Rhodium(i) N-heterocyclic carbene complexes: synthesis and cytotoxic properties

{"full_text": " NJC\n View Article Online\n PAPER View Journal | View Issue\nPublished on 09 February 2021. Downloaded by Lomonosov Moscow State University on 5/12/2026 1:08:19 PM.\n\n\n\n\n Rhodium(I) N-heterocyclic carbene complexes:\n synthesis and cytotoxic properties\u2020\n Cite this: New J. Chem., 2021,\n 45, 5176 - ahin-Bo\u0308lu\u0308kbas- \u0131,c Mustafa Ulu,c Enes Evren,b Nevin Gu\u0308rbu\u0308z,bd\n Ichraf Slimani,a Serap S\n I\u0307lknur O\u0308zdemir, Naceur Hamdi *ae and I\u0307smail O\u0308zdemir *bd\n d\n\n\n\n Rhodium(I) complexes bearing N-heterocyclic carbene (NHC) ligands have been widely used in catalytic\n chemistry, but there are very few reports of biological properties of these types of complexes. A series\n of benzimidazolium salts and their [RhCl(NHC)(COD)] complexes were synthesized. The obtained\n 1 13\n complexes were synthesized and characterized by elemental analysis, FT-IR, H and C NMR.\n All compounds were screened for in vitro cytotoxic activities against a panel of human cancer cells\n (HT-29 colon, Ishikawa endometrial, and U-87 glioblastoma) using the MTT assay for 48 h of incubation\n time. Mouse fibroblast cells (L-929) were used as healthy cells. Complexes had exhibited significantly\n higher cytotoxic activity towards cancer cells than their ligands and complex 2b showed the most\n selective cytotoxic activity against HT-29 cancer cells (SI;7.05) and Ishikawa cancer cells (SI; more than\n 9.8). The complexes showed strong in vitro cytotoxic activity against cancer cells, with IC50 values of\n Received 10th January 2021, lower than 10 mM (except 2a against HT-29 (12.8 mM) and 2b against U-87 (11.1 mM)). All complexes\n Accepted 4th February 2021 (2a\u2013d) showed the highest in vitro cytotoxic activity against Ishikawa endometrial cancer cells with IC50\n DOI: 10.1039/d1nj00144b values of 2.93 \u0002 0.06, o1, 2.60 \u0002 0.05, and 2.85 \u0002 0.06 mM, respectively. Complexes were found to\n be highly cytotoxic against HT-29, Ishikawa, and U-87 cancer cells compared to the anticancer agents,\n rsc.li/njc cisplatin and 5-FU.\n\n\n\n 1. Introduction parameters of NHC complexes can be modified easily and they\n have greater stability towards air, moisture and heating when\n Ligand design is central to the development of new organometallic compared with phosphine analogs.\n and coordination compounds as they control the overall Organometallics bearing NHCs as ligands have been\n properties, the activities and the reactivities of a metal center. increasingly a focus for inorganic medicinal chemists.9\u201311 The\n Over recent years, N-heterocyclic carbenes (NHCs)1,2 are an advantages of N-heterocyclic carbene ligands and their\n interesting class of ligands with donor properties similar to chemical versatility not only imply a wide variety of structural\n phosphines.3 Since the discovery of the first N-heterocyclic diversity and coordination modes, but also a capability to form\n carbene transition metal complexes by Wanzlic4 and O\u0308fele5 in stable complexes with a large number of transition metals with\n the 1960s and later the successful isolation of a free NHC by different oxidation states.12,13 So far, metal-NHC complexes\n Arduengo in 1991,6 NHCs have become increasingly important have been mostly studied as new antibacterial and anticancer\n and the development of NHC metal complexes is now a well- agents. Although research on anti-infectives has been largely\n established area of research.7,8 The electronic and steric focused on silver(I)\u2013NHC complexes,14\u201321 gold(I)\u2013NHC derivatives\n are the most studied examples concerning new anticancer\n a\n Research Laboratory of Environmental Sciences and Technologies (LR16ES09), agents.18\u201326 Besides silver and gold, other metals including\n