Exploring the in vitro anticancer activities of Re(I) picolinic acid and its fluorinated complex derivatives on lung cancer cells: a structural study.

{"full_text": "JBIC Journal of Biological Inorganic Chemistry (2023) 28:29\u201341\nhttps://doi.org/10.1007/s00775-022-01971-2\n\n ORIGINAL PAPER\n\n\n\nExploring the in vitro anticancer activities of Re(I) picolinic acid and its\nfluorinated complex derivatives on lung cancer cells: a structural study\nMabu L. Matlou1 \u00b7 Frederick P. Malan2 \u00b7 Sanah Nkadimeng3 \u00b7 Lyndy McGaw4 \u00b7 Vuyelwa J. Tembu1 \u00b7\nAmanda\u2011Lee E. Manicum1\n\nReceived: 24 June 2022 / Accepted: 4 October 2022 / Published online: 4 December 2022\n\u00a9 The Author(s), under exclusive licence to Society for Biological Inorganic Chemistry (SBIC) 2022\n\n\nAbstract\nFifteen rhenium(I) tricarbonyl complexes of the form fac-[Re(N,O\u2019)(CO)3(X)], where N,O\u2019-bidentate ligand = 2-picolinic\nacid (Pico); 3,5-difluoropyridine-2-carboxylic acid (Dfpc); 3-trifluoromethyl-pyridine-2-carboxylic acid (Tfpc) and X =\u2009\u00adH2O;\npyrazole (Pz); pyridine (Py); imidazole (Im); and methanol \u00ad(CH3OH) were synthesized using the \u20182 + 1\u2019 mixed ligand\napproach with an average yield of 84%. The complexes were characterized using the following spectroscopic techniques: IR,\n1\n H and 13C NMR, UV/Vis, and single-crystal X-ray diffraction. The effect of the fluorine atoms on the backbone of the N,O\u2019-\nbidentate ligand was investigated and a trend was noticed in the carbonyl stretching frequencies: with Pico < Tfpc < Dfpc.\nThe in vitro biological screening on Vero (healthy mammalian), HeLa (cervical carcinoma) and A549 (lung cancer) cells\nrevealed one toxic complex, fac-[Re(Pico)(CO)3(H2O)], with respective \u00adLC50 values of 9.0 \u00b1 0.9, 15.8 \u00b1 4.9 (SI = 0.570) and\n20.9 \u00b1 0.8 (SI = 0.430) \u03bcg/mL. As a result, it can be used as a positive control drug of toxicity.\n\nKeywords Rhenium(I) tricarbonyl \u00b7 Picolinic acid derivatives \u00b7 Imidazole-based ligands \u00b7 Crystallography \u00b7 Cytotoxicity \u00b7\nN,O-Ligands\n\n\nIntroduction Furthermore, metal-based drugs have shown to be effective\n in treating numerous different ailments with applications as\nHumans have been suffering from cancer for a long time, and antimicrobial agents [7, 8], arthritis treatments [9], anti-ulcer\nthe oldest documented case was found on ancient Egyptian drugs [9], vasodilators [10], diagnostic contrasting agents\npapyrus documents in 1500 BC [1, 2]. Nevertheless, it was [11] and anticancer treatments [5]. As already mentioned,\nnot until the past century that medical science understood cis-platin remains the metal-based drug of choice in the\ncancer and how it develops in the human body [3, 4]. For- treatment of cancer; however, platinum drugs have disad-\ntunately, most people diagnosed with this ailment tend to vantages (i.e., side effects), as they continue to face numer-\nlive longer due to the continuous improvement of available ous challenges regardless of their widespread use. These\ntreatment such as cis-platin and its close derivatives [5, 6]. side effects are particularly harmful because of their toxic\n nature, which can cause nephrotoxicity, ototoxicity, and\n peripheral neuropathy [12]. This has prompted researchers\n* Amanda\u2011Lee E. Manicum to study other metals like rhenium, particularly the Re(I) tri-\n ManicumAE@tut.ac.za\n carbonyl group [13\u201315]. The cytotoxicity reported by several\n1\n Department of Chemistry, Tshwane University researchers on Re(I) tricarbonyl complexes and their ability\n of Technology, P.O. Box X680, Pretoria 0001, South Africa to be used for therapeutic purposes makes this element an\n2\n Department of Chemistry, University of Pretoria, 02 essential and attractive drug component [16\u201319]. Several\n Lynnwood Road, Hatfield, Pretoria 0001, South Africa rhenium complexes were studied and explored for potential\n3\n Department of Life and Consumer Sciences, University anticancer applications for liver cancer, lung cancer, and\n of South Africa, Private Bag X6, Florida Campus, glioblastoma [20\u201328]. In addition, the luminescent Re(I)\n Florida 1710, South Africa complexes are comprehensively explored for their potential\n4\n Phytomedicine Programme, Department of Paraclinical use as imaging agents and as photodynamic therapy (PDT)\n Sciences, University of Pretoria, Private Bag X04, candidates [29\u201335]. The fac-Re[(CO)3(H2O)3]+ synthon\n Onderstepoort 0110, South Africa\n\n\n 13\n Vol.:(0123456789)\n\f30 JBIC Journal of Biological Inorganic Chemistry (2023) 28:29\u201341\n\n\nis extensively studied and used because of its coordinated involving the cytotoxicity studies of Pico, high concentra-\nwater molecules, which altered chelating ligand systems tions of approximately 1\u20134 mM of Pico selectively inhibit\ncan proficiently replace with the \u20182 + 1\u2019 mixed ligand model a diversity of viruses in culture, including Human Immu-\n[36\u201343]. This versatile approach combines a bidentate and nodeficiency Virus (HIV), Herpes Simplex Virus (HSV),\na monodentate ligand to synthesize Re(I) tricarbonyl com- and Simian Virus (SV) in culture [52, 53]. Given the pres-\nplexes for anticancer applications [14, 26, 35, 44\u201347]. ence of the carboxylic acid molecule in biological systems,\n We employed picolinic acid (Pico) and its fluorinated it was established that Pico and its fluorinated derivatives,\nderivatives in this study (Fig. 1). Pico possesses efficient 3,5-difluoropyridine-2-carboxylic acid (Dfpc) and 3-trifluo-\nchelating characteristics and is composed of a six-membered romethyl pyridine-2-carboxylic acid (Tfpc) should form part\nring with nitrogen and carboxyl groups. This molecule is a of this study as the coordinating bidentate ligand to the Re(I)\nmetabolic product of the kynurenine pathway, as it gener- tricarbonyl synthon, fac-[Re(CO)3(H2O)3]+. Therefore, the\nates nicotinamide adenine dinucleotide (\u00ad NAD+), which is study aimed to synthesize and characterize a wide range of\nessential for all living cells [48]. Even though the physi- Re(I) tricarbonyl complexes bearing the picolinic acid biden-\nological function of Pico has not been recognized thus far, a tate ligand with its fluorinated analogues for the design of a\nvariety of biological mediums have been identified as con- wide range of possible anticancer agents. Herein, the authors\ntaining this compound (i.e., cell culture supernatants, blood describe a series of 15 Re(I) picolinic acid-based complexes\nserum cerebrospinal fluid, human milk, pancreatic juice, and of the form fac-[Re(N,O)(CO)3(X)], where N,O = 2-picolinic\nintestinal homogenates) [49\u201351]. According to some reports, acid (Pico),\n 3,5-difluoropyridine-2-carboxylic acid (Dfpc) and 3-tri-\n fluoromethyl pyridine-2-carboxylic acid (Tfpc); X =\u2009\u00adH2O,\n O\n O \u00adCH3OH, Pyridine (Py), Imidazole (Im) and Pyrazole (Pz),\n O\n N which have been synthesized from the precursor aqua\n N\n OH\n N OH complexes: fac-[Re(Pico)(CO)3(H2O)] (1), fac-[Re(Dfpc)\n OH\n F (CO)3(H2O)] (6) and fac-[Re(Tfpc)(CO)3(H2O)] (11), in\n F F F\n methanol at room temperature as indicated in Scheme 1.