untitled ISSN 215 Pd(II) a Synthes Abbas Wa 1 Department of 2 The School of C * Corresponding Tel.: +964.780.3 ARTICLE IN DOI: 10.5155/e Received: 20 De Received in rev Accepted: 09 Ja Published onlin Printed: 31 Mar KEYWORDS HCT 116 Anticancer Ag(I) complexe Pd(II) complexe Trans‐metallati N‐heterocyclic 1. Introduct The use o synthesis o received mu chemistry o recent attent them, NHC‐s for the num the palladium favorable an biological an metal‐carben agents with therapeutics anticancer a complexes w complexes h cancer cells, the infected be noted tha depending o prevent or a the cell mem 53‐2249 (Print) nd trinuc sis, structu asheel Salma f Chemistry, College Chemical Sciences, g author at: Depart 3529948. Fax: +964 FORMATION eurjchem.7.1.115‐1 ecember 2015 vised form: 08 Janu anuary 2016 ne: 31 March 2016 rch 2016 S es es ion carbene tion of N‐heterocycl of bis‐carbene‐ uch current f late transitio tion due to thei silver complexe merous biologic m complexes b nd can serve nd catalytic ap ne complexes a properties si s. However, des agents, only a were reported have almost the which involves site to interrup at release of si on the carbene allow the quick mbranes [7,8]. E / ISSN 2153‐225 htt Europ clear Ag(I) ural and i an 1,2 ,* and R e of Science, Wasit Universiti Sains Ma tment of Chemistry, 4.780.3529948. E‐m 120.1387 uary 2016 lic carbene (NH ‐transition me interest. Espe on metal comp r versatile stru es act as highly al applications bearing NHC lig as promising pplications [3‐ are an interestin imilar to platin spite their pote limited numbe for anticancer e same mode o s the slow relea pt their functio ilver(I) ions at e‐silver bond s k release silver( uropean Journal Europ 57 (Online)  20 tp://dx.doi.org/ pean Jo Journal web ) bis‐N‐he in vitro an Rosenani A. University, Kut, Wa alaysia, 11800 USM y, College of Science mail address: aws.ch ABSTRACT The synthesis imidazole‐bas that the choi architectures. Despite being 5 by trans‐me 1‐5 were test than the rest. Cite this: Eur. HC) as a ligand f etal complexes ecially, the ca plexes gained ctural motifs. A y efficient cand s [1,2]. Alternat gand system ar candidates in ‐6]. Aforement ng class of antic num‐based me ential applicatio er of palladium activity. Silver of action again ase of silver(I) i n. Therefore, it the required s strength, whic (I) ions to ente l of Chemistry 7 pean Journal of C 016 Atlanta Pub 10.5155/eurjche ournal bpage: www. eterocycli nticancer Haque 2 asit, 52010, Iraq M, Penang, Malaysia e, Wasit University, hem@gmail.com (A s and characteriz sed NHC proliga ce of the count . Complex 3 is g structurally diff etallation metho ted for their anti . J. Chem. 2016, for the s has arbene much Among idates tively, e also both tioned cancer etallo‐ ons as m‐NHC r‐NHC st the ons at t must site is h can er into liga thes che and inte com inte thes coo com sup betw pall app Con com plat targ pall dist apo (1) (2016) 115‐ Chemistry lishing House LL em.7.1.115‐120. of Che .eurjchem.co ic carbene activity a Kut, Wasit, 52010, A.W. Salman). zation of two Ag ands 1 and 2, re ter ions is cruc a trinuclear, wh fferent entities, t od, which is a cis icancer activitie 7(1), 115‐120 Several silver ands have been se complexes emistry due to t d interesting eractions [1,2]. mplexes of non‐ eresting as they se complexes ordination, it ca mplexes conne pramolecular ar Due to stru ween palladium ladium‐NHC co plications again nversely, the m mplexes toward tinum‐derived geting DNA in