Higher Institute of Environmental Sciences and Technology, University of palladium,27\u201329 platinum,30\u201334 ruthenium35\u201337 and rhodium31\n Carthage, Hammam-Lif, Tunisia. E-mail: naceur.hamdi@isste.rnu.tn\n b\n have also been used as bioactive complexes. However, the anti-\n Ino\u0308nu\u0308 University, Catalysis Research and Application Center, 44280 Malatya,\n Turkey. E-mail: ismail.ozdemir@inonu.edu.tr\n cancer properties of rhodium(I)-N-heterocyclic carbene complexes\n c\n Sivas Cumhuriyet University, Faculty of Pharmacy, Department of Biochemistry, have rarely been studied.38\u201340 Rhodium(I) is isoelectronic with\n 58140 Sivas, Turkey platinum(I), and rhodium(I)-NHC complexes have a square planar\n d\n Ino\u0308nu\u0308 University, Faculty of Science and Arts, Department of Chemistry, geometry like cis-platinum, a clinically used anticancer drug.\n 44280 Malatya, Turkey\n e\n In a recent study, we have reported the synthesis of azolium\n Department of Chemistry, College of Science, Qassim University, Buraidah, 51452,\n Saudi Arabia\n salts and their silver(I), gold, ruthenium, and palladium complexes,\n \u2020 Electronic supplementary information (ESI) available. See DOI: 10.1039/ which were tested as potential biologically active agents.41\u201350\n d1nj00144b In this work, we report the synthesis and characterization of\n\n\n\n 5176 | New J. Chem., 2021, 45, 5176\u00035183 This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021\n\f View Article Online\n\n Paper NJC\nPublished on 09 February 2021. Downloaded by Lomonosov Moscow State University on 5/12/2026 1:08:19 PM.\n\n\n\n\n Scheme 1 Synthesis of rhodium\u2013NHC complexes.\n\n\n\n 1,3-dialkylbenzimidazolium salts (1a\u2013d) and novel benzimidazol- ether (15 mL) was added to obtain a white crystalline solid,\n 2-ylidene rhodium(I) (2a\u2013d) complexes of the general formula which was subsequently filtered off. The solid was washed with\n [RhCl(NHC)(COD)] (2a\u2013d) (Scheme 1). The cytotoxic properties of diethyl ether (3 \u0004 10 mL), dried under vacuum and the crude\n the synthesized benzimidazolium salts (1a\u2013d) and rhodium product was recrystallized from dichloromethane/diethyl ether\n complexes (2a\u2013d) were tested against the human cancer cell lines, (1 : 3 ratio).\n HT-29 colon, Ishikawa endometrial, and U-87 glioblastoma. 2.2.1. 1-(isoButyl)-3-(2,3,4,5,6-pentamethylbenzyl)-5,6-dimethyl-\n benzimidazolium chloride, (1a). Yield 93%, mp: 219.9 1C, n(CN) =\n 1550 cm\u00031. 1H NMR (CDCl3, 400 MHz) d (ppm) 0.98 (d, 6H,\n 2. Materials and methods CH3(a,b), J = 8 Hz), 2.14 (hept., 1H, H20 , J = 8 Hz), 2.25 (s, 6H,\n CH3(c,d)), 2.28 (s, 3H, CH3(e)), 2.30 (s, 6H, CH3(f,h)), 2.32 (s, 3H,\n 2.1. Materials and measurements\n CH3(i)), 2.41 (s, 3H, CH3(g)), 4.46 (d, 2H, H10 , J = 8 Hz), 5.80 (s, 2H,\n All reactions for the preparation of benzimidazolium salts and H100 ), 7.05 (s, 1H, H7), 7.38 (s, 1H, H4), 10.48 (s, 1H, H2). 13C NMR\n their complexes were carried out under argon in flame-dried (CDCl3, 100 MHz) d (ppm) 16.9 (Cf,h), 17.1 (Ce,i), 17.3 (Cg), 19.7\n glassware using standard Schlenk techniques. Chemicals and (Ca,b), 20.6 (Cc,d), 28.7 (C20 ), 47.9 (C100 ), 54.1 (C10 ), 112.7 (C4), 113.4\n solvents were purchased from Sigma-Aldrich, and Merck. The (C7), 125.2 (C500 ), 129.9 (C8), 130.43 (C9), 133.8 (C300 ;700 ), 133.5 (C400 ;600 ),\n solvents used were purified by distillation over the drying 136.8 (C5), 136.9 (C6), 137.1 (C200 ), 142.3 (C2).\n agents indicated and were transferred under Ar:Et2O, and 2.2.2. 1-(isoButyl)-3-(2,3,4,5,6-pentamethylbenzyl)benzimi-\n THF (Na/K alloy), CH2Cl2 (P4O10), hexane, and toluene (Na). dazolium chloride, (1b). Yield 92%, mp: 198.2 1C, n(CN) = 1546 cm\u00031.