\n F We further investigate and comprehensively discuss the\n 1-5 (Pico) 6-10 (Dfpc) 11-15 (Tfpc) solid-state molecular structures of eight complexes: fac-\n [Re(Pico)(CO)3(Pz)] (2), fac-[Re(Pico)(CO)3(Py)] (3), fac-\nFig. 1\u2002\u2009Picolinic acid derivatives, and their corresponding complex [Re(Dfpc)(CO)3(H2O)] (6), fac-[Re(Dfpc)(CO)3(Pz)] (7),\nnumbers used in this study fac-[Re(Dfpc)(CO)3(Py)] (8), fac-[Re(Tfpc)(CO)3(Pz)] (12),\n\n Scheme 1\u2002\u2009Synthesis of the\n Re(I) tricarbonyl complexes\n with different N,O\u2019-donor N\n bidentate ligands (2-picolinic H\n OHCH3\n acid (Pico), 3,5-difluoropyri- N\n OC N\n dine-2-carboxylic acid (Dfpc) OC N\n and 3-trifluoromethyl pyridine- Re\n Re\n 2-carboxylic acid (Tfpc)) and OC O\n monodentate ligands (pyrazole OC O\n CO CH3OH, rf 60, Pz, CH3OH,\n (Pz), pyridine (Py), imidazole 24 hrs rf 60, 24 hrs CO\n (Im), aqua \u00ad(H2O) and methanol 5, 10, 15\n\u00ad(CH3OH)) OH2 2, 7, 12\n OC N H\n Re\n N\n OC O\n CO\n\n Py, CH3OH, 1, 6, 11 N\n N Im, CH3OH,\n rf 60, 24 hrs rf 60, 24 hrs OC N\n OC N\n Re\n Re\n OC O\n OC O\n CO\n CO\n 3, 8, 13 4, 9, 14\n\n\n\n13\n\fJBIC Journal of Biological Inorganic Chemistry (2023) 28:29\u201341 31\n\nfac-[Re(Tfpc)(CO)3(Py)] (13) and fac-[Re(Tfpc)(CO)3(Im)] adding the [Re(CO)5Br] to the reaction mixture (i.e., \u00adNEt4Br\n(14). Moreover, the cytotoxicity of the 15 synthesized com- in diglyme) as a solid and stirring the reaction mixture at\nplexes (1\u201315) towards Vero cells (healthy mammalian), 120 \u00b0C for 22 h (as opposed to the reported 115 \u00b0C for\nHeLa (cervical carcinoma) and A549 (lung cancer) cells 4\u20135 h). Scheme 1 illustrates the synthesis of the complexes\nwas examined utilizing the 3-(4,5-dimethyl-2-thiazolyl)- (1\u201318) investigated in this study. Complexes 1 (previously\n2,5-diphenyltetrazolium bromide (MTT) assay. reported complex) [56], 6 and 11 were synthesized as fol-\n lows: fac-[NEt4]2[ReBr3(CO)3] (1010 mg; 1.3110 mmol) was\n dissolved in 15 mL of water (pH 2.2) by stirring for 20 min\nExperimental at room temperature. A \u00ad gNO3 (668 mg; 3.93 mmol) was\n added to the solution and stirred for 24 h at room tempera-\nMaterials and methods ture. Pico (165.9 mg; 1.3476 mmol), 3,5-Difluoropyridine-\n 2-carboxylic acid (Dfpc = 217 mg; 1.3640 mmol) and 3-Tri-\nReagents utilized to synthesize and characterize the products fluoromethyl-pyridine-2-carboxylic acid, (Tfpc = 216 mg;\nformed were purchased from Strem Chemicals Newburyport 1.2898 mmol) were added, respectively, to the filtrates and\n(USA) and Sigma Aldrich (South Africa) and were of analyt- stirred for 24 h at room temperature. Light-yellow precipi-\nical grade, unless stated otherwise. The reagents and organic tates formed, the excess solvent was filtered off and the pre-\nsolvents used for these experiments were not further purified cipitate was left to dry and weighed. Complexes 2, 7 and\nor modified but were used as received. All the experiments 12 were synthesized as follows: 1 (92 mg, 0.2236 mmol), 6\nwere conducted in aerobic conditions using methanol and (94 mg, 0.2107 mmol) and 11 (93 mg, 0.1944 mmol) were,\ndeionized water at a controlled pH. For infrared (IR) charac- respectively, dissolved in 5 mL methanol and mixed with\nterization, a PerkinElmer FT-IR Spectrometer Spectrum two, pyrazole (16 mg, 0.2394 mmol) dissolved in 3 mL of metha-\noperating in the 4000\u2013370 \u00adcm\u22121 region, was used to record nol. The mixtures were refluxed for 24 h at a temperature of\nthe spectra. The IR is connected to a computer and has a 60 \u00b0C and yellow precipitates formed after the evaporation\nbuilt-in temperature cell regulator, accurate to 0.3 \u00b0C. All of the excess solvent. The yellow precipitates were recrystal-\nthe IR spectra of the synthesized complexes were recorded lized with cold methanol, forming the desired complexes,\nat room temperature. A PerkinElmer Lambda XLS + Ultra- which were confirmed with single-crystal X-ray diffrac-\nviolet/Visible (UV/Vis) spectrometer was used to collect the tion. Complexes 3, 8 and 13 were synthesized as follows:\nUV/Vis data using a 1.000 \u00b1 0.001 cm quartz cuvette cell. 1 (83 mg, 0.2015 mmol), 6 (102 mg, 0.2273 mmol) and\nThe Elemental Analysis was performed at the University of 11 (109 mg, 0.2266 mmol) separately dissolved in 7 mL of\nKwa Zulu Natal. The Nuclear Magnetic Resonance (NMR) methanol were reacted with pyridine (16 mg, 0.2015 mmol)\ndata were acquired from a Bruker MHz nuclear magnetic and refluxed for 24 h at 60 \u00b0C and yellow precipitates formed\nresonance spectrometer operating at 500.00 MHz for 1H and after the evaporation of the excess solvent. The yellow pre-\n13\n C at room temperature with deuterated dimethyl sulfide cipitates were recrystallized with methanol, forming the\n(DMSO-d6) as the solvent. Chemical shifts are reported in desired complexes, which were confirmed with single-\nppm relative to the DMSO-d6 (2.50 ppm on 1H NMR and crystal X-ray diffraction. Complexes 4, 9 and 14 were syn-\n39.52 ppm on 13C NMR) peak. All coupling constants, J, are thesized as follows: 1 (93 mg, 0.2258 mmol), 6 (91.8 mg,\nreported in Hertz (Hz). Scheme 1 illustrates the synthesis of 0.2052 mmol) and 11 (103 mg, 0.2153 mmol) were individu-\nthe following complexes: fac-[Re(Pico)(CO)3(H2O)] (1), fac- ally dissolved in methanol (5 mL) and mixed with imidazole\n[Re(Pico)(CO)3(Pz)] (2), fac-[Re(Pico)(CO)3(Py)] (3), fac- (15 mg, 0.2262 mmol) dissolved in 3 mL of methanol and\n[Re(Pico)(CO)3(Im)] (4), fac-[Re(Pico)(CO)3(CH3OH)] (5), refluxed for 24 h at a temperature of 60 \u00b0C. The solvents\nfac-[Re(Dfpc)(CO)3(H2O)] (6), fac-[Re(Dfpc)(CO)3(Pz)] were left to evaporate and a yellow precipitate formed which\n(7), fac-[Re(Dfpc)(CO)3(Py)] (8), fac-[Re(Dfpc)(CO)3(Im)] was left to dry and weighed. Complexes 5, 10 and 15 were\n(9), fac-[Re(Dfpc)(CO)3(CH 3OH)] (10), fac-[Re(Tfpc) synthesized as follows: 1 (89 mg, 0.2019 mmol), 6 (102 mg,\n(CO) 3(H 2O)] (11), fac-[Re(Tfpc)(CO) 3(Pz)] (12), fac- 0.2272 mmol) and 11 (100 mg, 0.2098 mmol) were dis-\n[Re(Tfpc)(CO)3(Py)] (13), fac-[Re(Tfpc)(CO)3(Im)] (14), solved separately in 10 mL of methanol and refluxed for 24 h\nand fac-[Re(Tfpc)(CO)3(CH3OH)] (15). at room temperature. The methanol ligand substituted the\n aqua ligand and the excess solvent was left to evaporate, as\nSynthesis and characterization of complexes reported in previous studies [39, 55]. The yellow precipitates\n were dried and weighed.\nThe starting material, fac-[NEt4]2[ReBr3(CO)3], used for the fac-[Re(Pico)(CO)3(H2O)] (1): Yield = 475 mg, 88%;\n 1\nsynthesis of the aqua complexes (1, 6, and 11), was pre- H NMR (500 MHz, DMSO-d6) \u03b4 (ppm) 8.81 (d, J = 5 Hz,\npared using the method presented by Alberto et al. 1996 1H), 8.29 (t, J = 8 Hz, 1H), 8.10 (d, J = 8 Hz, 1H), 7.82 (t,\n[54, 55], with some adjustments. These adjustments are: J = 6 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): \u03b4 (ppm)\n\n\n 13\n\f32 JBIC Journal of Biological Inorganic Chemistry (2023) 28:29\u201341\n\n 198.16, 198.10, 194.88, 172.27, 152.48, 150.14, 141.74, 158.12, 138.90, 135.70, 134.80, 134.58, 119.14, 114.40;\n 129.41, 127.10; IR \u00ad(cm \u22121 ): \ud835\udf10 CO = 2039, 1862; UV/ IR \u00ad(cm\u22121): \ud835\udf10CO = 2035, 1869; UV/Vis: \ud835\udf06max = 333 nm, \ud835\udf00 =\n Vis: \ud835\udf06max = 330 nm, \ud835\udf00 = 2431 \u00adM\u22121.cm\u22121; Anal. Calc. for 1893 \u00adM\u22121.cm\u22121; Anal. Calc. for C\u00ad 9H4F2NO6Re: C, 24.22; H,\n \u00adC9H6NO6Re: C, 26.34; N, 3.41; H, 1.47; Found: C, 26.05; 0.90; Found: C, 24.25; H, 0.92%. The crystals were obtained\n N, 3.32; H, 1.74%. from a saturated C\n \u00ad H3OH solution at room temperature over-\n fac-[Re(Pico)(CO)3(Pz)] (2): Yield = 99 mg, 96%; 1H night to yield yellow block-like crystals.\n NMR (500 MHz, DMSO-d6) \u03b4 (ppm): 8.96 (d, J = 5 Hz, 1H), fac-[Re(Dfpc)(CO)3(Pz)] (7): Yield = 80.9 mg, 77%; 1H\n 8.22 (t, J = 8 Hz, 1H), 7.97 (d, J = 8 Hz, 1H), 7.90 (s, 1H), NMR (400 MHz, DMSO-d6) \u03b4 (ppm) 8.94 (s, 1H), 8.40 (s,\n 7.83 (t, J = 7 Hz, 1H), 7.42 (s, 1H), 6.32 (s, 1H); 13C NMR 1H), 7.94 (s, 1H), 7.61 (d, J = 2 Hz, 1H), 6.37 (t, J = 2 Hz,\n (126 MHz, DMSO-d6): \u03b4 (ppm) 197.03, 196.68, 195.80, 1H); 13C NMR (126 MHz, DMSO-d6): \u03b4 (ppm) 196.60,\n 172.08, 153.17, 149.77, 141.49, 141.44, 132.93, 129.59, 196.11, 195.24, 168.29, 168.25, 159.76, 159.67, 142.11,\n 127.05, 106.94; IR \u00ad(cm\u22121): \ud835\udf10CO = 2028, 1926, 1866; UV/ 140.00, 139.72, 133.07, 118.94; IR (\u00ad cm\u22121): \ud835\udf10CO = 2027,\n Vis: \ud835\udf06max = 336 nm, \ud835\udf00 = 1835 \u00adM\u22121.cm\u22121; Anal. Calc. for 1888; UV/Vis: \ud835\udf06max = 338 nm, \ud835\udf00 = 1480 \u00adM\u22121.cm\u22121; Anal.