ladium ions ca tinctive binding optosis [10]. ‐120 LC ‐ All rights re .1387 emistry m e complex Iraq. g(I)‐ N‐heterocyc espectively, are ial, which can l hereas its analo these complexes s‐platinum analo s, where compo r‐carbene com n reported for v s have show the presence of intra and These interact functionalized y do not posses still contain a an be anticipate cted by halid rchitecture. uctural and t m and platinu omplexes are nst different h mode of action ds cancer cells complexes em n the infected an also able to g modes that af served ‐ Printed y xes: clic carbene com described. The lead to differen ogue complex 4 form cis‐palladi ogue. All the rep ounds 2 and 3 fo mplexes of pol various applica wn fascinating f additional coo intermolecular tions in the pol NHCs, however s additional do a free halide ed that new pol de units to fo thermodynamic um‐NHC compl reported for human cancer of palladium‐ is presumed mployed for can d cell. Like p interact with ffect cell replica d in the USA mplexes 3 and 4 findings reveale nt supramolecul 4 is mononuclea ium‐NHC comple orted compound ound more pote lydentate NHC ations. Some of coordination ordinating sites r silver‐silver lynuclear silver r, are still more nor sites. Since ion for silver lynuclear silver orm a feasible c correlations lexes, some of the anticancer cell lines [9]. based carbene to be same as ncer treatment, platinum ions, DNA, showing ation including of ed ar ar. ex ds nt C f n s r r e e r r e s f r . e s , , g g 116 Salman and Haque / European Journal of Chemistry 7 (1) (2016) 115‐120 Scheme 1 However, trans‐palladium‐NHC complexes found more effective than their cis‐counterparts, whose mode of action cannot be explained on the basis of platinum complexes. Recently, we have reported that silver and palladium‐NHC complexes can serve as excellent antibacterial and anticancer agents against E. coli and S. aureus strains and human colorectal cancer (HCT 116) cell line, respectively [11,12]. Herein, we report the synthesis, molecular structures and anticancer efficiencies of both silver and palladium‐NHC complexes. Furthermore, two of the reported complexes have been characterized by single crystal X‐ray diffraction technique. 2. Experimental 2.1. Materials and instrumentation All chemicals and solvents were obtained from commercial sources and all reagents and solvents were of analytical grade and used without further purifications. NHC precursors 1 and 2, and silver complex 4 were reported in our previous reports [13,14]. NMR spectra were recorded using Bruker 400 MHz Ultrashield TM and Bruker Avance 300 MHz spectrometers at ambient temperature. The 1H and 13CNMR peaks were labeled as singlet (s), doublet (d), triplet (t), and multiplet (m). Chemical shifts were referenced with respect to solvent signals. Elemental analysis was carried out on a Perkin‐Elmer Series II, 2400 microanalyzer. The X‐ray diffraction data were collected using a Bruker SMART APEX2 CCD area‐detector diffractometer. The above‐mentioned instruments are available at the School of Chemical Sciences and the School of Physics, Universiti Sains Malaysia (USM). 2.2. Synthesis of Ag(I) and Pd(II)‐NHC complexes 2.2.1. Synthesis of complex 3 Ag2O (0.4 g, 1.7 mmol) was added to a solution of compound 1 (0.5 g, 2.4 mmol) in 30 mL of dichloromethane. The reaction mixture was stirred for 12 h in a round bottom flask in dark to exclude light. Colorless solution with a black suspension was obtained, which was filtered through a pad of celite. The solvent was removed under reduced pressure to afford a grey precipitate, which was recrystallized several times using dichloromethane to produce light‐grey solid 3 (Scheme 1) 9. Yield: 71.5%. M.p.: 142‐143 °C. 