\n Melting points were measured in open capillary tubes with an 1\n H NMR (CDCl3, 400 MHz) d (ppm) = 1.05 (d, 6H, CH3 (a,b),\n Electrothermal-9200 melting point apparatus and are uncor- J = 4 Hz), 2.24 (s, 6H, CH3(c,g)), 2.28 (s, 6H, CH3(d,f)), 2.28 (s, 3H,\n rected. IR spectra were recorded using an ATR unit in the range CH3(e)), 2.38 (Hep, 1H, H2 0 , J = 8 Hz), 4.51 (d, 2H, H1 0 , J = 8 Hz),\n of 400\u20134000 cm\u00031 with a PerkinElmer Spectrum 100 spectro- 5.94 (s, 2H, H100 ), 7.22\u20137.70 (m, 4H, H4,5,6,7), 11.29 (s, 1H, H2).\n photometer. 1H NMR and 13C NMR spectra were recorded using 13\n C NMR (CDCl3, 100 MHz) d (ppm) =16.9 (Cc,g), 17.1 (Cd,f), 17.3\n a Varian As 400 Merkur spectrometer operating at 400 MHz (1H) (Ce), 19.7 (Ca,b), 28.8 (C2 0 ), 48.5 (C100 ), 54.2 (C1 0 ), 113.0 (C4), 113. 8\n and 100 MHz (13C) in CDCl3 with tetramethylsilane as an (C7), 125.1 (C500 ), 126.8 (C5), 126.9 (C6), 131.3 (C400 ), 131.8 (C600 ),\n internal reference. Coupling constants (J values) are given in 133.5 (C300 ;700 ), 133.8 (C8;9), 137.2 (C200 ), 143.7 (C2).\n hertz. NMR multiplicities are abbreviated as follows: s = singlet, 2.2.3. 1-(isoButyl)-3-(2,4,6-trimethylbenzyl)-5,6-dimethyl-\n d = doublet, t = triplet, and m = multiplet signal. benzimidazolium chloride (1c). Yield 89%, mp: 249.7 1C,\n n(CN) = 1550 cm\u00031. 1H NMR (CDCl3, 400 MHz) d (ppm) = 1.01\n 2.2. General procedure for the synthesis of benzimidazolium (d, 6H, CH3(a,b), J = 8 Hz), 2.29 (s, 3H, CH3(c)), 2.30 (s, 3H,\n salts CH3(d)), 2.32 (s, 6H, CH3(e,g)), 2.40 (s, 3H, CH3(f)), 2.44 (Hep, 1H,\n The following benzimidazolium salt (1a\u2013d) precursors were H2 0 , J = 8 Hz), 4.40 (d, 2H, H1 0 , J = 8 Hz), 5.84 (s, 2H, H100 ), 6.9\u2013\n synthesized according to the literature.46,48 7.38 (m, 4H, H4,7,400 , 600 ), 11.34 (s, 1H, H2). 13C NMR (CDCl3,\n The benzimidazolium salts 1a\u2013d were prepared by reacting 100 MHz) d (ppm) = 19.7 (Ca,b), 20.2 (Cc,d), 20.6 (Ce), 20.8 (Cg),\n 1-isobutylbenzimidazole (1 mmol) with various alkyl chlorides 21.0 (Cf), 28.7 (C2 0 ), 47.1 (C100 ), 54.1 (C1 0 ), 112.6 (C4), 113.5 (C7),\n (1.1 mmol) in dimethylformamide (5 mL) at 80 1C and the 125.4 (C400 ;600 ), 130.0 (C300 ;500 ;700 ), 137.0 (C8;9), 137.8 (C5;6), 139.5\n resulting mixture was stirred for 24 hours (Scheme 1). Diethyl (C200 ), 142.9 (C2).\n\n\n\n This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021 New J. Chem., 2021, 45, 5176\u00035183 | 5177\n\f View Article Online\n\n NJC Paper\n\n 2.2.4. 1-(isoButyl)-3-(2,4,6-trimethylbenzyl)benzimidazolium (d, 2H, CHCOD, H400 0 ,500 0 , J = 8 Hz), 3.80 (s, 9H, CH3(e,f,g)), 4.73\n chloride (1d). Yield 94%, C21H27ClN2, M = 342.91 g mol\u00031, mp: (d, 2H, CHCOD, H100 0 ,800 0 , J = 8 Hz), 5.14 (d, 2H, H1 0 , J = 8 Hz), 6.06\n 218.3 1C, n(CN) = 1469 cm\u00031. 1H NMR (CDCl3, 400 MHz) d (ppm) (s, 2H, H100 ), 6.74 (s, 2H, H300 ,700 ), 7.26 (s, 2H, H4,7). 13C NMR\n 1.00 (d, 6H, CH3 (a,b), J = 8 Hz), 2.25 (s, 3H, CH3(d)), 2.28 (s, 6H, (CDCl3, 100 MHz) d (ppm) 20.2 (Cc), 20.2 (Cd), 20.6 (Ca), 20.8\n CH3(c,e)), 2.37 (hept, 1H, H20 , J = 8 Hz), 4.42 (d, 2H, H10 , J = 8 Hz), (Cb), 28.1 (C2 0 ), 29.1, (C600 0 ), 29.5 (C700 0 ), 32.2(C300 0 ), 33.5 (C200 0 ), 53.1\n 5.90 (s, 2H, H100 ), 6.88 (s, 2H, H400 ,600 ), 7.10 (d, 1H, H4, J = 8 Hz), 7.37 (C100 ), 55.6 (C1 0 ), 56.5 (Ce;g), 60.8 (Cf), 99.5 (C400 0 ), 99.5 (C500 0 ), 99.9\nPublished on 09 February 2021. Downloaded by Lomonosov Moscow State University on 5/12/2026 1:08:19 PM.\n\n\n\n\n (t, 1H, H5, J = 8 Hz), 7.51(t, 1H, H6, J = 8 Hz), 7.64(d, 1H, H7, J = (C100 0 ), 100.0 (C800 0 ), 104.8 (C300 ;700 ), 110.7 (C4), 111.3 (C7), 128.8,\n 8 Hz), 11.61 (s, 1H, H2). 13C NMR (CDCl3, 100 MHz) d (ppm) 19.8 131.1 (C200 ), 131.9 (C8,9), 132.9 (C5), 134.4 (C5), 137.4 (C500 ), 153.4\n (C(c,e)), 20.3 (C(a,b)), 21.1(C(d)), 28.9 (C20 ), 47.5 (C100 ), 54.3 (C10 ), 113.1 (C400 ,600 ), 194.9 (d, J = 50.0 Hz) (C2).