm): fac-[Re(CO)3(4,4\u2032- 2023, 360 (3 680) \u2013\n168.9, 158.3, 154.4, 152.4, 133.0, 132.9, 132.2, 132.1, 129.3, 129.2, DiMBpy)(H2O)]\u00fe (1) 1914, 1868\n fac-[Re(CO)3(5,5\u2032- 2017, 1888 355 (3 235)\n128.6, 128.5, 116.6, 113.5, 110.7, 58.1; 31P NMR (400 MHz, CDCl3), \u03b4 \u2013\n DiMBpy)(H2O)]\u00fe (2)\n(ppm): 29.1; IR (KBr, cm\u2212 1), vCO : 2027, 1911; UV/Vis, \u03bbmax, nm (\u03b5, M\u2212 1 fac-[Re(CO)3(4,4\u2032- 2021, 1879 350 (4 720) \u2013\ncm\u2212 1): 354 (3964); Anal. Calc. for C33H30N3O8PRe: C, 48.70; H, 3.72; N, DiMoxBpy)(H2O)]\u00fe (3)\n5.16; Found: C, 48.72; H, 3.70; N, 5.14 %. fac-[Re(CO)3(4,4\u2032- 2013, 380 (3 685) \u2013\n fac-[Re(CO)3(4,4\u2032 -DiMoxBpy)(PTA)][NO3] (16). Yield: 50 mg, DiMBpy)(Br)] (4) 1881, 1864\n fac-[Re(CO)3(5,5\u2032- 2018, 375 (2 925)\n78.90 %; 1H NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.49\u20138.47 (d, J = 5 Hz,\n \u2013\n DiMBpy)(Br)] (5) 1934, 1897\n2H, H6/6\u2032 ), 7.99\u20137.98 (d, J = 3 Hz, 2H, H3/3\u2032 ), 6.87\u20136.85 (dd, J = 3 Hz, fac-[Re(CO)3(4,4\u2032- 2024, 1886 365 (3 995) \u2013\nJ = 6 Hz, 2H, H5/5\u2032 ), 4.63 (s, 6H, -PTA), 4.08\u20134.06 (d, J = 10 Hz, 6H, DiMoxBpy)(Br)] (6)\n-PTA), 3.96 (s, 6H, 4,4\u2032 -2xOCH3); 13C NMR (151 MHz, CDCl3), \u03b4 (ppm): fac-[Re(CO)3(4,4\u2032- 2025, 1909 347 (3 860) 29.13\n DiMBpy)(PPh3)]\u00fe (7)\n166.7, 157.9, 150.1, 111.1, 106.2, 73.5, 73.5, 72.4, 72.3, 55.3, 50.4,\n fac-[Re(CO)3(4,4\u2032- 2029, 1914 361 (2 810) \u2212 79.26\n50.2; 31P NMR (400 MHz, CDCl3). \u03b4 (ppm): \u2212 77.8; IR (KBr, cm\u2212 1), vCO : DiMBpy)(PTA)]\u00fe (8)\n2026, 1908; UV/Vis, \u03bbmax, nm (\u03b5, M\u2212 1 cm\u2212 1): 352 (1962); Anal. Calc. for fac-[Re(CO)3(4,4\u2032- 2026, 1900 354 (4 147) 60.64\nC21H27N6O8PRe: C, 35.59; H, 3.84; N, 11.86; Found: C, 35.55; H, 3.82; DiMBpy)(CyPh2P)]\u00fe (9)\nN, 11.84 %. fac-[Re(CO)3(4,4\u2032- 2022, 1981 355 (4 572) 34.26\n DiMBpy)(Cy2PhP)]\u00fe\n fac-[Re(CO)3(4,4\u2032 -DiMoxBpy)(CyPh2P)][NO3] (17). Yield: 34 mg,\n (10)\n75.63 %; 1H NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.91\u20138.89 (d, J = 6 Hz, fac-[Re(CO)3(5,5\u2032- 2022, 1902 350 (3 873) 29.13\n2H, H6/6\u2032 ), 8.18\u20138.17 (d, J = 6 Hz, 2H, H3/3\u2032 ), 7.83\u20137.78 (m, 2H, DiMBpy)(PPh3)]\u00fe (11)\n-Ph2P), 7.51\u20137.48 (m, 7H, -Ph2P), 7.42\u20137.40 (m, 3H, -Ph2P), 7.02\u20137.00 fac-[Re(CO)3(5,5\u2032- 2020, 1905 355 (2 874) \u2212 79.31\n(dd, J = 3 Hz, J = 3 Hz, 2H, H5/5\u2032 ), 4.26 (s, 6H, 4,4\u2032 -2xOCH3), 2.30\u20132.21 DiMBpy)(PTA)]\u00fe (12)\n fac-[Re(CO)3(5,5\u2032- 2022, 1898 352 (3 915) 51.14\n(m, 1H, -CyP), 1.83\u20131.82 (m, 2H, -CyP), 1.73\u20131.71 (m, 8H, -CyP); 13C DiMBpy)(CyPh2P)]\u00fe\nNMR (151 MHz, CDCl3), \u03b4 (ppm): 168.8, 158.2, 152.7, 133.8, 133.7, (13)\n131.7, 131.2, 131.1, 129.5, 129.4, 128.8, 128.6, 116.8, 27.8, 26.4, 26.3, fac-[Re(CO)3(5,5\u2032- 2023, 1901 356 (3 884) 34.53\n25.7, 24.7; 31P NMR (400 MHz, CDCl3), \u03b4 (ppm): 34.3; IR (KBr, cm\u2212 1), DiMBpy)(Cy2PhP)]\u00fe\n (14)\nvCO : 2026, 1905; UV/Vis, \u03bbmax, nm (\u03b5, M\u2212 1 cm\u2212 1): 349 (3596); Anal.