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 3.77 (s, 18H, N‐CH3), 5.31 (s, 12H, benzylic CH2), 7.29‐7.35 (m, 30H, 10 × Ar‐H), 7.45 (d, 6H, J = 5.2 Hz, imidazolium H5’) and 7.53 (d, 6H, J = 5.2 Hz imidazolium H4’). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 39.0 (N‐CH3), 54.9 (benzylic CH2) 123.0, 124.2 (imidazolium C5’ and C4’), 128.5, 128.8, 129.6, 138.2 (4 × Ar‐CH) and 179.9 (C2'‐Ag). 2.2.2. Synthesis of complex 4 To a stirred solution of compound 2 (0.5 g, 1.57 mmol) in acetonitrile (40 mL), Ag2O (0.37 g, 1.6 mmol) was added. The mixture was refluxed at 70 °C for 18 h in dark to exclude the light. Resultant solution was passed through a bed of celite to remove unreacted Ag2O and the solvent was evaporated under reduced pressure. So obtained white residue of complex 4 was washed with diethyl ether (2 × 3 mL) to afford an off‐white powder (Scheme 1). Yield: 70.3%. M.p.: 148‐149 °C. 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 3.76 (s, 6H, 2 × CH3), 5.31 (s, 4H, 2 × benzylic CH2), 7.26‐7.33 (m, 10H, 10 × Ar‐H), 7.44 (d, 2H, J = 5.8 Hz, 2 × imidazolium H5′), 7.54 (d, 2H, J = 5.8 Hz, 2 × imidazolium H4′). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 39.0 (CH3), 54.8 (benzylic CH2) 123.2, 124.1 (imidazolium C5′ & C4′), 128.4 (2 × Ar‐CH), 128.9 (4 × Ar‐CH), 129.6 (4 × Ar‐CH), 138.2 (2 × Ar‐CH) and 180.6 (C2′‐Ag). 2.2.3. Synthesis of complexes 5 To a stirred solution of compound 3 or 4 (0.05 mmol) in 15 mL of dichloromethane, [PdCl2(CH3CN)2] (27 mg, 0.102 mmol) was added and was stirred overnight. A yellow solution with black precipitate was obtained, which was filtered off through a bed of celite to give a clear yellow solution. This filtrate was concentrated to 3 mL under vacuum, and then petroleum ether 20 mL was added. The resulted precipitate was isolated by decantation and washed with petroleum ether (2 × 5 mL) to give a pale‐yellow solid which was recrystallized Salman and Haque / European Journal of Chemistry 7 (1) (2016) 115‐120 117 using dichloromethane several times (Scheme 1). Yield = 69.0% from compound 3 and 71.7% from compound 4. M.p.: 189‐190 °C. 1H NMR (400 MHz, CDCl3, δ, ppm): 4.06 (s, 3H, N‐ CH3), 4.21 (s, 3H, N‐CH3), 5.65 (s, 2H, benzylic CH2), 5.84 (s, 2H, benzylic CH2), 6.68 (s, br, 2H, imidazolium H5′ and H4′), 6.81 (d, 2H, J = 8.0 Hz, imidazolium H5′ and H4′), 7.28 (t, 2H, J = 7.5 Hz, ArH), 7.40 (t, 4H, J = 7.2 Hz, 2 × ArH), 7.56 (d, 4H, J = 7.2, 2 × ArH). 13C NMR (100 MHz, CDCl3, δ, ppm): 38.3 (CH3), 54.6 (benzylic CH2) 120.9, 122.8 (imidazolium C5′ and C4′), 128.5 (2 × Ar‐CH), 129.1 (4 × Ar‐CH) 129.6 (4 × Ar‐CH), 136.8 (2 × Ar‐CH) and 170.1 (C2′‐Pd). Anal. cald. for C22H24Cl2N4Pd: C, 50.6; H, 4.6; N, 10.7. Found: C, 51.2; H, 4.3; N, 10.5%. 2.3. Anticancer activity 2.3.1. Cell culture Initially, HCT 116 cells were allowed to grow under optimal incubator conditions. Cells that reached a confluence of 70‐80% were chosen for cell plating purposes. The old medium was carefully aspirated out of the plate. Next, cells were washed twice using sterile phosphate buffered saline (PBS) with a pH of 7.4. The PBS was completely discarded after washing, and then trypsin was added and distributed evenly onto the cell surfaces. The cells were incubated at 37 °C in 5% CO2 for 