\n (C4), 114.0 (C7), 125.2 (C5;6), 126.9 (C400 ), 127.1 (C600 ), 130.2 (C8), 2.3.4. Chloro[1-((isobutyl)-3-(2,4,6-trimethylbenzyl)\n 131.3 (C9), 131.8 (C300 ), 137.9 (C500 ;700 ), 139.6 (C200 ), 144.2 (C2). benzimidazole-2-ylidene] rhodium(I) 2d. Yield 79%, mp:\n 206.1 1C, n(CN) = 1452 cm\u00031. 1H NMR (CDCl3, 400 MHz)\n 2.3. General procedure for the synthesis of the rhodium d (ppm) 1.05 (d, 6H, CH3(a,b), J = 8 Hz, J = 8 Hz), 1.85\u20132.15\n carbene complexes (m, 4H, CH2COD, H200 0 ,300 0 ), 2.26\u20132.59 (m, 4H, CH2COD, H600 0 ,700 0 ),\n A solution of benzimidazolium salts (1a\u2013d) (10 mmol) and 2.99 (Hep, 1H, H2 0 ), 3.32 (d, 2H, CHCOD, H400 0 ,500 , J = 8 Hz 0 ), 3.80\n rhodium dimer [RhOMe(COD)]2 (5 mmol) in THF (15 mL) was (d, 9H, CH3(c,d,e)), 4.58 (d, 2H, CHCOD, H100 0 ,800 0 , J = 8 Hz), 5.16\n stirred and heated under reflux for 5 h. Upon cooling to room (d, 2H, H1 0 , J = 8 Hz), 6.07 (s, 2H, H100 ), 6.75 (s, 2H, H300 ,700 ), 7.03\u2013\n temperature, yellow crystals of (2a\u2013d) were obtained. The 7.34 (m, 4H, H4,5,6,7). 13C NMR (CDCl3, 100 MHz) d (ppm) 20.6\n crystals were filtered, washed with diethyl ether (2 \u0004 15 mL) (Ca), 20.8 (Cb), 28.1 (C2 0 ), 29.2, (C600 0 ), 29.5 (C700 0 ), 32.1(C300 0 ), 33.6\n and dried under vacuum. The crude product was recrystallized (C200 \u2019), 53.4 (C100 ), 55.7 (C1), 56.4 (Cc;e), 60.8 (Cd), 99.8 (C400 0 ), 99.9\n from CH2Cl2/Et2O. (C500 0 ), 100.3 (C100 0 ), 100.3 (C800 0 ), 104.8 (C300 ;700 ), 110.2 (C4), 111.0\n 2.3.1. Chloro[1-isobutyl-3-(2.3.4.5.6-pentamethylbenzyl)- (C7), 127.2 (C5,6), 131.6 (C8), 134.3 (C9), 135.8, (C200 ), 137.4 (C500 ),\n 5,6-dimethylbenzimidazole-2-ylidene]rhodium(I) 2a. Yield 78%, 153.2 (C400 ,600 ), 196.8 (d, J = 50.2 Hz) (C2).\n mp: 228.6 1C, n(CN) = 1450 cm\u00031. 1H NMR (CDCl3, 400 MHz)\n d (ppm) 1.07 (d, 6H, CH3 (a,b) J = 8 Hz), 1.94 (d, 4H, CH2COD, 2.3. Cell lines and culture conditions\n H200 0 ,300 0 , J = 8 Hz), 2.23 (s, 3H, CH3(g)), 2.25 (s, 6H, CH3(c,d)), 2.30 Human colorectal adenocarcinoma HT-29 (ATCCs HTB-38t),\n (m, 12H, CH3(e,f,h,i)), 2.35\u20132.55 (m, 4H, CH2COD, H600 0 ,700 0 ), 2.96 human brain glioblastoma U-87 (ATCCs HTB-14t), FBS (ATTC,\n (Hep, 1H, H2 0 , J = 8 Hz), 3.47 (d, 2H, CHCOD, H400 0 ,500 0 , J = 8 Hz), FBS, 30-2020), RPMI-1640 media (ATTC, 30-2001), and\n 4.51 (d, 2H, CHCOD, H100 0 ,800 0 , J = 8 Hz), 5.12 (d, 2H, H1 0 , J = 8 Hz), 100 units per mL penicillin and 100 mg mL\u00031 streptomycin\n 5.91 (m, 2H, H100 ), 6.40\u20137.26 (m, 2H, H4,7). 13CNMR (CDCl3, (ATTC, 30-2300) were obtained from the American Type Culture\n 100 MHz) d (ppm) 16.8 (Cf,h), 17.2 (Ce,i), 17.3 (Cg), 20.1 (Ca), 20.3 Collection (ATCC; Manassas, VA, USA). Human endometrial\n (Cb), 20.6 (Cc), 20.9 (Cd), 28.3 (C2 0 ), 29.2 (C600 0 ), 29.3 (C700 0 ), 32.5 adenocarcinoma Ishikawa (ECACC, 99040201) and L-929 mouse\n (C300 0 ), 33.3 (C200 0 ), 51.2 (C100 ), 55.6 (C1 0 ), 99.0 (C400 0 ), 99.1 (C500 0 ), adipose fibroblast cells L929(NCTC) (ECACC 85103115) were\n 99.1 (C100 0 ), 99.2 (C800 0 ), 110.2 (C4), 111.8 (C7), 125.2 (C500 ), 128.6 supplied by European Collection of Authenticated Cell Cultures\n (C8;9), 130.3 (C300 ;700 ), 130.4 (C400 ;600 ), 132.8 (C5;6), 135.6 (C200 ,5\u2019\u2019), (ECACC) (Salisbury, UK). Dulbecco\u2019s modified Eagle\u2019s medium\n 194.8 (d, J =50.1Hz) (C2). (DMEM, D6429), MTT, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-\n 2.3.2. Chloro[1-isobutyl-3-(2,3,4,5,6-pentamethylbenzyl)benzi- tetrazolium bromide; M-2128) and trypsin\u2013EDTA solution\n midazole-2-ylidene]rhodium(I) 2b. Yield 80%, mp: 225.6 1C, (T-3924) were purchased from Sigma-Aldrich Chemie GmbH\n n(CN) = 1483 cm\u00031. 