\n fac-[Re(CO)3(4,4\u2032- 2027, 1911 354 (3 964) 29.08\nCalc. for C33H36N3O8PRe: C, 48.35; H, 4.43; N, 5.13; Found: C, 48.33; H, DiMoxBpy)(PPh3)]\u00fe\n4.40; N, 5.10 %. (15)\n fac-[Re(CO)3(4,4\u2032 -DiMoxBpy)(Cy2PhP)][NO3] (18). Yield: 35 mg, fac-[Re(CO)3(4,4\u2032- 2026, 1908 352 (1 962) \u2212 77.76\n78.01 %; 1H NMR (400 MHz, CDCl3), \u03b4 (ppm): 8.50\u20138.48 (d, J = 6 Hz, DiMoxBpy)(PTA)]\u00fe (16)\n fac-[Re(CO)3(4,4\u2032- 2023, 1897 349 (3 777) 59.84\n2H, H6/6\u2032 ), 8.02\u20138.01 (d, J = 3 Hz, 2H, H3/3\u2032 ), 7.71\u20137.65 (m, 1H, -PhP), DiMoxBpy)(CyPh2P)]\u00fe\n7.54\u20137.45 (m, 3H, -PhP), 7.35\u20137.33 (m, 1H, -PhP), 6.89\u20136.87 (dd, J = 3 (17)\nHz, J = 6 Hz, 2H, H5/5\u2032 ), 3.97 (s, 6H, 4,4\u2032 -2xOCH3), 2.08\u20132.02 (m, 1H, fac-[Re(CO)3(4,4\u2032- 2026, 1905 357 (3 596) 34.32\n-Cy2P), 1.95\u20131.76 (m, 11H, -Cy2P), 1.69\u20131.60 (m, 10H, -Cy2P); 13C NMR DiMoxBpy)(Cy2PhP)]\u00fe\n (18)\n(151 MHz, CDCl3), \u03b4 (ppm): 166.7, 175.9, 154.0, 150.1, 131.5, 131.4,\n\n 4\n\fL. Moherane et al. Polyhedron 228 (2022) 116178\n\n\nthe UV/Vis data of the complexes are reported in Table 1, with the ligands for the successful synthesis of the fac-[Re(CO)3(H2O)3]+ inter\u00ad\nmaximum wavelength and the absorptivity coefficient; GC-acetone was mediate. Most of the synthesized complexes formed yellow to orange\nused as the solvent. Furthermore, the same samples for UV/Vis ab\u00ad precipitates in moderate to high yields (60\u201385 % yield). The aqua (1\u20133)\nsorption were utilized for the photoluminescence analysis. and bromide coordinated Re(I) complexes (4\u20136) had lower yields\n because some complexes dissolved when the precipitates were washed\n2.5. Photoluminescence studies with cold ethanol. Two moles of the N,N\u2032 -bid ligands were reacted with\n one mole of fac-[NEt4]2[Re(CO)3(Br)3], and an increase in the reflux\n An Edinburgh Instruments FLS980 machine with a 450 W xenon temperature to 50\u02daC was required to increase the yields of 1\u20133 and 4\u20136.\nlamp steady-state excitation source was used to measure the photo\u00ad The aqua complexes (1\u20133) dissolved almost immediately after being\nluminescence emission and excitation spectra. Quantum yields were washed with cold ethanol and afforded crystals of fac-[Re(CO)3(5,5\u2032 -\nthen measured near the maximum excitation wavelength using an DiMBpy)(NO3)] (2a) and fac-[Re(CO)3(4,4\u2032 -DiMoxBpy)(NO3)]\nintegrating sphere accessory by dividing the luminescence output (i.e. [(CH3)2CO] (3a) from the filtrates of 2 and 3, respectively. The pre\u00ad\nintegrated area under the emission curve) by the absorbed light (i.e. cipitates of all the complexes were dried and recrystallized with a sol\u00ad\nintegrated difference of the sample and pure solvent near the excitation vent mixture of hexane:DCM (1:1), which afforded the molecular\nwavelength). A neutral density filter was applied when measuring the structure of fac-[Re(CO)3(4,4\u2032 -DiMBpy)(Br)] (4). What is notable is that\nabsorbed light and compensated for using its measured transmission complexes 2a and 3a were obtained from the somewhat solvent-\ncurve. contaminated filtrates of the mother complexes. Furthermore, the suc\u00ad\n cessful syntheses of complexes 1\u20133 required more effort. The synthesis\n2.6. Biological studies of complexes 7 to 18 was conducted through the substitution of the aqua\n ligand in fac-[Re(CO)3(N,N\u2032 -bid)(H2O)]+ by different monodentate\n2.6.1. Cell culture phosphines (PPh3, PTA, CyPh2P, Cy2PhP) via the \u20182 + 1\u2019 approach. fac-\n The human breast adenocarcinoma MDA-MB-231 (triple-negative) [Re(CO)3(N,N\u2032 -bid)(H2O)]+ was dissolved in methanol at 80 C\u030a before\nand MCF-7 (estrogen receptor-positive) cells were maintained in DMEM the addition of the different monodentate phosphines, then the reaction\n(Highveld Biologicals, Lyndhurst, United Kingdom (UK) and RPMI 1640 mixture was refluxed for 48 h to afford the desired product. Full char\u00ad\n(Highveld Biologicals, Lyndhurst, United Kingdom (UK) respectively, acterization of these complexes was done using IR, NMR and UV/Vis\nsupplemented with 10 % Fetal Bovine Serum (FBS) and 100 U/ml characterization methods.