\n \u00adC12H8N3O5Re: C, 31.30; N, 9.13; H, 1.75; Found: C, 31.70; Calc. for \u00adC12H5F2N3O5Re: C, 29.09; H, 1.02; Found: C,\n N, 8.92; H, 1.76%. The crystals were obtained from a satu- 29.11; H, 1.00%. The crystals were obtained from a satu-\n rated \u00adCH3OH solution at room temperature overnight to rated \u00adCH3OH solution at room temperature overnight to\n yield yellow block-like crystals. yield yellow block-like crystals.\n fac-[Re(Pico)(CO)3(Py)] (3): Yield = 82 mg, 87%; 1H fac-[Re(Dfpc)(CO)3(Py)] (8): Yield = 100 mg, 86%; 1H\n NMR (500 MHz, DMSO-d6) \u03b4 9.05 (d, J = 5 Hz, 1H), 8.82 NMR (500 MHz, DMSO-d6): \u03b4 (ppm) 9.03 (s, 1H), 8.60 (d,\n (d, J = 5 Hz, 1H), 8.56 (s, 1H), 8.24 (t, J = 7 Hz, 1H), 8.11 (d, J = 5 Hz, 2H), 8.40 (t, J = 9 Hz, 1H), 8.04 (t, J = 8 Hz, 1H),\n J = 8 Hz, 1H), 8.03 (d, J = 8 Hz, 1H), 7.96 (d, J = 8 Hz, 1H), 7.57 (t, J = 7 Hz, 2H); 13C NMR (126 MHz, DMSO-d6):\n 7.88 (t, J = 6 Hz, 1H), 7.55 (s, 1H); 13C NMR (126 MHz, \u03b4 (ppm) 197.02, 196.45, 194.71, 168.19, 162.50, 162.03,\n DMSO-d6): \u03b4 (ppm) 197.45, 197.07, 195.30, 171.91, 153.01, 160.43, 159.89, 152.53, 140.52, 139.81, 127.04, 119.18;\n 152.29, 149.44, 141.80, 140.50, 130.06, 127.23, 127.01; IR IR \u00ad(cm\u22121): \ud835\udf10CO = 2024, 1885; UV/Vis: \ud835\udf06max = 330 nm,\n\u00ad(cm\u22121): \ud835\udf10CO = 2024, 1911, 1862; UV/Vis: \ud835\udf06max = 340 nm, \ud835\udf00 \ud835\udf00 = 1296 \u00adM\u22121.cm\u22121; Anal. Calc. for \u00adC14H7F2N2O5Re: C,\n = 1667 \u00adM\u22121.cm\u22121; Anal. Calc. for \u00adC14H9N2O5Re: C, 35.67; 33.14; H, 1.39; Found: C, 29.11; H, 1.03%. The crystals\n N, 5.94; H, 1.92; Found: C, 36.01; N, 5.73; H, 1.98%. The were obtained from a saturated \u00adCH3OH solution at room\n crystals were obtained from a saturated C \u00ad H3OH solution temperature overnight to yield yellow block-like crystals.\n at room temperature overnight to yield yellow block-like fac-[Re(Dfpc)(CO)3(Im)] (9): Yield = 81 mg, 80%; 1H\n crystals. NMR (400 MHz, DMSO-d6) \u03b4 8.91 (m, 1H), 8.40 (ddd,\n fac-[Re(Pico)(CO)3(Im)] (4): Yield = 95 mg, 91%; 1H J = 11, 9, 2 Hz, 1H), 8.03 (m, 1H), 7.25 (d, J = 3 Hz, 1H),\n NMR (400 MHz, DMSO-d6) \u03b4 8.92 (dt, J = 5, 1.2 Hz, 1H), 6.96 (d, J = 1 Hz, 1H); 13C NMR (126 MHz, DMSO-d6):\n 8.22 (td, J = 8, 1.5 Hz, 1H), 7.99 (m, 1H), 7.81 (ddd, J = 8, \u03b4 (ppm) 197.58, 196.91, 195.35, 168.26, 160.24, 139.44,\n 5.4, 1.5 Hz, 1H), 7.20 (t, J = 1 Hz, 1H), 7.10 (d, J = 1 Hz, 139.09, 128.48, 119.01, 118.81, 118.65; IR (\u00adcm \u22121): \ud835\udf10\n 1H), 6.82 (t, J = 1 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): CO = 2031, 1880; UV/Vis: \ud835\udf06max = 334 nm, \ud835\udf00 = 2004 \u00adM\u22121.\n \u03b4 198.01, 197.58, 195.89, 172.04, 152.76, 149.84, 141.38, cm\u22121; Anal. Calc. for C \u00ad 12H5F2N3O5Re: C, 29.09; H, 1.02;\n 138.87, 135.55, 129.62, 128.05, 127.13, 118.79; IR (\u00ad cm\u22121): Found: C, 29.10; H, 1.03%.\n\ud835\udf10CO = 2020, 1870; UV/Vis: \ud835\udf06max = 325 nm, \ud835\udf00 = 1504 \u00adM\u22121. fac-[Re(Dfpc)(CO)3(CH3OH)] (10): Yield = 82 mg, 78%;\n cm\u22121; Anal. Calc. for \u00adC12H8N3O5Re: C, 31.30; N, 9.13; H, 1\n H NMR (400 MHz, DMSO-d6) \u03b4 8.83 (d, J = 2 Hz, 1H),\n 1.75; Found: C, 31.29; N, 8.70; H, 1.74%. 8.50 (d, J = 2 Hz, 1H), 3.37 (s, 3H); 13C NMR (126 MHz,\n fac-[Re(Pico)(CO)3(CH3OH)] (5): Yield = 73 mg, 84%; DMSO-d6): \u03b4 (ppm) 197.70, 197.41, 194.29, 168.48, 163.76,\n 1\n H NMR (500 MHz, DMSO-d6) \u03b4 8.82 (d, J = 5 Hz, 1H), 138.91, 134.77, 119.14, 114.41; IR (\u00ad cm\u22121): \ud835\udf10CO = 2031,\n 8.30 (td, J = 8, 1.5 Hz, 1H), 8.11 (d, J = 8 Hz, 1H), 7.83 1892; UV/Vis: \ud835\udf06max = 329 nm, \ud835\udf00 = 2948 \u00adM\u22121.cm\u22121; Anal.\n (dt, J = 9, 3 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): \u03b4 Calc. for C\u00ad 10H6F2NO6Re: C, 27.79; H, 1.31; Found: C,\n (ppm) 198.16, 198.10, 194.87, 172.27, 152.63, 152.48, 27.77; H, 1.33%.\n 150.14, 141.74, 141.56, 129.41, 129.21, 127.10; IR (\u00ad cm\u22121): fac-[Re(Tfpc)(CO)3(H2O)] (11): Yield = 493 mg, 84%;\n 1\n\ud835\udf10CO = 2024, 1915, 1881; UV/Vis: \ud835\udf06max = 333 nm, \ud835\udf00 = 1 H NMR (500 MHz, DMSO-d6): \u03b4 (ppm) 9.07 (d, J = 5 Hz,\n 831 \u00adM\u22121.cm\u22121; Anal. Calc. for C \u00ad 10H8NO6Re: C, 28.30; N, 1H), 8.66 (d6: tri-aqua, J = 8 Hz, 1H), 7.97 (m, 1H); 13C\n 3.30; H, 1.90; Found: C, 28.00; N, 3.63; H, 1.74%. NMR (126 MHz, DMSO-d 6): \u03b4 (ppm) 197.96, 197.88,\n fac-[Re(Dfpc)(CO)3(H2O)] (6): Yield = 435 mg, 75%; 194.40, 168.84, 156.09, 149.16, 140.33, 129.34; IR (\u00ad cm\u22121):\n 1\n H NMR (500 MHz, DMSO-d6) \u03b4 (ppm) 8.78 (s, 1H), 8.49 \ud835\udf10CO = 2031, 1877; UV/Vis: \ud835\udf06max = 333 nm, \ud835\udf00 = 2876 \u00adM\u22121.\n (s, 1H); 13C NMR (126 MHz, DMSO-d6): \u03b4 (ppm) 197.70, cm\u22121; Anal. Calc. for C \u00ad 13H5F3NO6Re: C, 25.11; H, 1.05;\n 197.41, 194.28, 168.49, 163.71, 162.28, 160.14, 159.82, Found: C, 25.12; H, 1.03%.\n\n\n13\n\fJBIC Journal of Biological Inorganic Chemistry (2023) 28:29\u201341 33\n\n fac-[Re(Tfpc)(CO)3(Pz)] (12): Yield = 79 mg, 77%; 1H Cryostat. All structures were solved by direct methods with\n NMR (400 MHz, DMSO-d6): \u03b4 (ppm) 9.22 (d, J = 7 Hz, SHELXTS-2013 [58] and refined using the SHELXL-2013\n 1H), 8.60 (m, 1H), 7.99 (dd, J = 8, 6 Hz, 1H), 7.93 (d, [58] algorithm. All H atoms were placed in geometrically\n J = 3 Hz, 1H), 7.49 (d, J = 2 Hz, 1H), 6.35 (t, J = 2 Hz, idealized positions and constrained to ride on their parent\n 1H); 13C NMR (126 MHz, DMSO-d6): \u03b4 (ppm) 196.76, atoms. For data collection and refinement parameters, see the\n 196.53, 195.33, 168.63, 156.87, 148.77, 141.73, 140.20, SI (Tables S1\u2013S3). The X-ray crystallographic coordinates\n 133.16, 129.46, 107.03; IR \u00ad(cm\u22121): \ud835\udf10CO = 2028, 1870; UV/ for all structures have been deposited at the Cambridge Crys-\n Vis: \ud835\udf06max = 336 nm, \ud835\udf00 = 1706 \u00adM\u22121.cm\u22121; Anal. Calc. for tallographic Data Centre (CCDC), with deposition numbers\n \u00adC13H6F3N3O5Re: C, 29.61; H, 1.15; Found: C, 29.59; H, CSD 2,150,078\u20132,150,089. The data can be obtained free of\n 1.14%. The crystals were obtained from a saturated C \u00ad H3OH charge from The Cambridge Crystallographic Data Centre\n solution at room temperature overnight to yield yellow via www.\u200bccdc.\u200bcam.\u200bac.\u200buk/\u200bdata_\u200breque\u200bst/\u200bcif.\n block-like crystals.\n fac-[Re(Tfpc)(CO)3(Py)] (13): Yield = 117 mg, 96%; 1H Biological studies\n NMR (400 MHz, DMSO-d6) \u03b4 9.31 (dd, J = 6, 1 Hz, 1H),\n 9.07 (td, J = 5, 1 Hz, 1H), 8.67 (dd, J = 8, 1 Hz, 1H), 8.59 (m, African green monkey kidney (Vero) normal cells, A549\n 1H), 8.04 (tdd, J = 8, 3, 2 Hz, 1H), 7.79 (tt, J = 8, 2 Hz, 1H), lung cancer, and HeLa cervical carcinoma cells purchased\n 7.57 (m, 1H), 7.39 (m, 1H); 13C NMR (126 MHz, DMSO- from American Type Culture Collection were used in the\n d6): \u03b4 (ppm) 197.13, 196.91, 194.78, 168.51, 156.65, 152.36, study. Cells of sub-confluent cultures were harvested and\n 150.11, 148.45, 140.59, 136.63, 129.95, 127.10, 124.40; centrifuged at 200 \u00d7 g for 5 min and suspended in a growth\n IR \u00ad(cm\u22121): \ud835\udf10CO = 2028, 1870; UV/Vis: \ud835\udf06max = 330 nm, medium. The growth medium used for the Vero cells was\n\ud835\udf00 = 1213 \u00adM\u22121.cm\u22121; Anal. Calc. for \u00adC15H8F3N2O5Re: C, Minimal Essential Medium (MEM, Biocom Africa) supple-\n 29.61; H, 1.49; Found: C, 29.63; H, 1.49%. The crystals mented with 0.1% gentamicin (Virbac) and 5% fetal bovine\n were obtained from a saturated \u00adCH3OH solution at room serum (FBS) (Gibco, Sigma Aldrich). The cancer cell lines\n temperature overnight to yield yellow block-like crystals. (A549 and MCF-7) were maintained in Dulbecco\u2019s Modi-\n fac-[Re(Tfpc)(CO)3(Im)] (14): Yield = 110 mg, 96%; 1H fied Eagle\u2019s medium (DMEM) (Pan Biotech, Separation\n NMR (400 MHz, DMSO-d6) \u03b4 9.19 (dd, J = 5, 1 Hz, 1H), Scientific) supplemented with 10% FBS and 1% of penicil-\n 8.60 (m, 1H), 8.00 (m, 1H), 7.23 (t, J = 1 Hz, 1H), 7.04 (d, lin (100 units/mL) and streptomycin (100 \u00b5g/mL) (Celtic\n J = 3 Hz, 1H), 6.86 (t, J = 1 Hz, 1H); 13C NMR (126 MHz, Molecular Diagnostics). The cells were allowed to reach\n DMSO-d 6): \u03b4 (ppm) 197.70, 197.38, 195.39, 168.63, 80% confluence in an incubator (HERAcell 150, Thermo\n 156.40, 148.77, 140.06, 139.03, 129.54, 128.07, 118.94; IR Electron Corp) at 37 \u00b0C in a 5% C\u00ad O2 atmosphere. Cells were\n\u00ad(cm\u22121): \ud835\udf10CO = 2024, 1904, 1877; UV/Vis: \ud835\udf06max = 337 nm, seeded at a concentration of 1 \u00d7\u2009\u00ad104 per well in columns 2\n\ud835\udf00 = 1928 \u00adM\u22121.cm\u22121. Anal. Calc. for C \u00ad 13H6F3N3O5Re: C, to 12 into a 96-well tissue cultured plate (NEST, Whitehead\n 29.61; H, 1.15; Found: C, 29.60; H, 1.16%. The crystals Scientific). The medium (200 \u00b5L) was added to the wells\n were obtained from a saturated \u00adCH3OH solution at room of the first column and used as a blank (no cells), while the\n temperature overnight to yield yellow block-like crystals. last two columns were left untreated and used as controls.