1 min. Then, the flasks containing the cells were gently tapped to aid cell segregation and then observed under an inverted microscope (if cell segregation was not sufficient, the cells were incubated for another minute). Trypsin activity was inhibited by adding 5 mL of fresh complete media of 10% fetal bovine serum (FBS). The cells were counted, diluted to obtain a final concentration of 2.5 × 105 cells/mL, and inoculated into wells (100 mL cells per well). Finally, the plates containing the cells were incubated at 37 °C with an internal atmosphere of 5% CO2. 2.3.2. MTT assay The cancer cells (100 mL cells per well, 1.5 × 105 cells/mL) were inoculated in wells of a microtiter plate, which was incubated in a CO2 incubator overnight to facilitate cell attachment. A total of 100 mL of test complexes were added into each well containing the cells. The test complexes were diluted with media into the desired concentrations from the stock. The plates were incubated at 37 °C with an internal atmosphere of 5% CO2 for 72 h. A 20 mL MTT [3‐(4,5‐ dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide] rea‐ gent was added into each well, which was incubated again for 4 h. Next, 50 mL MTT lysis solution (DMSO) was added into the wells. The plates were further incubated for 5 min in a CO2 incubator. Finally, the plates were read at 570 and 620 nm wavelengths using a standard ELISA microplate reader (Ascent Multiskan). Data were recorded and analyzed for the assessment of the effects of the test complexes on cell viability and growth inhibition. The percentage of growth inhibition was calculated from the optical density (OD), which was obtained from the MTT assay. 5‐FU was used as the standard reference drug. The formula used for the calculation of growth inhibition was carried out using the following equation. % Growth inhibition = {OD(control)‐OD(survived)/OD(control)} × 100 (1) 3. Results and discussion 3.1. Synthesis and characterization In analogy to the potent anticancer activity of cis‐platin and its analogues, cis‐palladium‐NHC complexes having varied ancillary ligands were targeted. The synthetic route for the preparation of NHC precursors and their silver and palladium complexes is outlined in Scheme 1. Synthesis, structural and detailed spectral and analytical characterizations of compound 3, 4 and 5 are presented in the present work along with biological activates of compound 1‐5. Compound 1 was easily generated by treatment of 1‐methylimidazole with benzyl chloride in dioxane at refluxing temperature for 12 h. This compound was converted into its hexafluorophosphate counterpart 2 following standard procedures for the salt metathesis reactions [15]. To better understand the effect of counter ions on the structure of silver complexes and their reactivity in the formation of corresponding palladium complexes, therefore, compound 1 and 2 were treated with half an equivalent of Ag2O to get corresponding silver complexes 3 and 4, respectively, in good yields. Further, both the silver complexes (3 and 4) were stirred with one equivalent of [PdCl2(MeCN)2] for 12 h in DCM to yield cis‐ palladium‐NHC complex 5 via the technique of trans‐ metallation. From both reactions, cis‐palladium complex 5 was isolated as a pale yellow solid in appreciable yields. Both, NHC proligands and their carbene complexes were fully characterized by 1H and 13C NMR and elemental analysis. The 1H and 13C NMR spectra of compound 1 and 2 showed the diagnostic C2' proton/carbon