1H NMR (CDCl3, 400 MHz) d (ppm) 1.08 (Steinheim, Deutschland). The cells were grown in T-75 flasks\n (d, 6H, CH3 (a,b) J = 8 Hz), 1.86\u20132.13 (m, 4H, CH2COD, H200 0 ,300 0 ), in an incubator with 5% CO2, 95% humidity, at 37 1C using a\n 2.26 (s, 12H, CH3(c,d,f,g)), 2.32 (s, 3H, CH3(e)), 2.36\u20132.60 (m, 4H, culture medium, supplemented with 10% fetal bovine serum\n CH2COD, H600 0 ,700 0 ), 2.99 (Hept, 1H, H2 0 J = 8 Hz), 3.49 (d, 2H, and antibiotics. HT-29, Ishikawa, and U-87 cells were grown in\n CHCOD, H400 0 ,500 J = 8 Hz 0 ), 4.54 (d, 2H, CHCOD, H100 0 ,800 0 J = 8 Hz), Dulbecco\u2019s Modified Eagle\u2019s Medium (DMEM), and L-929\n 5.15 (d, 2H, H1 0 , J = 8 Hz), 6.04 (s, 2H, H100 ), 6.46\u20137.26 (m, 4H, healthy cells were cultured in RPMI-1640 medium. All cell lines\n H4,5,6,7). 13C NMR (CDCl3, 100 MHz) d (ppm) 16.8 (Cc,g), 17.2 were subcultured when they reached 70\u201380% confluency.\n (Cd,f), 17.3 (Ce), 20.7 (Ca), 21.0 (Ca), 28.3 (C2 0 ), 29.2 (C600 0 ), 29.5 2.3.1 Cell viability assay. The in vitro cytotoxic activities of\n (C700 0 ), 32.4 (C300 0 ), 33.3 (C200 0 ), 51.6 (C100 ), 55.7 (C1 0 ), 99.4 (C400 0 ,500 0 ), the salts (1a\u2013d) and Rh complexes (2a\u2013d) toward cancer cell\n 99.6 (C100 0 ,800 0 ), 109.8 (C4), 111.1 (C7), 121.4 (C5), 122.0 (C6), 128.4 lines (HT-29, Ishikawa, and U-87) were evaluated with the MTT\n (C400 ,600 ), 133.0 (C300 ;700 ), 135.0 (C8), 135.6 (C9), 135.7 (C200 ,500 ), 196.7 assay.51 In brief, 1 \u0004 105 cells per mL were seeded in 96-well\n (d, J =50.2 Hz) (C2). microplates in respective media (100 mL) and incubated at 37 1C\n 2.3.3. Chloro[1-(isobutyl)-3-(2,4,6-trimethylbenzyl)-5,6- in a 5% CO2 atmosphere under the 95% humidified condition.\n dimethylbenzimidazole-2-ylidene]rhodium(I) 2c. Yield 87%, After incubation for 24 h for the cell attachment, the cells were\n mp: 209.3 1C, n(CN) = 1433 cm\u00031. 1H NMR (CDCl3, 400 MHz) treated with different concentrations of the salts (1\u2013100 mM)\n d (ppm) 1.07 (d, 6H, CH3 (a,b), J = 8 Hz), 1.79\u20132.13 (m, 4H, and complexes (1\u201330 mM) and incubated for 48 h. All compounds\n CH2COD, H200 0 ,300 0 ), 2.21 (d, 6H, CH3(c,d), J = 8 Hz), 2.33\u20132.56 were dissolved in DMSO and diluted in the complete culture medium\n (m, 4H, CH2COD, H600 0 ,700 0 ), 2.89 (Hep, 1H, H2 0 , J = 8 Hz), 3.31 (DMSO concentration in each well would not exceed 0.5%).\n\n\n\n 5178 | New J. Chem., 2021, 45, 5176\u00035183 This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021\n\f View Article Online\n\n Paper NJC\n\n The same amount of DMSO was added to the control wells. resonance signals of benzimidazolium C2 proton at 10.48,\n At the end of the incubation time, 10 mL MTT (5 mg mL\u00031, in 11.29, 11.34 and 11.61 ppm and C2 carbon at 142.3, 143.7,\n PBS, pH 7.2) was added to each well. After incubation for 2 h 142.9 and 144.2 ppm for 1a\u2013d, respectively, in 1H NMR and 13C\n with an MTT solution at 37 1C, the medium was removed and NMR spectra. The 13C-NMR chemical shifts, which provide a\n 100 mL of DMSO was added. The cell viability was analyzed by useful diagnostic tool for metal carbene complexes, show that\n measuring the absorbance at 570 nm using a BioTek plate reader Ccarbene is substantially deshielded. The resonance of the\nPublished on 09 February 2021. Downloaded by Lomonosov Moscow State University on 5/12/2026 1:08:19 PM.\n\n\n\n\n (BioTek, Epoch, USA). carbene carbon of rhodium complexes was observed as a\n doublet at 194.8, 196.7, 194.9 and 196.8 ppm; and coupling\n 2.4. Statistical analysis constants J(103Rh\u201313C) were 50.1, 50.2, 50.0 and 50.2 Hz for\n The data presented here are means of at least three independent 2a\u2013d, respectively, in 13C NMR spectra (see ESI\u2020). These values\n experiments; in a single experiment, each concentration was were similar to those found for other rhodium(I) carbene\n assayed in triplicate. All results are expressed as means \u0002 SD. complexes.56\u201358\n Data were analyzed using one-way analysis of variance and 3.2. Cytotoxic activity\n di\ufb00erences were considered significant at *p o 0.05, **p o\n 0.005, #p o 0.0005, and ##p o 0.0001. IC50 values (drug Salts (1a\u2013d) and Rh complexes (2a\u2013d) were screened for their\n