\n Fac-[Re(Tfpc)(CO)3(CH 3OH)] (15): Yield = 76 mg, The plates were incubated for 24 h at 37 \u00b0C in a 5% \u00adCO2\n 74%; 1H NMR (500 MHz, DMSO-d6) \u03b4 9.08 (d, J = 5 Hz, incubator. The medium was then aspirated from the cells\n 1H), 8.68 (d, J = 8 Hz, 1H), 7.98 (dd, J = 8, 6 Hz, 1H); 13C and substituted with 200 \u00b5L of test compounds at various\n NMR (126 MHz, DMSO-d 6): \u03b4 (ppm) 197.96, 197.88, concentrations (0.025, 0.05, 0.075, 100, 150, and 200 \u03bcg/\n 194.41, 168.85, 156.09, 149.16, 140.39, 129.35; IR (\u00ad cm\u22121): mL) in fresh medium and incubated at 37 \u00b0C in 5% \u00adCO2 for\n\ud835\udf10CO = 2026, 1883; UV/Vis: \ud835\udf06max = 347 nm, \ud835\udf00 = 1132 \u00adM\u22121. 48 h. Doxorubicin (Pfizer Laboratories) was included as a\n cm\u22121; Anal. Calc. for C \u00ad 11H7F3NO6Re: C, 26.83; H, 1.43; positive control. After 48 h, the medium was removed, and\n Found: C, 26.83; H, 1.42%. cells were washed with 200 \u00b5L of phosphate-buffered saline\n (PBS). A 100 \u03bcL aliquot of fresh medium was added fol-\nCrystallography lowed by 30 \u03bcL of MTT (Inqaba Biotec) solution prepared at\n a 5 mg/mL concentration in PBS. The cells were incubated\nSingle crystals of selected complexes 2, 3, 6, 7, 8, and for 4 h at 37 \u00b0C in 5% C \u00ad O2. After incubation, the medium\n12\u201314 were analyzed on a Rigaku XtaLAB Synergy R with MTT was carefully removed without disturbing the\ndiffractometer, with a rotating-anode X-ray source and a MTT crystals in the wells. Solubilization solution (50 \u00b5L\nHyPix CCD detector. Data reduction and absorption were DMSO) was then added, and the plates were gently shaken\ncarried out using the CrysAlisPro (version 1.171.40.23a) to dissolve the MTT formazan crystals. The absorbance was\nsoftware package [57]. All X-ray diffraction measurements read at 570 nm wavelengths and a referenced wavelength of\nwere performed at 150(2) K, using an Oxford Cryogenics 630 using a microplate reader (Biotek, Synergy HT). The\n\n\n 13\n\f34 JBIC Journal of Biological Inorganic Chemistry (2023) 28:29\u201341\n\nviability of cells in percentages was calculated using the methods IR, NMR, and UV/Vis. Complexes 1\u20134 were rela-\nformula: %Viability = ((Sample Absorbance/control Absorb- tively pure, based on the elemental analysis that was done\nance) \u00d7 100). The results were expressed as the lethal aver- to determine the purity.\nage concentration of a sample necessary to kill 50% of the\nexposed population of animals or viable cells \u00ad(LC50), under IR characterization\nspecific conditions. The tests were done in triplicate and\nrepeated three times at different times. The spectra of the complexes can be found in the Supple-\n mentary Information (Figure S16\u2013S29) and the IR spectral\n data of the synthesized complexes are listed in Table 1. In\nResults and discussion complexes 1 and 6 the broad bands at around 3 362 \u00adcm\u22121 can\n be assigned to the stretching frequency of hydroxyl group\nSynthesis from the water molecules. The complexes display a C=N\n peak ranging between 1601 and 1693 \u00adcm\u22121, with a trend\n The synthesis of 15 complexes (1\u201315) is reported in this noted in complexes 2 (1673 \u00adcm\u22121) and 12 (1693 \u00adcm\u22121), bear-\n study, using 3 different N,O-donor bidentate ligands (2-Pico- ing the Pz ligand in the axial position. This could possibly be\n linic acid (Pico); 3,5-difluoropyridine-2-carboxylic acid an effect caused by the electron-withdrawing fluoro atoms\n (Dfpc); and 3-trifluoromethyl-pyridine-2-carboxylic acid on the ligand backbone, causing a higher C= N stretching\n (Tfpc)) that are coordinated to the fac-[Re(CO)3]+ core vibrations. The absorption peaks observed between 772 and\n to investigate their coordination modes. The Re(I) tricar- 760 \u00adcm\u22121 for the complexes are assigned to deformation\n bonyl complexes were synthesized using the [2 + 1] mixed vibration of the pyridine ring, which confirms that the pyri-\n ligand method [59]. The tri-aqua complex fac-[NEt4]2[Re\u00ad dyl N atom and carboxyl O atom are coordinated with the\n (CO)3(H2O)3]+ is synthesized first as the intermediate prod- center metal ion [60]. No definitive trend can be deduced\n uct, by adding three equivalents of \u00adAgNO3 to the starting in the complexes, as indicated in complexes 1, 2 and 3,\n material fac-[NEt4]2[Re(CO)3Br3]. The stirring of the solu- with the stretching bands, respectively, noted at 768, 765\n tion for 24 h at pH of 2.2 ensures that the aqua ligands dis- and 764 \u00adcm\u22121. All these complexes (1\u201315) show the typical\n place all three of the bromide ligands. In the second step, the carbonyl stretching frequencies with bands in the range of\n N,O-donor bidentate ligand is added to fac-[NEt4]2[Re(CO)3 2035\u20131862 \u00adcm\u22121 [46, 61\u201363]. A trend is noted in the car-\n (H2O)3]+ to generate the series of fac-[Re(N,O)(CO)3(H2O)] bonyl stretching frequencies for the aqua complexes (1, 6 and\n complexes (1, 6, 11). The monodentate ligands (Pz, Py, Im, 11): 2035 \u00adcm\u22121 fac-[Re(Dfpc)(CO)3(H2O)] (6) > 2031 \u00adcm\u22121\n\u00adCH3OH) are then added to the aqua complexes at 60 \u00b0C for fac-[Re(Tfpc)(CO)3(H2O)] (11) > 2024 \u00adcm\u22121 fac-[Re(Pico)\n 24 h to produce complexes 2\u20135; complexes 7\u201310; and com- (CO)3(H2O) (1). This trend confirms that 2-Picolinic acid\n plexes 12\u201315 in moderate to good yields, 74\u201396%. Most is the N,O\u2019-donor bidentate ligand with the better electron\n of the synthesized complexes formed yellow products and donating properties, thus increasing the electron density on\n all the complexes were fully characterized by spectroscopic the Re(I) metal center as well as the \ud835\udf0b-backbonding from\n\n\nTable 1\u2002\u2009Summary of the Complex \ud835\udf10CO \u00ad(cm\u22121) \ud835\udf06max (nm) \ud835\udf00(M\u22121.cm\u22121)\nspectroscopic data for\ncomplexes 1\u201315 fac-[Re(Pico)(CO)3(H2O)] (1) 2024, 1862 330 2 431\n fac-[Re(Pico)(CO)3(Pz)] (2) 2028, 1926, 1866 336 1 835\n fac-[Re(Pico)(CO)3(Py)] (3) 2024, 1911, 1862 340 1 667\n fac-[Re(Pico)(CO)3(Im)] (4) 2020, 1870 325 1 504\n fac-[Re(Pico)(CO)3(CH3OH)] (5) 2024, 1915, 1881 333 1 831\n fac-[Re(Dfpc)(CO)3(H2O)] (6) 2035, 1869 333 1 893\n fac-[Re(Dfpc)(CO)3(Pz)] (7) 2027, 1888 338 1 480\n fac-[Re(Dfpc)(CO)3(Py)] (8) 2024, 1885 330 1 296\n fac-[Re(Dfpc)(CO)3(Im)] (9) 2031, 1880 334 2 004\n fac-[Re(Dfpc)(CO)3(CH3OH)] (10) 2031, 1892 329 2 948\n fac-[Re(Tfpc)(CO)3(H2O)] (11) 2031, 1877 333 2 876\n fac-[Re(Tfpc)(CO)3(Pz)] (12) 2028, 1870 336 1 706\n fac-[Re(Tfpc)(CO)3(Py)] (13) 2028, 1870 330 1 213\n fac-[Re(Tfpc)(CO)3(Im)] (14) 2024, 1904, 1877 337 1 928\n fac-[Re(Tfpc)(CO)3(CH3OH)] (15) 2026, 1883 347 1 132\n\n\n\n13\n\fJBIC Journal of Biological Inorganic Chemistry (2023) 28:29\u201341 35\n\nthe tricarbonyl ligands. It is also noticed that complexes around 168.4 ppm which is the same chemical shift of the\nhaving the coordinated Dfpc ligand (5\u201310) have the highest ligand in its uncoordinated state. For complexes 11\u201315, the\n 13\ncarbonyl stretching frequencies, ranging between 2027 and C spectra show upfield shifts instead of downfield shifts\n2035 \u00adcm\u22121, indicating the electron-withdrawing effects of of the carbonyls upon coordination compared to free Tfpc\nthe fluoride atoms on the ligand backbone. The Tfpc com- which is abnormal. All 15 complexes showed presence of the\nplexes (11\u201315) have the second highest carbonyl stretching tricarbonyls ranging between 194 and 198 ppm.