\npenicillin and 100 \u00b5g/ml streptomycin. The MRC-5 human lung fibro\u00ad The Re(I) tricarbonyl complexes reported in this study have a d6\nblasts were cultured in DMEM supplemented with 20 % FBS and 100 U/ configuration and their lowest excited state usually is metal-to-ligand\nml penicillin and 100 \u00b5g/ml streptomycin. When treated with the test charge transfer (MLCT) in character. There is a broad range in the\ncompounds, the MRC-5 cells were cultured in DMEM medium supple\u00ad determined molar absorptivity (\u03b5) observed for complexes 1\u201318, which\nmented with 10 % FBS. All cells were maintained at 37 \u25e6 C in a 5 % differ between 1962 and 4720 M\u2212 1 cm\u2212 1, and compare well with similar\nCO2\u201395 % air-humidified incubator. structures [29\u201331].\n The carbonyl stretching frequencies of the Re(I) complexes 1\u201318 are\n2.6.2. Cell treatments pretty similar and are comparable to reported similar structures, con\u00ad\n The compounds were dissolved in dimethyl sulfoxide (DMSO) sisting of values ranging from 2029 to 1864 cm\u2212 1 [32,33]. Complexes\n(Merck 48856212719) to achieve a final stock concentration of 5 mM, 4\u20136, with the coordinated bromide ligand, are found to have stretching\nheated at 100\u25e6 C for 2 min and then stored at room temperature for a frequencies in the range 2013 to 2024 cm\u2212 1, with complex 6 at the\nmaximum of 5 days before use. The 5 mM stock solutions were further higher stretching frequency, possibly due to the coordinated methoxy\ndiluted using cell culture medium to attain final experimental concen\u00ad group on the chelating bidentate ligand.\ntrations of 10 \u03bcM and a vehicle control (DMSO) of the equivalent highest There is an increase in the carbonyl band ranges for the phosphine\ncompound concentration was prepared simultaneously. Cisplatin (Pfizer coordinated complexes 7\u201318; this is particularly evident in the triphe\u00ad\nltd, New York, USA) was used as the positive control at its reported IC50 nylphosphine containing complexes (11 < 7 < 15). Even though there\nvalues for MCF-7, MDA-MB-231 and MRC-5 cells. are outliers in the IR data obtained for the phosphine coordinated\n complexes, a noticeable trend was observed in the 31P shifts, showing\n2.6.3. Cytotoxicity assay the following electron donating effect: PTA > PPh3 > Cy2PhP > CyPh2P.\n The MCF-7 and MDA-MB-231 breast cancer cells, along with MRC-5 In the 5,5\u2032 -DiMBpy and 4,4\u2032 -DiMoxBpy coordinated complexes, the IR\nfibroblasts, were plated in 96-well plates and treated with a concen\u00ad frequency differences are small, however there are noticeable differ\u00ad\ntration of 10 \u03bcM of the compounds or vehicle (DMSO) for a period of 48 ences in the IR carbonyl stretching frequencies of the 4,4\u2032 -DiMBpy co\u00ad\nh. The cytotoxicities of these compounds were evaluated using a 3-(4,5 ordinated complexes with different monodentate ligands.