resonances at downfield regions δ 8.58, 9.2 and 133.9 and 137.5 ppm, respectively, indicating the formation of desired salts. The most significant resonance spectroscopic feature of carbene complexes 3‐5 is the absence of C2' proton resonance in their 1H NMR spectra and the presence of a distinguished singlet at δ 179.9, 180.6 and 170.1 ppm corresponding to the carbenic carbon nuclei in their 13C NMR spectra. These observations are well within the range reported for the similar silver and palladium‐NHC complexes [16,17]. Interestingly, a mixture of two palladium complexes was observed with similar proton NMR resonance patterns in the spectrum of complex 5. These two conformers of complex 5 are indicative of the presence of high degree of flexibility of the NHC ligand system. This observation has been noted previously for numerous palladium‐NHC complexes having analogues ligand architectures and is assigned to the existence of isomeric complexes in solution [18]. Therefore, it can be concluded that the carbene ligand in complex 5 is non‐ equivalent, which is due to the bulkier hindrance around the Pd‐C bond arising from the phenyl substitution. 3.2. Crystallographic determination Single crystal X‐ray diffraction studies of carbene complexes confirmed the above structural assignments. Crystals of these complexes suitable for X‐ray diffraction studies were grown at low temperature by slow evaporation for compound 3 in DCM, and slow evaporation of compound 5 in dichloromethane:diethyl ether (3:1, v:v). The crystallo‐ graphic data and selected bond lengths and angles of complexes are presented in Table 1‐4. Silver complex 3 is crystallized in trigonal space group R‐3c, as an unsymmetrical trinuclear compound having a triply bridged chloride anion bonded to the three silver centers. A perspective view of the complex is shown in Figure 1. This is a rare example of a trinuclear cationic silver carbene complex having triply bridged chloride. The bond angles between the silver centers through bridging chloride anion and the bond distances of silver centers with bridged chloride anion are 120 ° and 2.9956(1) Å, respectively, and are almost identical to each other. The bond distance between triply bridged chloride and the three silver centers is much longer than those of the non‐bridged and doubly bridged Ag‐Cl bonds, indicating the presence of a weak bonding. These bond distances and angles are well in the range compared to a similar trinuclear silver complex having triply bridged iodide anion [19]. In each silver complex unit, the metal center is coordinated by two carbene carbon atoms of the two NHC ligands in highly distorted linear geometry [C(1)‐Ag(1)‐C(1a) = 167.06 (7) °] with the bond distances of Ag(1)‐C(1) and Ag(1)‐C(1a) are 2.1046(13) Å. 118 Table 1. Crysta Compound Formula Formula weight Crystal System space group a (Å) b (Å) c (Å) α (°) β (°) γ (°) V (Å3) Z D(calc) g/cm‐3 F(000) Crystal Size (mm Temperature (K Θmin, max (°) Total data Unique Data Rint R1 wR2 S Table 2. Selecte Bond lengths (Å Ag1‐C1 Ag1‐C1a N1‐C1 Bond angles (°) C1‐Ag1‐C1a N1‐C4‐C5 Table 3. Selecte Bond lengths (Å Pd1‐Cl1 Pd1‐C8 Bond angles (°) Cl1‐Pd1‐Cl2 Cl2‐Pd1‐C19 Cl2‐Pd1‐C8 Table 4. Selecte Bond lengths (Å Pd1‐Cl1 Pd1‐C8 Bond angles (°) Cl1‐Pd1‐Cl2 Cl2‐Pd1‐C19 Cl2‐Pd1‐C8 Figure 1. Solid displacement e independent ch al data and structur t m) K) ed bond lengths (Å (Å) °) ed bond lengths (Å (Å) °) ed bond lengths (Å (Å) °) d‐state structure ellipsoids drawn a hloride ions