\nfrequencies, and even though there are three fluoro atoms\non this ligand, the carbonyl stretching frequencies are not XRD characterization\nthe highest. This could be because the fluoro atoms are not\ndirectly attached to the ring, leading to a less pronounced As a continuation into the investigation of the effect of the\ninfluence due to inductive effects. N,O-ligands and their substituents on the structural and elec-\n tronic properties of the rhenium complexes, the structural\nUV/Vis characterization elucidation of selected complexes were performed. Figures 2\n and 3 show perspective views of the molecular structures\nAll 15 of the synthesized complexes in this study show char- of 2, 3, 6, 7, 8, and 12\u201314. For more information including\nacteristic UV/Vis absorptions of the low-spin d6 Re(I) metal tables of bond lengths, bond and torsion angles, as well as\ncenter. At their low energy region, transitions from a largely other crystallographic parameters, see Tables S1\u2013S4 in the\nmetal-based orbital to an orbital that is ligand based is Supplementary Information. The structure of 3 corresponds\nreferred to as Metal-to-Ligand charge transfer (MLCT), and to the published structure of Hayes et al. (CSD refcode PUD-\nare observed with the \ud835\udf06max varying between 330 and 347 nm. VIV), but is included here for structural comparison pur-\nNo definitive trend could be deduced from the absorption poses [64].\nin the ultraviolet region for the complexes 1 to 5, since no In general, all the structures exhibited slightly distorted\nsignificant influence by the ligands is noted. The calculated octahedral geometries around the central rhenium center,\nmolar absorptivities (\ud835\udf00) range between 1132 and 2948 \u00adM\u22121. with three carbonyl ligands coordinated to Re in a facial\ncm\u22121, respective to complexes 15 and 10. From the results, manner, along with the N,O-bidentate ligand in the basal\nit is noted that at wavelengths of 330, 333 and 336 nm, the plane, and a monodentate N/O ancillary ligand occupy-\nrespective molar absorptivity trends of the complexes are ing the remaining apical coordination site. The deviation\nas follows: 1 > 8 > 13 at 330 nm, 11 > 6 > 4 at 333 nm, and from the perfect octahedral geometry is mainly due to the\n2 > 12 at 336 nm, showing more intense absorption of 1, 11 N,O ligand that bends in the direction of the N/O ancillary\nand 2 at the indicated wavelengths. ligand (Figs. 2 and 3, Table 2), with average bond angles\n ranging between 79.41(19) and 87.79(18)\u00b0 (N1\u2013Re1\u2013N2),\nNMR characterization 78.6(2) and 84.38(9)\u00b0 (N2\u2013Re1\u2013O1), 92.1(2) and 95.92(13)\u00b0\n (N2\u2013Re1\u2013CCO), and 173.1(2) and 177.1(3)\u00b0 (N2\u2013Re1\u2013CCO).\nThe 1H and 13C NMR analyses of the Re(I) tricarbonyl com- The bidentate N,O-ligands also binds strongly to the rhenium\nplexes synthesized in this study were conducted in deuter- center with a relatively small bite angle ranging between\nated dimethyl sulfoxide at 25 \u00b0C as mentioned in the method. 74.61(16)\u00b0 and 75.90(9) \u00b0, compared to analogous N\u2013Re\u2013O\nThe NMR data acquired show that some of the complexes angles in related Re(I) complexes [65\u201368]. Little variation\nsynthesized are compatible with the proposed structures. on the Re1\u2013N1 bond length is observed across the range\nIn complexes 2\u20134 and 6\u201315, downfield shifts of the proton (2.176(4)\u20132.191(5) \u00c5), whereas the range is more noticeable\nadjacent to the nitrogen atom of the N,O-bidentate ligands for the Re1\u2013O1 bond length of between 2.108(5) \u00c5 (complex\nare noted upon coordination ranging from 0.03 to 0.53 ppm 3) and 2.146(3) \u00c5 (complex 7). This is reasoned to be due to\ncompared to the uncoordinated ligands. Complexes with the increased electron density on the rhenium center (due to\nthe Dfpc (6\u201310) and Tfpc (11\u201315) showed the most promi- the monodentate sigma N,O-donor ligand, which increases\nnent shifts on the 1H NMR spectra compared to those with \u03c0-back donation to the carbonyl and N,O-bidentate ligands,\nthe Pico ligand, this is because these ligands are better \ud835\udf0b essentially strengthening the corresponding Re1\u2013CCO and\n-acceptors. In the 13C NMR of complexes bearing the Pico Re1\u2013O1 bonds and hence shortening of these bonds. For\nligand, coordination of the carboxylate constituent of the example, comparing complexes 2 and 3 (each with the same\nligand is noted by the downfield shifts of its carbonyl upon Pico ligand present): Complex 3 (featuring a pyridine ligand)\ncoordination, from a shift of 168.3 ppm in its free state to an shows a shorter Re1\u2013O1 bond as compared to 2 (featuring\naverage shift of 172.1 ppm. However, an anomaly is noted a pyrazole ligand). The corresponding Re1\u2013CCO (trans to\nfor complexes 6\u201310 with the Dfpc ligand, their 13C spec- N,O ligand) bonds are also slightly shorter in the case of 3\ntra show no prominent downfield shifts upon coordination. (1.897(7) \u00c5 vs 1.910(3) \u00c5 (2); 1.915(8) \u00c5 vs 1.925(3) \u00c5 (2)).\nThe carbonyl shifts of the Dfpc bearing complexes appeared The expected elongation of the C \u00ad CO\u2013OCO bond lengths are\n\n\n 13\n\f36 JBIC Journal of Biological Inorganic Chemistry (2023) 28:29\u201341\n\n\n\n\nFig. 2\u2002\u2009Molecular structures of complexes 2, 3, 6, and 7 with thermal ellipsoids drawn at 50% probability level\n\n\n\nalso observed in 3 (1.159(9) \u00c5 vs 1.149(4) \u00c5 (2); 1.152(9) to the series Pz > Im > Py. The combination of these two\n\u00c5 vs 1.145(4) \u00c5 (2)). Subsequent inclusion of fluorine series allows for the ligands to be organized according to\natoms in the N,O ligand backbone increases its \u03c0-accepting decreasing electron donating character according to the\ncharacter, with an expected decrease in the Re1\u2013O1 bond series Py >\u2009\u00adH2O > Im > Pz. All the other Re\u2013O, Re\u2013C, and\nlengths (2.145(2) \u00c5 (2) vs 1.1396(19) \u00c5 (12)). Separated Re\u2013N bond lengths appear in the expected range for related\nconsideration of the electronic effect of monodentate ligands complexes [68\u201371]. Several unique networks of hydrogen\non the resulting complexes leads to similar observations: bonds were observed in several of the structures studied,\n(i) In the Dfpc ligand series (6 \u00ad(H2O), 7 (Pz), 8 (Py)) the particularly between N\u2013H (or O\u2013H) groups (N/O ancillary\nRe1\u2013O1 bond length decreases according to the series ligands) and N,O-ligands (see Figure SI1b in the Supplemen-\nPz >\u2009\u00adH2O > Py; (ii) in the Tfpc ligand series (12 (Pz), 13 tary Information). All the complexes, except those featuring\n(Py), 14 (Im)), the Re1\u2013O1 bond length decreases according Py ligands (3, 8, 13), exhibited hydrogen bonds. Complexes\n\n\n13\n\fJBIC Journal of Biological Inorganic Chemistry (2023) 28:29\u201341 37\n\n\n\n\nFig. 3\u2002\u2009Molecular structures of complexes 7, 8, and 12\u201314, with thermal ellipsoids drawn at 50% probability level\n\n\nTable 2\u2002\u2009Selected bond lengths and angles of compounds 2, 3, 6, 7, 8, and 12\u201314\nComplex Re1\u2013N1 (\u00c5) Re1\u2013O1 (\u00c5) Re1\u2013CCO N1\u2013Re1\u2013O1 (\u00b0) X\u2013Re1\u2013N1a (\u00b0) X\u2013Re1\u2013O1a (\u00b0)\n (apical) (\u00c5)\n\nfac-[Re(Pico)(CO)3(Pz)] (2) 2.179(3) 2.145(2) 1.923(4) 75.90(9) 85.92(10) 