\ndimethylthiazol-2-yl)-2,5-diphenyltrazolium bromide (MTT) assay All the NMR spectra were obtained from the solvents as stated in the\n(M21281G, Sigma-Aldrich), according to the manufacturer\u2019s in\u00ad procedure. The 1H and 13C NMR data obtained for the synthesized\nstructions. The mean cell viability was calculated as a percentage of the complexes are consistent with the proposed structures and existing\nmean of the vehicle control. At least two independent experiments in literature data for some of the complexes. In the coordinated state of the\nquadruplicate were performed, from which the half maximal inhibitory 4,4\u2032 -DiMBpy, 5,5\u2032 -DiMBpy and 4,4\u2032 -DiMoxBpy ligands, characteristic\nconcentration (IC50) was determined using graph prism version 6.0. The shifts are prominent compared to their non-coordinated states. Addi\u00ad\nselectivity index (SI) was calculated using the following formula (IC50 tionally, as expected, the methoxy group (in 4,4\u2032 -DiMoxBpy) was more\nfor normal MRC-5 fibroblasts) / (IC50 for breast cancer cell line). upfield than the methyl group (in 4,4\u2032 -DiMBpy) due to the attached\n oxygen atom [34]. Furthermore, for most complexes, the CO signals\n3. Results and discussion were not detected, because it required the samples to be run for longer\n periods on the NMR instrument. The 31P NMR data of complexes 7\u201318\n Synthesis and Characterisation: This study reports on the synthesis were obtained, displaying a single peak, as illustrated in Table 1,\nand spectroscopic characterisation of eighteen Re(I) tricarbonyl com\u00ad proving the absence of isomers. These complexes also show significant\nplexes (1\u201318). Initially, the rhenium precursor fac-[NEt4]2[Re downfield shifts compared to the free phosphine ligands, confirming the\n(CO)3(Br)3] was dissolved in H2O at an adjusted pH of 2.2 to prevent the formation of a Re-P bond. During the phosphine complexes\u2019 initial\nformation of a polymeric species in the solution. This was followed by synthesis, some of the mono-phosphine ligands were oxidized. There\u00ad\nthe addition of three equivalents of AgNO3 to remove all the bromide fore, to overcome the oxidation of the phosphine ligands, the reagent\n\n 5\n\fL. Moherane et al. Polyhedron 228 (2022) 116178\n\n\nbottles were sealed and stored in a desiccator. Additionally, 85 % interactions and is critical in determining the structural and molecular\nphosphoric acid was used as a reference to prevent sidebands that might recognition properties in biological studies, such as proteins, nucleic\noccur for the 31P NMR spectra [35]. In the PTA coordinated complexes 8, acids and peptides [53]. Literature reports by Walters (2002) [53], Zhao\n12 and 16, the significant donating ability of the PTA ligand is observed, et al. (2015) [54] and Wolff et al. (2013) [55] were used to determine the\nwith upfield shifts of \u03b4 \u2212 79.26, \u2212 79.31 and \u2212 77.76 ppm respectively. A geometry. There are three primary geometries of aromatic interactions,\ndownfield 31P NMR shift was noted for 7, 9, 10, 11, 13, 14, 15, 17 and namely edge-face (4.96\u20135.025 \u00c5), offset stacked (3.4\u20133.6 \u00c5) and face-to-\n18, displaying the electron withdrawing effect of the CyPh2P ligand, as face stacked (3.3\u20133.8 \u00c5); however, the offset stacked confirmation is the\nthe CyPh2P coordinated complexes appeared more downfield (at \u03b4 ideal geometry [54]. The only structure that had \u03c0\u22c5\u22c5\u22c5\u03c0 interactions worth\n60.64, 51.14 and 59.84 ppm for 9, 13 and 17). A trend can be deduced noting, based on the criteria reported in the literature, is 2a, with a face-\nfrom the phosphine coordinated ligands in terms of their electron to-face stacked geometry (3.730(10) \u00c5).