concentrations responsible for 50% cell growth inhibition) were in vitro anticancer activities on HT-29, Ishikawa, and U-87\n calculated by GraphPad Prism 7 (GraphPad Software, San Diego, cancer cell lines using the MTT test in the different concen-\n CA, USA). tration range. After 48 h of treatment, a significant reduction in\n cell survival was observed depending on the concentration of\n the compounds and cell line type as shown in Fig. 1(a\u2013h). The\n 3. Results and discussion IC50 values (the half-maximal inhibitory concentration) of the\n salts (1a\u2013d) and Rh complexes (2a\u2013d) are given in Table 1.\n 3.1. Synthesis of benzimidazolium salts and their rhodium(I) The IC50s for complexes (2a\u2013d) were higher in healthy cells\n complexes compared to the HT-29 human colon adenocarcinoma cells and\n According to the literature,46,48 ligand precursors (1a\u20131d) were Ishikawa human endometrial adenocarcinoma, suggesting that\n synthesized by quaternization of 1-isobutyl-benzimidazole in DMF complexes possessed noteworthy selectivity for these cells. The\n with the corresponding benzyl chlorides in nearly quantitative selectivity index was calculated by dividing the IC50 values of\n yield, 89\u201394% (Scheme 1). The salts are stable in solid-state and the compound into healthy cells by the IC50 value of the same\n solution in air and moisture. All salts are soluble in chlorinated compound in cancer cells. Compounds with SI values of 3 and\n solvents, alcohols, and water. The NCHN protons appear in the above represent more toxicity towards cancer cells compared to\n 1\n H NMR range of 1a\u20131d at 10.48, 11.29, 11.34 and 11.61 ppm, healthy cells. SI values of complexes (2a\u2013d) against HT-29 and\n respectively, and these downfield signals confirm the formation of Ishikawa cells were found to be o1, 7.05, 2.31, 3.11 and 3,\n the benzimidazolium salts. The 1H-NMR shifts of 1b\u20131d are 49.8, 7.04, 4.26, and 2.20, respectively. Ishikawa cells were the\n identical to those of the other characterized benzimidazolium most sensitive to compounds displaying the IC50 range from\n salts.18,20,21 o1 to 2.60 \u0002 0.05 mM. The most important result was obtained\n NHC-Rh complexes are prepared using a variety of methods: with the complex 2b exhibiting the highest in vitro cytotoxic\n (i) reaction of a free carbene with dimeric precursor activity against the Ishikawa and HT-29 cancer cells, with IC50\n [Rh(COD)Cl2]2,52 (ii) in situ deprotonation of azolium salts with values o1 mM and 1.39 \u0002 0.05 mM, respectively. The results\n a rhodium dimer [Rh(OMe)COD]2,53 (iii) reaction of electron-rich showed that complex 2b was the most selectively toxic towards\n enetetramines with [Rh(COD)Cl2]2 under CQC bond cleavage,54 Ishikawa and HT-29 cancer cells with SI values 49.8 and 7.05,\n (iv) transfer of the carbene unit from the silver(I)\u2013NHC complex respectively. Complexes 2a and 2c were also determined to be\n to the rhodium metal.55 We chose the second preparation toxic towards Ishikawa endometrium cancer cells with SI values\n pathway for the synthesis of Rh(I)\u2013NHC complexes. The advantage of 3 (IC50: 2.93 \u0002 0.06 mM) and 4.26 (IC50: 2.60 \u0002 0.05 mM),\n of this route is that no pre-generation of the free carbene is respectively. Complex 2d was determined to be toxic against HT-29\n necessary and the methoxy ligands are protonated to give colon cancer cells with SI values of 3.11 (IC50: 2.02 \u0002 0.03 mM).\n methanol upon reaction with the benzimidazolium salt. Rhodium As the SI values of complexes (2a\u2013d) against U-87 glioblastoma\n N-heterocyclic carbene complexes 2a\u2013d were prepared by treatment cells were lower than 2, they did not show significant selective\n of rhodium dimer [Rh(OMe)COD]2 with two equivalents of 1,3- in vitro cytotoxic activity on U-87 cells. Our result also indicated\n dialkylbenzimidazolium chloride salts in tetrahydrofuran that complexes (2a\u2013d) have greater selectivity (SI values of\n under reflux. The complexes 2a\u2013d were obtained as yellow- from o1 to 49.8) against cancer cells than cisplatin and\n orange crystalline solids in 78\u201387% yields (Scheme 1). 