81.46(10)\nfac-[Re(Pico)(CO)3(Py)] (3) 2.185(5) 2.108(5) 1.927(7) 75.4(2) 85.1(2) 80.7(2)\nfac-[Re(Dfpc)(CO)3(H2O)] (6) 2.188(7) 2.134(6) 1.924(9) 75.4(2) 80.9(2) 78.6(2)\nfac-[Re(Dfpc)(CO)3(Pz)] (7) 2.176(4) 2.146(3) 1.920(5) 74.71(13) 83.38(14) 81.07(13)\nfac-[Re(Dfpc)(CO)3(Py)] (8) 2.184(2) 2.124(3) 1.920(3) 75.67(10) 84.05(9) 84.38(9)\nfac-[Re(Tfpc)(CO)3(Pz)] (12) 2.184(2) 2.1396(19) 1.913(3) 74.62(8) 83.35(8) 81.36(8)\nfac-[Re(Tfpc)(CO)3(Py)] (13) 2.191(5) 2.112(4) 1.915(7) 74.61(16) 87.79(18) 82.73(18)\nfac-[Re(Tfpc)(CO)3(Im)] (14) 2.182(6) 2.127(4) 1.917(7) 74.62(18) 79.41(19) 81.56(19)\na\n X = heteroatom (N) in all cases except 6 (O)\n\n\n 13\n\f38 JBIC Journal of Biological Inorganic Chemistry (2023) 28:29\u201341\n\n7 and 14 each feature two intermolecular N\u2013H\u00b7\u00b7\u00b7O bonds and Fig. 4 gives a graphical illustration of the \u00adLC50 values\n(2.7971\u20132.8731 \u00c5 between the donor and acceptor atoms; (in \u03bcg/mL) obtained from the different cells (Vero and HeLa)\nN\u2013H\u00b7\u00b7\u00b7O angles between 158 and 168\u00b0) which links two mol- versus the positive control (Doxorubicin). \u00adLC50 represents\necules to form dimers. the concentration that inhibits 50% of growth. The HeLa\n The hydrogen-bonding network in complexes 2 and 12 cells were chosen for this investigation because they are one\ndiffers in that a one-dimensional chain is formed. The net- of the most popular models for assessing chemotherapeu-\nwork in each complex structure is formed through a bifurcate tic effects, and they are very well characterized. A549 cells\nhydrogen bond that exists between an N\u2013H bond and two were chosen as their origin is from lung tissue and doxoru-\noxygen atoms of the acetate group of an adjacent molecule bicin was the positive control. Table S5 was added with the\n(2.7763\u20133.1274 \u00c5 between the donor and acceptor atoms; calculated \u00adIC50 values of the complexes.\nN\u2013H\u00b7\u00b7\u00b7O angles between 121 and 167\u00b0). Structure 6 also The \u00adLC50 of complexes 1\u201315 range from 9.0 \u00b1 0.9 to\nforms a one-dimensional chain, although it is unique in that 99.5 \u00b1 4 \u03bcg/mL, with the majority of the complexes being\ntwo layers of complex molecules each interact via bifur-\ncate O\u2013H\u00b7\u00b7\u00b7O bonds: first via the between formation of a\nchain with an intermolecular O\u2013H\u00b7\u00b7\u00b7O bond linking adjacent\nmolecules, and secondly via linking two separate chains by\nthe second O\u2013H\u00b7\u00b7\u00b7O interaction of the bifurcate bond. No\nmentionable \u03c0\u2013\u03c0 stacking interactions were found in the\nthree-dimensional packing of the structures investigated.\nThe packing along each of the crystallographic axes a, b,\nand c are unique, apart from complexes 2 and 3. In the latter\ncase, the two complexes exhibit isostructural features (see\nFigure SI1a in the Supplementary Information).\n\nBiological studies\n\nOur next objective was to examine the in vitro anticancer Fig. 4\u2002\u2009Graphical representation of the L\u00ad C50 values (concentration\nactivities of the Pico-based complexes (1\u201315), in Vero, HeLa inhibiting 50% of growth, values given as (\u03bcg/mL)) of each com-\n pound (1\u201315), against Vero, HeLa and A549 cells, versus the posi-\nand A549 cells with the colorimetric 3-(4,5-dimethylthia-\n tive control doxorubicin. Data are represented with error bars show-\nzol-2-yl)-2,5-tetrazolium bromide (MTT) assay. The data ing their corresponding standard deviations from three independent\nobtained from this investigation are summarized in Table 3, experiments with nine replicates\n\n\n\nTable 3\u2002\u2009A summary of the Complex Vero \u00adLC50 (\u03bcg/mL) HeLa \u00adLC50 (\u03bcg/mL) SI (HeLa) A549 \u00adLC50 (\u03bcg/mL) SI (A549)\n\u00adLC50 results obtained from the\nin vitro cancer screening of (1) 9.0 \u00b1 0.9 15.8 \u00b1 4.9 0.570 20.9 \u00b1 0.8 0.430\ncomplexes 1\u201315 against HeLa,\n (2) 65.1 \u00b1 6.3 48.9 \u00b1 3.8 1.105# 84.3 \u00b1 4.6 0.772\nA549 and Vero cells\n (3) 72.4 \u00b1 4.4 89.6 \u00b1 12.6 0.808 99.5 \u00b1 4 0.728\n (4) 77.7 \u00b1 4.8 35.3 \u00b1 1.3 2.201# > 100 na\n (5) 34 \u00b1 2 42.1 \u00b1 4.6 0.808 54.1 \u00b1 5 0.628\n (6) 24.5 \u00b1 2.6a > 100 na 97 \u00b1 8.7 0.253\n (7) 57.3 \u00b1 5.9 60 \u00b1 2.5 0.955 94.6 \u00b1 8.6 0.606\n (8) 45.9 \u00b1 5.1 75.8 \u00b1 0.8 0.606 80.2 \u00b1 2.9 0.572\n (9) 53.1 \u00b1 4.1 32.7 \u00b1 3.4 1.624# 50 \u00b1 4.2 1.062#\n (10) 88 \u00b1 10.6a > 100 na > 100 na\n (11) 75.7 \u00b1\u2009\u00ad14a > 100 na > 100 na\n (12) 89.5 \u00b1 6.8a > 100 na > 100 na\n (13) > 100 > 100 na > 100 na\n (14) > 100 > 100 na > 100 na\n (15) 54.5 \u00b1\u2009\u00ad6a > 100 na > 100 na\n Doxorubicin 9.9 \u00b1 1 1.5 \u00b1 0.5 6.6 1.6 \u00b1 0.4 6.188\n a\n More toxic to Vero than to cancerous cell lines; na = not able to be calculated at concentrations tested;\n #\n promising Selectivity Index (SI) values; most toxic are highlighted in bold\n\n\n13\n\fJBIC Journal of Biological Inorganic Chemistry (2023) 28:29\u201341 39\n\nnon-toxic towards healthy and cancerous cells. Complex 1 Data availability statement The in vitro biological datasets generated\nwith the Pico bidentate ligand exhibited the highest cyto- during and/or analysed during this study are available from the cor-\n responding author on reasonable request.\ntoxic effect towards HeLa \u00ad(LC50 = 15.8 \u00b1 4.9 \u03bcg/mL) and\nA549 cells \u00ad(LC50 = 20.9 \u00b1 0.8 \u03bcg/mL), with comparable Declarations\ntoxicity (to the positive control Doxorubicin); however, it\nwas also toxic on the Vero cells \u00ad(LC50 = 9 \u00b1 0.9 \u03bcg/mL). Conflict of interest There is no conflict of interest to report.\nComplexes 2 and 4 displayed promising selectivity index\n(SI) values (of 1.105 and 2.201 respectively) on HeLa cells.\nComplexes 6\u201310 with the coordinated Dfpc bidentate ligand\nshowed little to no cytotoxicity towards the cancerous lines, References\nwith complex 6 being more toxic to healthy Vero cells than\n 1. DeVita VT Jr, Rosenberg SA (2012) Two hundred years of cancer\ncancerous cell lines. Complex 9 had good selectivity on research. New Eng J Med 366:2207\u20132214\nboth HeLa and A549 (of 1.624 and 1.062, respectively). 2. Di Lonardo A, Nasi S, Pulciani S (2015) Cancer: we should not\nThe Tfpc-coordinated complexes (11\u201315) were found to be forget the past. J Can 6:29\u201339\n 3. Hajdu SI (2011) A note from history: landmarks in history of\nthe least toxic towards cancerous cells with the majority of\n cancer, part 1. Cancer 117:1097\u20131102\nthe \u00adLC50 values being > 100 \u03bcg/mL against HeLa and A549 4. Mitrus I, Bryndza E, Sochanik A, Szala S (2012) Evolving models\ncells. Again, complexes 11 and 12 were found to be more of tumor origin and progression. Tumour Biol J. Int. Soc. Onco.\ntoxic to Vero cells as compared to the cancerous HeLa and Biol. & Med. 33:911\u2013917\n 5. Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy:\nA549 cells, with respective \u00adLC50 values of 75.7 \u00b1 14 and\n molecular mechanisms of action. Eur J Pharm 740:364\u2013378\n89.5 \u00b1 6.8 \u03bcg/mL. Looking at the N,O-bidentate ligands used 6. Mcquitty RJ (2014) Metal-based drugs. Sci Prog 97:1\u201319\nin this study, it is noted that the fluorine atoms present on the 7. Ip M, Lui SL, Poon VKM, Lung I, Burd A (2006) Antimicrobial\nligand backbones of Dfpc and Tfpc have a negative effect activities of silver dressings: an in vitro comparison. J Med Micro\n 55:59\u201363\non the cytotoxicity of the complexes towards cancerous cell\n 8. Thomas S, McCubbin P (2003) A comparison of the antimicrobial\nlines. effects of four silver-containing dressings on three organisms. J\n Wound Care 12:101\u2013107\n 9. Guo Z, Sadler PJ (1999) Metals in medicine. Ang. Chem. (Int. ed.