\nwithdrawing nature, as observed in the 31P NMR, with the following Photoluminescence studies: The focus of numerous researchers is on\ndecreasing arrangement: CyPh2P > Cy2PhP > PPh3, which correlates a vital class of complexes of the form: fac-[Re(CO)3(N,N\u2032 )(X)], where N,\nwell with similar studies [22,23,36]. N\u2032 = diimine and X = halides, and these complexes produce remarkable\n X-ray crystallography: The crystal structures of fac-[Re(CO)3(5,5\u2032 - phosphorescent characteristics [56\u201358]. This study involves aqua, bro\u00ad\nDiMBpy)(NO3)] (2a), fac-[Re(CO)3(4,4\u2032 -DiMoxBpy)(NO3)][(CH3)2CO] mide and phosphorous coordinated Re(I) complexes. To confirm the\n(3a) and fac-[Re(CO)3(4,4\u2032 -DiMBpy)Br] (4) were obtained from the slow suitability for the synthesized complexes as PDT and MI agents, a so\u00ad\nevaporation of the solvents, as described in the experimental section. lution state luminescence study was performed on all the synthesized\nThe crystal data of 2a, 3a and 4 are presented in Table SI 1 (\u2020ESI) and the complexes 1\u201318 and the results are compared with the literature on\nmolecular diagrams illustrating the numbering scheme are given in different N,N\u2032 -donor coordinated complexes. Fig. 2 below, shows the\nFig. 1. combined excitation and emission spectra of all the complexes, whereas\n Literature and crystal structures involving Re(I) tricarbonyl com\u00ad Table 2 summarizes the UV/Vis excitation wavelengths, emission\nplexes have been intensively studied [37\u201340]. 2a crystallized in the wavelengths, stokes shifts and the quantum yield data of the respective\ntriclinic crystal system, in the P 1 space group, with two molecules in the complexes.\nunit cell (Z = 2), 3a in the monoclinic crystal system, in the C2/c space The complexes display characteristic broad emission peaks ranging\ngroup, with eight molecules in the unit cell (Z = 8) and finally 4 in the from 545 to 620 nm, with a slightly broad excitation range of 347 to 380\nmonoclinic crystal system, P21/c space group, with Z = 4. A summary of nm. The difference in the observed excitation wavelengths is induced by\nthe bond distances and angles for 2a, 3a, and 4 are presented in Table SI the nature of the bidentate ligand used and/or the coordinated mono\u00ad\n2 (\u2020ESI) for the sake of comparison. dentate ligands in the sixth position (see Scheme 1). The complexes 8, 12\n The complexes 2a, 3a and 4 have a rhenium metal center covalently and 16 are evident to the latter statement, exhibiting PTA coordinated\nbonded to three facially orientated carbonyl ligands with a chelate N,N\u2032 - complexes having untraceable emission properties within the range.\nbidentate ligand (4,4-DiMBpy for 4, 5,5\u2032 -DiMBpy for 2a and 4,4\u2032 - Seldomly observed, ligands infested with C\u2013H bonds, which are known\nDiMoxBpy for 3a), and either a nitrate (2a and 3a) or a bromide (4) for promoting effective thermal relaxations from the excited state often\nsubstituent in the 6th position. Furthermore, the rhenium to carbon leading to quenched luminescence, are of no surprise with low complex\nbond distances range from 1.893 to 1.926 \u00c5, and the rhenium to nitro\u00ad quantum yields [74,75]. The notable, \u22645 nm, difference in the absorp\u00ad\ngen bond distances from 2.169(4) to 2.175(6) \u00c5. The bond distances tion nature amongst these complexes leads to ca. a 60 nm deviation of\nfrom the rhenium atom to the axial position substituent for 2a (Re01- the stoke shifts, as illustrated in Table 2. Contrary to common observed\nO4) is 2.152(5) \u00c5, 3a (Re01-O4) is 2.156(3) \u00c5 and 4 (Re1-Br1) is 2.631 behavior [30], we herein have noticeable hypsochromic shifts for all the\n(7), as summarised in Table SI 2 (\u2020ESI), which are considered to be PR3 coordinated complexes as compared to the aqua and bromido co\u00ad\nwithin the normal range [41\u201344]. ordinated complexes 1\u20136.