5-FU (SI values of from o1 to 1.27). Complexes did not have\n The new Rh complexes are very stable in the solid-state and greater cytotoxic activity than 5-FU against U-87 glioblastoma\n have been characterized by 1H and 13C-NMR spectroscopy and cells and cisplatin against L-929 cells. Complexes display\n FTIR. They show a characteristic (NCN) band at 1450, 1483, greater cytotoxic activity than cisplatin against HT-29 colon\n 1433 and 1452 cm\u00031 for 2a\u2013d, respectively. The formation of cancer cells (with 1.24, 11.24-fold, 3.32-fold, 7.87-fold, 2a,\n Rh(I)\u2013NHC complexes 2a\u2013d was confirmed by the loss of the 2b, 2c, and 2d, respectively), Ishikawa endometrial cancer cells\n\n\n\n This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021 New J. Chem., 2021, 45, 5176\u00035183 | 5179\n\f View Article Online\n\n NJC Paper\nPublished on 09 February 2021. Downloaded by Lomonosov Moscow State University on 5/12/2026 1:08:19 PM.\n\n\n\n\n Fig. 1 Dose-dependent in vitro cytotoxic activities of the ligands (1a\u2013d) and Rh complexes (2a\u2013d) on HT-29 colon, Ishikawa endometrial, U-87\n glioblastoma and L-929 healthy cells of 48 h incubation (n = 9). Data are representative of the mean of three separate experiments and are reported at\n the \u0002SD. (*p o 0.05, **p o 0.005, #p o 0.0005, ##p o 0.0001 vs. control).\n\n\n\n\n 5180 | New J. Chem., 2021, 45, 5176\u00035183 This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021\n\f View Article Online\n\n Paper NJC\n\n Table 1 In vitro cytotoxic activities of compounds for 48 h of incubation time\n\n IC50 (mM)a\n Compounds HT-29 Ishikawa U-87 L-929b SIHT-29 SIISH SIU-87\n Salts\n 1a 71.9 \u0002 0.03 7.80 \u0002 0.08 19.6 \u0002 0.04 26.3 \u0002 0.98 o1 3.37 1.34\n 1b 9.58 \u0002 0.05 12.5 \u0002 0.03 21.9 \u0002 0.02 17.9 \u0002 0.04 1.86 1.43 o1\nPublished on 09 February 2021. Downloaded by Lomonosov Moscow State University on 5/12/2026 1:08:19 PM.\n\n\n\n\n 1c 12.3 \u0002 0.02 4.71 \u0002 0.07 9.73 \u0002 0.06 13.6 \u0002 0.01 1.11 2.88 1.39\n 1d 14.6 \u0002 0.06 9.36 \u0002 0.12 10.2 \u0002 0.02 14.7 \u0002 0.03 1.00 1.57 1.44\n Complexes\n 2a 12.8 \u0002 0.02 2.93 \u0002 0.06 6.59 \u0002 0.02 8.78 \u0002 0.04 o1 3 1.33\n 2b 1.39 \u0002 0.05 o1 11.5 \u0002 0.04 9.81 \u0002 0.02 7.05 49.8 o1\n 2c 4.79 \u0002 0.06 2.60 \u0002 0.05 8.24 \u0002 0.02 11.1 \u0002 0.09 2.31 4.26 1.34\n 2d 2.02 \u0002 0.03 2.85 \u0002 0.06 6.81 \u0002 0.02 6.30 \u0002 0.01 3.11 2.20 o1\n Cisplatinc 15.9 \u0002 1.2759 1360 36.2 \u0002 1.5561 16.5 \u0002 2.3862 1.03 1.27 o1\n 5-FUd 4100 4100 8.22 \u0002 0.3763 0.55 \u0002 0.0464 o1 o1 o1\n a\n IC50 \u0002 SD values are determined by the MTT assay. SD, standard deviation. b Healthy cells (mouse adipose fibroblast). c Cisplatin and d5-FU,\n 5-fluorouracil were standard drugs. See the Experimental section for full details. HT-29,; human colon adenocarcinoma; Ishikawa, human\n endometrial adenocarcinoma; U-87, human brain glioblastoma. d SI, selectivity index calculated [IC50 for healthy cell]/[ IC50 for cancer cell].