\n in Eng) 38:1512\u20131531\n 10. Arnold WP, Longnecker DE, Epstein RM (1984) Photodegra-\nConclusion dation of sodium nitroprusside: biologic activity and cyanide\n release. Anesthesiology 61:254\u2013260\n In this study, the synthesis, spectroscopic characterization 11. Yan G-P, Robinson L, Hogg P (2007) Magnetic resonance imag-\n ing contrast agents: Overview and perspectives. Radiography\n (IR, 1H 13C NMR, and UV/Vis) with the solid-state crystal\n 13:e5\u2013e19\n structures of seven complexes, and the in vitro biological 12. Hartmann JT, Lipp HP (2003) Toxicity of platinum compounds.\n applications of the complexes are reported. The IR carbonyl Exp Op Pharma 4:889\u2013901\n stretching frequencies observed illustrate the electron-with- 13. King AP, Marker SC, Swanda RV, Woods JJ, Qian S-B, Wilson\n JJ (2019) A rhenium isonitrile complex induces unfolded pro-\n drawing effect of the fluoro-containing groups of selected\n tein response-mediated apoptosis in cancer cells. Chem. A Eur. J.\n N,O-bidentate ligands. This was furthermore corroborated 25:9206\u20139210\nwith the 13C signals of the CO ligands (13C NMR), as well 14. Marker SC, King AP, Granja S, Vaughn B, Woods JJ, Boros\nas Re\u2013O, Re\u2013N and Re\u2013C bond lengths (SCXRD). The E, Wilson JJ (2020) Exploring the in vivo and in vitro anti-\n cancer activity of rhenium isonitrile complexes. Inorg Chem\nrange of complexes was also evaluated as anticancer agents\n 59:10285\u201310303\nwhere the majority of the complexes exhibited low to no 15. Delasoie J, Pavic A, Voutier N, Vojnovic S, Crochet A, Nikodi-\ntoxicity to both healthy and cancerous cells. fac-[Re(Pico) novic-Runic J, Zobi F (2020) Identification of novel potent and\n(CO)3(H2O)] showed the highest cytotoxicity towards Vero non-toxic anticancer, anti-angiogenic and antimetastatic rhe-\n nium complexes against colorectal carcinoma. Eur J Med Chem\n\u00ad(LC50 = 9 \u00b1 0.9 \u03bcg/mL), HeLa \u00ad(LC50 = 15.8 \u00b1 4.9 \u03bcg/mL) and\n 204:112583\nA549 cells (\u00ad LC50 = 20.9 \u00b1 0.8 \u03bcg/mL). Of the 15 complexes 16. Liew HS, Mai CW, Zulkefeli M, Madheswaran T, Kiew LV,\n that were used in the in vitro biological study, 1 displayed Delsuc N, Low ML (2020) Recent Emergence of Rhenium(I)\n favorable cytotoxicity \u00ad(LC50) towards HeLa and A549 cells. Tricarbonyl Complexes as Photosensitisers for Cancer Therapy.\n Molecules 25:4179\u20134199\nSupplementary Information The online version contains supplemen- 17. Mkhatshwa M, Moremi JM, Makgopa K, Manicum AE (2021)\ntary material available at https://d\u200b oi.o\u200b rg/1\u200b 0.1\u200b 007/s\u200b 00775-0\u200b 22-0\u200b 1971-2. Nanoparticles functionalised with Re(I) tricarbonyl complexes for\n cancer theranostics. Int J Mol Sci 22:6546\u20136563\nAcknowledgements We would like to thank the National Research 18. Capper MS, Enriquez Garcia A, Macia N, Lai B, Lin JB, Nomura\nFoundation South Africa (Grant No. 129468), Tshwane University of M, Alihosseinzadeh A, Ponnurangam S, Heyne B, Shemanko\nTechnology and the University of Pretoria for institutional and financial CS, Jalilehvand F (2020) Cytotoxicity, cellular localization and\nsupport. photophysical properties of Re(I) tricarbonyl complexes bound to\n cysteine and its derivatives. J Biol Inorg Chem 25:759\u2013776\n\n\n 13\n\f40 JBIC Journal of Biological Inorganic Chemistry (2023) 28:29\u201341\n\n19. Ranasinghe K, Handunnetti S, Perera IC, Perera T (2016) Synthe- 34. Striplin DR, Crosby GA (2001) Photophysical investigations of\n sis and characterization of novel rhenium(I) complexes towards rhenium(I)Cl(CO)3(phenanthroline) complexes. Coord Chem Rev\n potential biological imaging applications. Chem Cent J 10:71\u201381 211:163\u2013175\n20. Darshani T, Fronczek FR, Priyadarshani VV, Samarakoon SR, 35. Ramos LD, de Macedo LH, Gobo NRS, de Oliveira KT, Cerchi-\n Perera IC, Perera T (2020) Synthesis and characterization of novel aro G, Morelli Frin KP (2020) Understanding the photophysical\n naphthalene-derivatized tridentate ligands and their net neutral properties of rhenium(I) compounds coordinated to 4,7-diamine-\n rhenium tricarbonyl complexes and cytotoxic effects on non-small 1,10-phenanthroline: synthetic, luminescence and biological stud-\n cell lung cancer cells of interest. Polyhedron 187:114652\u2013114667 ies. Dalt Trans 49:16154\u201316165\n21. Knopf KM, Murphy BL, MacMillan SN, Baskin JM, Barr MP, 36. Manicum A-L, Alexander O, Schutte-Smith M, Visser HG\n Boros E, Wilson JJ (2017) In vitro anticancer activity and in vivo (2020) Synthesis, characterization and substitution reactions of\n biodistribution of rhenium(I) tricarbonyl aqua complexes. J Am fac-[Re(O, O\u2032-bid)(CO)3(P)] complexes, using the \u201c2+1\u201d mixed\n Chem Soc 139:14302\u201314314 ligand model. J Mol Str 1209:127953\u2013127964\n22. Murphy BL, Marker SC, Lambert VJ, Woods JJ, MacMillan SN, 37. Manicum A-LE, Schutte-Smith M, Alexander OT, Twigge L,\n Wilson JJ (2020) Synthesis, characterization, and biological prop- Roodt A, Visser HG (2019) First kinetic data of the CO substi-\n erties of rhenium(I) tricarbonyl complexes bearing nitrogen-donor tution in fac-[Re(L, L\u2032-Bid)(CO)3(X)] complexes (L, L\u2032-Bid =\n ligands. J Org Chem 907:121064\u2013121084 acacetylacetonate or tropolonate) by tertiary phosphines PTA and\n23. Stout MJ, Skelton BW, Sobolev AN, Raiteri P, Massi M, Simpson \u00adPPh3: Synthesis and crystal structures of water-soluble rhenium(I)\n PV (2020) Synthesis and photochemical properties of Re(I) tricar- tri- and dicarbonyl complexes with 1,3,5-triaza-7-phosphaada-\n bonyl complexes bound to thione and thiazol-2-ylidene ligands. mantane (PTA). Inorg Chem Comm 101:93\u201398\n Organometallics 39:3202\u20133211 38. Manicum A-LE, Schutte-Smith M, Visser HG (2018) The syn-\n24. Paparidis G, Akrivou M, Tsachouridou V, Shegani A, Vizirianakis thesis and structural comparison of fac-[Re(CO)3]+ containing\n IS, Pirmettis I, Papadopoulos MS, Papagiannopoulou D (2018) complexes with altered \u03b2-diketone and phosphine ligands. Poly-\n Synthesis and evaluation of 99mTc/Re-tricarbonyl complexes hedron 145:80\u201387\n of the triphenylphosphonium cation for mitochondrial targeting. 39. Manicum A, Schutte-Smith M, Kemp G, Visser HG (2015) Illus-\n Nucl Med Biol 57:34\u201341 tration of the electronic influence of coordinated \u03b2-diketone type\n25. Sovari SN, Golding TM, Mbaba M, Mohunlal R, Egan TJ, Smith ligands: a kinetic and structural study. Polyhedron 85:190\u2013195\n GS, Zobi F (2022) Rhenium(I) derivatives of aminoquinoline and 40. Gantsho VL, Dotou M, Jakubaszek M, Goud B, Gasser G, Visser\n imidazolopiperidine-based ligands: synthesis, in vitro and in silico HG, Schutte-Smith M (2020) Synthesis, characterization, kinetic\n biological evaluation against Plasmodium falciparum. J Inorg Bio investigation and biological evaluation of Re(I) di- and tricarbonyl\n 234:111905\u2013111915 complexes with tertiary phosphine ligands. Dalt Trans 49:35\u201346\n26. Collery P, Mohsen A, Kermagoret A, Corre S, Bastian G, Tomas 41. Priyatharsini M, Mishra I, Shankar B, Srinivasan N, Krishnaku-\n A, Wei M, Santoni F, Guerra N, Desma\u00eble D, d\u2019Angelo J (2015) mar RV, Sathiyendiran M (2021) fac-Re(CO)3 core-based complex\n Antitumor activity of a rhenium (I)-diselenoether complex in featuring benzimidazole as pendant motif from hydroxyquinoline\n experimental models of human breast cancer. Invest New Drugs and pyridylbenzimidazole. J Org Chem 953:122052\u2013122062\n 33:848\u2013860 42. Manicum A-LE, Schutte-Smith M, Malan FP, Visser HG (2022)\n27. Veena V, Harikrishnan A, Lakshmi B, Khanna S, Desmaele Steric and electronic influence of Re(I) tricarbonyl complexes with\n D, Collery P (2020) A New model applied for evaluating a various coordinated \u03b2-diketones. J Mol Str 1264:133278\u2013133290\n rhenium-diselenium drug: breast cancer cells stimulated by 43. Manicum A-L, Schutte-Smith M, Visser HG, Pretorius C, Roodt\n cytokines induced from polynuclear cells by LPS. Anticancer Res A (2016) Crystal structure of tetraethylammonium fac-tricarbo\n 40:1915\u20131920 nyl(hexafluoroacetylacetonato-\u03ba2O, O\u2032)-(nitrato-\u03baO)rhenium(I),\n28. Domenichini