\n Octahedral distortion was noted in all the complexes by the deviation Tsubaki and co-workers reported that PR3 derivatives with trialkyl or\nof the bond angles from the ideal value of 180\u25e6 , with the following an\u00ad triaryl substituents allow intramolecular interactions with the Bp\ngles in 2a and 3a (O4-Re1-C1) of 171.40(2) \u25e6 and 173.72(15) \u25e6 , bidentate ligand [76], promoting bathochromic shifts, which is\nrespectively, and in 4 (Br1-Re1-C1) of 177.57(14) \u25e6 . The ligand bite completely contrary to the phenyl and cyclohexyl PR3 ligands, which\nangles (N1-Re1-N2) for 2a (74.80(2) \u25e6 ), 3a (74.57(13) \u25e6 ) and 4 (74.74 arguably act as spacers, forbidding any intra-ligand interactions in this\n(15) \u25e6 ) are within the same range and correlate well with similar work. Moreover, complexes 1 and 4 record the highest stoke shifts of\nstructures [45\u201352]. This study also reports on the type of geometries 260 and 270 nm in the range, with the lowest being 200 and 196 nm\nfound with regards to the \u03c0\u22c5\u22c5\u22c5\u03c0 interactions that were identified in the from complexes 15 and 17. The low stokes shifts were evidently due to\nreported solid-state structures (\u2020ESI, Figure SI 1). This information is the observed 55 nm blue-shifted emission wavelengths for complexes 15\nessential since it provides a basic understanding of drug-drug and 17, respectively, as observed in Fig. 2. Interestingly, complexes 5,\n\n\n\n\nFig. 1. Molecular representation of the crystal structures of fac-[Re(CO)3(5,5\u2032 -DiMBpy)(NO3)] (2a), fac-[Re(CO)3(4,4\u2032 -DiMoxBpy)(NO3)][(CH3)2CO] (3a) and fac-\n[Re(CO)3(4,4\u2032 -DiMBpy)(Br)] (4). Hydrogen atoms and numbering for certain atoms are omitted for clarity.\n\n 6\n\fL. Moherane et al. Polyhedron 228 (2022) 116178\n\n\n\n\n Fig. 2. An illustration of the combined excitation and emission spectra of the complexes 1\u201318.\n\n\n11, 15 and 17 proved to have the highest quantum yields and that all the synthesized complexes to determine their activity and cytotox\u00ad\ncorrelates quite well with the results obtained from the literature icity towards female-related cancerous cells, MCF-7, and triple-negative\n[34,59\u201366]. breast cancer cell lines, MDA-MB-231. This study was motivated by\n It is further worth noticing an overarching observation in the numerous literature reports on Re(I) tricarbonyl complexes that display\nquantum yields of the complexes with the various N,N\u2032 -donor coordi\u00ad cytotoxicity against breast cancer cell lines [60,67\u201377]. The results from\nnated ligands: 4,4\u2032 -DiMBpy < 4,4\u2032 -DiMoxBpy < 5,5\u2032 -DiMBpy with this study are illustrated in Figure SI 2 (\u2020ESI), and the data are sum\u00ad\nrespective coordinated monodentate ligands (aqua, PR3 and bromide). marised in Table 3. The values in Table 3 are the averages of two in\u00ad\n4,4\u2032 -DiMBpy < 5,5\u2032 -DiMBpy in the comparisons is likely due to the dependent experiments, each performed in quadruplicate.