\n\n\n\n (with 4.43-fold, 413-fold, 5-fold, 4.56-fold, 2a, 2b, 2c, and 2d, their cytotoxic activity against HT29, T47D, A2780 and A2780cisR\n respectively), and U-87 glioblastoma cells (5.49-fold, 3.14-fold, cancer cell lines. They had reported that the cytotoxic activity of\n 4.40-fold, 5.31-fold, 2a, 2b, 2c, and 2d, respectively). Complexes complexes depends on the metal center. The IC50 values of the\n have been found to have quite high cytotoxic activity on HT-29 Rh-complex with the methyl ligand were found to be 450, 8.97,\n colon cancer cells (with 47.8-fold, 472-fold, 43.32-fold, 8.05 and 5.27 mM and those of the Rh-complex with the benzyl\n o49.5-fold, 2a, 2b, 2c, and 2d, respectively) and Ishikawa cancer ligand were found to be 5.37, 22, 6.64 and 4.36 mM for HT29,\n cells (with 434.3-fold, 4100-fold, 438.5-fold, 435.1-fold, 2a, 2b, T47D, A2780 and A2780cisR cancer cells, respectively. Researchers\n 2c, and 2d, respectively) compared to 5-FU. also found that the cytotoxicity of the Rh-complexes against the\n Although Pt-based cytotoxic agents, such as cisplatin, carbo- HT-29, T47D and A2780cisR cell lines is higher than that of the\n platin, and oxaliplatin, are e\ufb00ective in treating di\ufb00erent types of widely used drug, cisplatin, under similar conditions.68\n cancer, their use has been limited because of their high\n toxicities.65 Recent relevant studies are based on testing transition\n metal complexes other than platinum(II). The anticancer 4. Conclusions\n properties of some Rh(II) and Rh(III) complexes have also been\n evaluated. Researchers designed, synthesized and investigated In the present study, a series of 1,3-dialkylbenzimidazolium\n the cytotoxic activity of Rh(III) complexes with thiabendazole salts and their [RhCl(NHC)(COD)] complexes were synthesized\n and N-benzyl-thiabendazole ligands. Cytotoxic activity of and characterized by an appropriate method. The in vitro\n complexes was determined against A549 human lung and cytotoxic e\ufb00ect of the new ligands and Rh-NHC complexes\n SW480 human colon cancer cells using the MTT assay for was evaluated against the human colon (HT-29), endometrial\n 24 h of incubation. IC50 values of Rh-complexes (IC50s for (Ishikawa) and glioblastoma (U-87) cancer cells. Rh-NHC\n A549 10.3 \u0002 0.1 and 4.1 \u0002 0.2 mM; IC50s for SW480 7.7 \u0002 0.4 complexes showed larger in vitro cytotoxic e\ufb00ects than ligands\n and 3.3 \u0002 0.1 mM) were found to be lower than cisplatin against on HT-29, Ishikawa and U-87 cells. Complex 2b showed a\n both cell lines. It was also determined that bearing the N-benzyl- significant selectivity index (SI) for Ishikawa (49.8) and HT-29\n thiabendazole ligand exhibits higher cytotoxic activity than (7.05) cancer cells. Furthermore, the IC50 values suggest that the\n bearing thiabendazole ligands.66 Rh-complex is a potential anticancer candidate against the HT-29\n Esteghamat-Panah et al. synthesized a mononuclear Rh(III) and especially Ishikawa cell lines. Results also showed that\n complex and characterized it by elemental analysis and spectro- complexes were more cytotoxic against cancer cells than cisplatin\n scopic techniques with the bzimpy ligand in the in vitro anti- and 5-FU which are widely used chemotherapeutic drugs.\n cancer activity of the ligand and the complex was assessed\n against human breast (MCF-7), leukemia (K562), and colorectal\n (HT-29) cancer cells by the MTT assay. Results showed that the Conflicts of interest\n complex was more cytotoxic than the bzimpy ligand (IC50s for There are no conflicts to declare.\n the bzimpy ligand and the Rh-complex, 114.66, 130.40, 95.74 and\n 8.14, 19.40, 43.02 against MCF-7, K562, and HT-29, respectively)\n and has the highest cytotoxic e\ufb00ect on MCF-7 breast cancer cells, Acknowledgements\n also the complex was more cytotoxic against MCF-7 and HT-29\n cancer cells than cisplatin.67 Yellol et al. synthesized benzimi- This work was financially supported by the I\u0307no\u0308nu\u0308 University\n dazole Ru, Ir and Rh cyclometalated complexes and screened for Research Fund (I\u0307U\u0308-BAP: FOA-2018-1135). Cytotoxic activity\n\n\n\n This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021 New J. Chem., 2021, 45, 5176\u00035183 | 5181\n\f View Article Online\n\n NJC Paper\n\n experiments have been carried out at Sivas Cumhuriyet 23 R. Visbal, V. 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