A, Casari I, Simpson PV, Desai NM, Chen L, Dus- C16H21O8N2F6Re. Zeits. f\u00fcr Krist. New Cryst. Str. 231:263\u2013266\n tin C, Edmands JS, van der Vliet A, Mohammadi M, Massi M, 44. Lo KK-W, Louie M-W, Sze K-S, Lau JS-Y (2008) Rhenium(I)\n Falasca M (2020) Rhenium N-heterocyclic carbene complexes polypyridine biotin isothiocyanate complexes as the first lumines-\n block growth of aggressive cancers by inhibiting FGFR- and SRC- cent biotinylation reagents: synthesis, photophysical properties,\n mediated signalling. J. Exp. Clin. Cancer Res. CR 39:276\u2013293 biological labeling, cytotoxicity, and imaging studies. Inorg Chem\n29. Artem\u2019ev AV, Petyuk MY, Berezin AS, Gushchin AL, 47:602\u2013611\n Sokolov MN, Bagryanskaya IY (2021) Synthesis and study of 45. Leonidova A, Gasser G (2014) Underestimated potential of orga-\n Re(I) tricarbonyl complexes based on octachloro-1,10-phen- nometallic rhenium complexes as anticancer agents. ACS Chem\n anthroline: towards deep red-to-NIR emitters. Polyhedron Biol 9:2180\u20132193\n 209:115484\u2013115499 46. Mansour AM (2021) Tricarbonyl triazolato Re(I) compounds of\n30. Zhong F, Yuan X, Zhao J, Wang Q (2016) Visible light-harvesting pyridylbenzimidazole ligands: spectroscopic and antimicrobial\n tricarbonyl Re(I) complex: synthesis and application in intracel- activity evaluation. RSC Adv 11:22715\u201322722\n lular photodynamic effect and luminescence imaging. Sci China 47. Schindler K, Zobi F (2022) Anticancer and antibiotic rhenium\n Chem 59:70\u201377 tri- and dicarbonyl complexes: current research and future per-\n31. Lo KK-W, Tsang KH-K, Zhu N (2006) Luminescent spectives. Molecules 27:539\u2013564\n tricarbonylrhenium(I) polypyridine estradiol conjugates: syn- 48. Mehler AH (1956) Formation of picolinic and quinolinic acids fol-\n thesis, crystal structure, and photophysical, electrochemical, and lowing enzymatic oxidation of 3-hydroxyanthranilic acid. J Biol\n protein-binding properties. Organometallics 25:3220\u20133227 Chem 218:241\u2013254\n32. Leonidova A, Pierroz V, Rubbiani R, Heier J, Ferrari S, Gasser 49. Dazzi C, Candiano G, Massazza S, Ponzetto A, Varesio L (2001)\n G (2014) Towards cancer cell-specific phototoxic organometallic New high-performance liquid chromatographic method for the\n rhenium(I) complexes. Dalt Trans 43:4287\u20134294 detection of picolinic acid in biological fluids. J. Chrom. B Biol.\n33. Leonidova A, Pierroz V, Rubbiani R, Lan Y, Schmitz AG, Kaech Sci. App. 751:61\u201368\n A, Sigel RKO, Ferrari S, Gasser G (2014) Photo-induced uncag- 50. Rebello T, L\u00f6nnerdal B, Hurley LS (1982) Picolinic acid in milk,\n ing of a specific Re(I) organometallic complex in living cells. pancreatic juice, and intestine: inadequate for role in zinc absorp-\n Chem Sci 5:4044\u20134056 tion. Am J Clin Nutr 35:1\u20135\n\n\n\n13\n\fJBIC Journal of Biological Inorganic Chemistry (2023) 28:29\u201341 41\n\n51. Peters JC (1991) Tryptophan nutrition and metabolism: an over- evaluation of 3-arylcoumarin derivatives of rhenium(I) tricarbonyl\n view. Adv Exp Med & Biol 294:345\u2013358 complexes as potent antibacterial agents against methicillin-resist-\n52. Fernandez-Pol JA, Johnson GS (1977) Selective toxicity induced ant Staphylococcus aureus (MRSA). Eur J Med Chem 205:112533\n by picolinic acid in simian virus 40-transformed cells in tissue 64. Hayes TR, Lyon PA, Barnes CL, Trabue S, Benny PD (2015)\n culture. Can Res 37:4276\u20134279 Influence of functionalized pyridine ligands on the radio/chemical\n53. Fernandez-Pol JA, Klos DJ, Hamilton PD (2001) Antiviral, cyto- behavior of [MI(CO)3]+ (M = Re and 99mTc) 2 + 1 complexes.\n toxic and apoptotic activities of picolinic acid on human immu- Inorg Chem 54:1528\u20131534\n nodeficiency virus-1 and human herpes simplex virus-2 infected 65. Brink A, Visser HG, Roodt A (2013) Activation of Rhenium(I)\n cells. Anticancer Res 21:3773\u20133776 toward substitution in fac-[Re(N, O\u2032-Bid)(CO ) 3(HOC H 3)]\n54. Alberto RA, Schibli R, Schubiger PA, Abram U, Kaden T (1996) by Schiff-Base bidentate ligands (N, O\u2032-Bid). Inorg Chem\n Reactions with the technetium and rhenium carbonyl complexes 52:8950\u20138961\n (NEt4)2[MX3(CO)3]. Synthesis and structure of [Tc(CN- 66. Czerwieniec, R.; Kapturkiewicz, A.; Anulewicz-Ostrowska, R.;\n But)3(CO)3](NO3) and (NEt4)[Tc2(\u03bc-SCH2CH2OH)3(CO)6]. Nowacki, J., ReI(CO)3+ complexes with N\u2229O\u2212 bidentate ligands.\n Polyhedron 15:1079\u20131089 J. Chem. Soc., Dalt. Trans. 2002, 3434\u20133441.\n55. Alberto, R.; Egli, A.; Abram, U.; Hegetschweiler, K.; Gramlich, V.; 67. Faller JW, Mason G, Parr J (2001) The synthesis of new com-\n Schubiger, P. A., Synthesis and reactivity of \u00ad[NEt4]2[ReBr3(CO)3]. plexes of rhenium(I) with heterotridentate [P, N, O] ligands. J Org\n Formation and structural characterization of the clusters [\u00ad NEt4] Chem 626:181\u2013185\n [Re3(\u00b53-OH)(\u00b5-OH)3(CO)9] and \u00ad[NEt4][Re2(\u00b5-OH)3(CO)6] by 68. Roodt A, Visser HG, Brink A (2011) Structure/reactivity relation-\n alkaline titration. J. Chem. Soc., Dalt. Trans. 1994, 2815\u20132820. ships and mechanism from X-ray data and spectroscopic kinetic\n56. Schibli R, La Bella R, Alberto R, Garcia-Garayoa E, Ortner K, analysis. Cryst Rev 17:241\u2013280\n Abram U, Schubiger PA (2000) Influence of the denticity of ligand 69. Booysen IN, Ebonumoliseh I, Akerman MP, Xulu B (2015) A\n systems on the in vitro and in vivo behavior of 99mTc(I)\u2212tricar- rhenium(I) compound bearing a dimerized chromone NO biden-\n bonyl complexes: a hint for the future functionalization of biomol- tate chelator. Inorg Chem Comm 62:8\u201310\n ecules. Bio Chem 11:345\u2013351 70. Schutte-Smith M, Visser HG (2015) The versatility of pyridine-\n57. Rigaku O (2018) CrysAlis PRO Soft. Syst, Rigaku Corporation, 2,5-dicarboxylic acid in the synthesis of fac-M(CO)3 complexes\n Oxford (M=Re, 99mTc): reactivity towards substitution reactions\n58. Sheldrick G (2015) SHELXT\u2014Integrated space-group and crys- and derivatization after coordination to a metal. Polyhedron\n tal-structure determination. Acta Cryst Sect A 71:3\u20138 89:122\u2013128\n59. Mundwiler, S.; K\u00fcndig, M.; Ortner, K.; Alberto, R., A new [2 + 1] 71. Triantis C, Shegani A, Kiritsis C, Ischyropoulou M, Roupa I, Psy-\n mixed ligand concept based on [99(m)Tc(OH2)3(CO)3]+: a basic charis V, Raptopoulou C, Kyprianidou P, Pelecanou M, Pirmettis\n study. Dalt. Trans. 2004, 1320\u20131328. I, Papadopoulos MS (2018) Dicarbonyl cis-[M(CO)2(N, O)(C)(P)]\n60. Li D, Zhong G-Q (2014) Synthesis, crystal structure, and thermal (M = Re, (99m)Tc) Complexes with a New [2 + 1 + 1] Donor\n decomposition of the cobalt(II) complex with 2-picolinic acid. Sci Atom Combination. Inorg Chem 57:8354\u20138363\n W J 2014:641608\u2013641615\n61. Manicum A-L, Alexander O, Schutte-Smith M, Visser HG, Roodt Publisher's Note Springer Nature remains neutral with regard to\n A (2017) Crystal structure of fac-(acetylacetonato-\u03ba2O, O\u2032)tricar jurisdictional claims in published maps and institutional affiliations.\n bonyl(benzyldiphenylphosphine-\u03baP)rhenium(I), C27H24O5PRe.\n Zeits. f\u00fcr Krist. New Cryst. Str. 232:957\u2013959 Springer Nature or its licensor (e.g. a society or other partner) holds\n62. Aleksanyan DV, Churusova SG, Rybalkina EY, Artyushin OI, exclusive rights to this article under a publishing agreement with the\n Peregudov AS, Nelyubina YV, Klemenkova ZS, Bykhovskaya author(s) or other rightsholder(s); author self-archiving of the accepted\n OV, Kozlov VA (2019) Tricarbonylrhenium(I) complexes with manuscript version of this article is solely governed by the terms of\n heterodentate ligands based on functionalized amides: synthesis, such publishing agreement and applicable law.\n structural features, and cytotoxic activity. J Org Chem 892:66\u201374\n63. Sovari SN, Vojnovic S, Bogojevic SS, Crochet A, Pavic A, Niko-\n dinovic-Runic J, Zobi F (2020) Design, synthesis and in vivo\n\n\n\n\n 13\n\f", "pages_extracted": 13, "text_length": 80539}