\nrelative inductive effect of the electron-donating groups attached to Bp- After a preliminary study, that involved the determination of mod\u00ad\nligands in synergy with the electron-withdrawing effect of not only the erate activity among the 18 complexes, it was determined that only 6\naqua and bromide but also the PR3 monodentate ligands, leading to and 13 showed considerable cytotoxicity. Furthermore, the stability of 6\nMLCT excited states. and 13 was determined in DMSO at 100 \u25e6 C, and the NMR results\n Biological studies: An in vitro biological cell study was conducted on confirmed that the complexes were stable under these conditions. 6\n\n 7\n\fL. Moherane et al. Polyhedron 228 (2022) 116178\n\n\nTable 2\nA summary of the photophysical properties for the synthesized complexes 1\u201318, compared with results obtained from previous studies.\n Compounds UV/Vis, nm Excitation, nm Emission, nm Stokes shift Quantum yield (%)\n nm cm\u00a11 *\n\n fac-[Re(CO)3(4,4\u2032-DiMBpy)(H2O)]\u00fe (1) 360 350 620 260 11,649 0.27\n fac-[Re(CO)3(5,5\u2032-DiMBpy)(H2O)]\u00fe (2) 355 365 605 250 11,640 0.71\n fac-[Re(CO)3(4,4\u2032-DiMoxBpy)(H2O)]\u00fe (3) 350 350 620 270 12,442 0.15\n fac-[Re(CO)3(4,4\u2032-DiMBpy)(Br)] (4) 380 365 610 230 9922 0.67\n fac-[Re(CO)3(5,5\u2032-DiMBpy)(Br)] (5) 375 335 600 225 10,000 1.5\n fac-[Re(CO)3(4,4\u2032-DiMoxBpy)(Br)] (6) 365 365 620 255 11,268 0.35\n fac-[Re(CO)3(4,4\u2032-DiMBpy)(PPh3)]\u00fe (7) 347 335 600 253 12,152 0.43\n fac-[Re(CO)3(4,4\u2032-DiMBpy)(PTA)]\u00fe (8) 361 \u2013 \u2013 \u2013 \u2013 \u2013\n fac-[Re(CO)3(4,4\u2032-DiMBpy)(CyPh2P)]\u00fe (9) 354 335 600 246 11,582 0.46\n fac-[Re(CO)3(4,4\u2032-DiMBpy)(Cy2PhP)]\u00fe (10) 355 335 600 245 11,502 0.49\n fac-[Re(CO)3(5,5\u2032-DiMBpy)(PPh3)]\u00fe (11) 350 330 600 250 11,905 1.1\n fac-[Re(CO)3(5,5\u2032-DiMBpy)(PTA)]\u00fe (12) 355 \u2013 \u2013 \u2013 \u2013 \u2013\n fac-[Re(CO)3(5,5\u2032-DiMBpy)(CyPh2P)]\u00fe (13) 352 335 600 248 11,742 0.92\n fac-[Re(CO)3(5,5\u2032-DiMBpy)(Cy2PhP)]\u00fe (14) 356 335 605 249 11,561 0.87\n fac-[Re(CO)3(4,4\u2032-DiMoxBpy)(PPh3)]\u00fe (15) 354 335 545 191 9900 1.0\n fac-[Re(CO)3(4,4\u2032-DiMoxBpy)(PTA)]\u00fe (16) 352 \u2013 \u2013 \u2013 \u2013 \u2013\n fac-[Re(CO)3(4,4\u2032-DiMoxBpy)(CyPh2P)]\u00fe (17) 349 335 545 196 10,305 1.1\n fac-[Re(CO)3(4,4\u2032-DiMoxBpy)(Cy2PhP)]\u00fe (18) 357 350 580 223 10,770 0.27\n\n*Stokes shifts [cm\u2212 1] calculated from \u0394\u03bd\u0303= \u03bd\u0303abs \u2212 \u03bd\u0303fluo of spectral maxima or weighted maxima.\n\n\n methods employed in the study are accurate and reproducible. The IR\nTable 3\n carbonyl stretching frequencies assisted in observing the electron-\nA summary of the results obtained from the screening of compound(s), fac-[Re\n withdrawing effects of the axially coordinated monodentate ligands.\n(CO)3(4,4\u2032 -DiMoxBpy)(Br)] (6) and fac-[Re(CO)3(5,5\u2032 -DiMBpy)(CyPh2P]+ (13)\nagainst cancerous (MCF-7 and MDA-MB-231) and healthy (MRC-5) cells (with\n The crystal structures of fac-[Re(CO)3(5,5\u2032 -DiMBpy)(NO3)], fac-[Re\nthe reported cisplatin results). (CO)3(4,4\u2032 -DiMoxBpy)(NO3)][(CH3)2CO] and fac-[Re(CO)3(4,4\u2032 -\n DiMBpy)(Br)] allowed for a discussion on the bond distances and angles,\n Compound Cell Line IC50 SI\n and the \u03c0\u2026\u03c0 interactions observed in fac-[Re(CO)3(5,5\u2032 -DiMBpy)\n fac-[Re(CO)3(4,4\u2032-dmoxbpy)Br] (6) MDA-MB- 10.92 \u00b1 1.49 (NO3)]. Moreover, all the complexes reveal suitable luminescence in\u00ad\n 231 2.3\n tensities and, more significantly, their emission and Stokes shift indicate\n MRC-5 16.25 \u00b1 \u2013\n 1.9 possible application in cancer therapy and diagnosis. The complexes of\n fac-[Re(CO)3(5,5\u2032-dmbpy)(CyhexPh2P)]\u00fe MCF-7 5.74 \u00b1 2.5 2.62 particular interest, with promising toxicity results respectively towards\n (13) MCF-7 and MDA-MB-231 breast cancer cell lines, are fac-[Re(CO)3(4,4\u2032 -\n MRC-5 15.04 \u00b1 \u2013 DiMoxBpy)(Br)] and fac-[Re(CO)3(5,5\u2032 -DiMBpy)(CyPh2P)][NO3], with\n 2.6\n cisplatin MCF-7 12 \u00b1 2.8 1.52\n comparable results to cisplatin.\n MDA-MB- 13 \u00b1 1.8 1.65\n 231 CRediT authorship contribution statement\n MRC-5 7.9 \u00b1 1.2\n Lehlohonolo Moherane: Data curation, Writing \u2013 original draft.\ndisplayed an IC50 value of 10.92 \u00b5M against MDA-MB-231 cancer cells Orbett T. Alexander: Data curation, Methodology. Marietjie Schutte-\nand 16.25 \u00b5M against MRC-5 cells. A selectivity index (SI = 1.55) of < 2 Smith: Writing \u2013 review & editing. Robin E. Kroon: Data curation,\nis noted for 6 on MDA-MB-231, which unfortunately shows that the Methodology. Penny P. Mokolokolo: Data curation, Methodology.\ncomplex is not only selective towards cancer cells, but can also kill Supratim Biswas: Data curation, Methodology. Sharon Prince: Data\nnormal human cells. Furthermore, 6 seems to be less lethal towards curation, Methodology. Hendrik G. Visser: Supervision, Writing \u2013 re\u00ad\nnormal cells (IC50 = 16.25 \u00b5M) as compared to the reported cisplatin view & editing. Amanda-Lee E. Manicum: Supervision, Conceptuali\u00ad\nresults (IC50 = 7.9 \u00b1 1.2), as seen in Table 3. zation, Methodology, Writing \u2013 original draft, Writing \u2013 review &\n When 13 was tested against MCF-7 cells, an IC50 value of 5.74 \u00b5M editing.\nwas determined. A selectivity index (SI = 2.62) of > 2 is obtained for 13,\nwhich shows that the complex is selective towards cancer cells and does Declaration of Competing Interest\nnot kill normal cells. It further indicates that 13 is more active than\ncisplatin, IC50 = 12 \u00b1 2.8 \u00b5M, against MCF-7 breast cancer cells. When The authors declare that they have no known competing financial\nthe results from this study were compared to that of the drug of choice, interests or personal relationships that could have appeared to influence\ncisplatin, it showed that cisplatin has a remarkable selectivity in killing the work reported in this paper.\ncancer cells, with IC50 values of 12 \u00b1 2.8, 13 \u00b1 1.8 and 7.9 \u00b1 1.2 against\nMCF-7, MDA-MB-231 and MRC-5, respectively. However, it shows that Data availability\ncisplatin is also toxic towards healthy cells.\n Data will be made available on request.\n4. Conclusions\n Acknowledgment\n Eighteen complexes were successfully synthesized using the \u201c2 + 1 \u2032\u2032\n\nmixed ligand approach in considerably high yield and purity. Further\u00ad We would like to thank the National Research Foundation (Grant No.\nmore, these complexes were characterized using the spectroscopic 129468), Tshwane University of Technology, University of the Free\nmethods IR, NMR (1H, 13C, 31P) and UV/Vis, and three solid state crystal State, South Africa, for institutional and financial support.\nstructures were determined using SCXRD. This proves that the synthesis\n\n\n 8\n\fL. Moherane et al. Polyhedron 228 (2022) 116178\n\n\nAppendix A. Supplementary data [30] B.L. Souza, L.A. Faustino, F.S. Prado, R.N. Sampaio, P.I.S. Maia, A.E.H. Machado,\n A.O.T. 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