have b Salma re refinement deta 3 C22H24AgN 487.77 trigonal R‐3c (No.1 12.8985(3 12.8985(3 68.2152(1 90° 90° 120° 9828.6(4) 18 1.483 4464 0.23 × 0.2 293 1.8, 34.4° 93204 4615 0.033 0.0279 0.0749 1.05 Å) and angles (o) fo 2.1046(13 2.1047(13 1.3480(17 167.04(7) 106.4(9) Å) and angles (o) fo 2.3573(1 1.992(5) 91.76 (5) 88.30(15 178.87(1 Å) and angles (o) fo 2.3562(14 2.005(6) 92.92(6) 178.83(15 89.2(2) of trinuclear silv at 50% probabilit been omitted for cla an and Haque / E ails for complexes N4Cl 167) 3) 3) 16) 5 × 0.33 or complex 3. 3) 3) 7) ) or compound 5A. 12) ) 5) 12) or compound 5B. 4) 5) ver‐NHC complex ty. Hydrogen atom arity. European Journa 3 and 5. 5 C44H4 1128 mono P21/ 15.33 9.635 34.68 90° 90.25 90° 5125 4 1.462 2280 0.06 × 293 1.8, 3 1170 1772 0.059 0.073 0.290 1.09 N2‐C N2‐C N1‐C4 N1‐C N2‐C Pd1‐C Pd1‐C C8‐Pd Cl1‐Pd Cl1‐Pd Pd1‐C Pd1‐C C8‐Pd Cl1‐Pd Cl1‐Pd 3 with ms and typ ster the ben bon thre cop bon com bon crys via (2.8 the com asy diff crys B, o al of Chemistry 7 48Cl4N8Pd2(CH2Cl2) .43 oclinic c (No. 14) 386(14) 56(8) 81(3) 56(2)° .7(8) 2 × 0.25 × 0.51 32.1 35 0 9 33 07 1 11 4 1‐N2 1‐Ag1 Cl2 C19 d1‐C19 d1‐C8 d1‐C19 Cl2 C19 d1‐C19 d1‐C8 d1‐C19 The arrangem ical asymmetri ric interaction complex units nzyl modules ar nd angles and b ee complex un planar showing nd angle at th mplex system is nd angles ment stal structure, CH‐‐‐Cl (inde 878‐2.879 Å) fo The structure monoclinic sp mplex and tw mmetric unit ferent variants o stal structure. P of complex 5 are 7 (1) (2016) 115‐ 1 1 1 1 1 2 1 9 8 1 2 1 9 1 8 ment of NHC lig ic fashion is lik between the b s of trinuclear re disordered o bond distances nits both the im a dihedral angl he carbene ca s 103.88(11) °, tioned for the the trinuclear ependent chlo orming three‐di of the cis‐palla pace group P21 wo dichlorom t. Interestingly of cis‐palladium Perspective vie e shown in Figu 120 1.3497(17) 1.457(2) 1.501(9) 103.88(11) 128.52(10) 2.3883(16) 1.999(4) 92.68(19) 87.27(12) 179.23(15) 2.3839(19) 1.992(5) 90.7(2) 177.5(2) 87.23(13) gands of the c kely caused by enzyl substitut silver compou over two sets w s as shown in F midazole rings le of 50.31(11) arbon center which is well free NHCs. In complex units ride ions) hy mensional netw adium complex 1/c, having occ methane mole y, two cryst m complex 5 we ews of the two v ure 3. complex 3 in a y the repulsive tions. In one of nd 3, both the with negligible Figure 2. In all are not being °. The internal (N1‐C1‐N2) of short of N‐C‐N n the extended are connected ydrogen bonds works. x 5 is solved in cupied two cis‐ ecules in an tallographically ere found in the variants, A and a e f e e l g l f N d d s n ‐ n y e d Figur Figure 3. S Bond d independent chemical co figures, the s cis‐palladium ligands arou center in co two chloride coordination [1.992(5) an trans Pd‐Cl2 indicating t species. Each which is alm to ab and bc extended s PdCl⋅⋅⋅HCH ( (3.326 Å) an form a three 3.3. Antibac Prompte and their determining cis‐palladium NHC prolig aforemention and chemica re 2. Solid‐state str Solid‐state structur distances and t species differ mposition rem structure deter m complex hav und the metal mplex 5 is coo e moieties in n geometry. Th nd 1.999(4) Å] a and Pd‐Cl1 bon the stronger c h imidazole ring most perpendicu c planes with a structure, com (3.708 Å), PdC nd ClCH2Cl⋅⋅⋅H2 ‐dimensional n terial and anti ed by the succes carbene com the anticance m complex 5, i gands. The d ned biological s al environment Salman and Ha ructure of one of th re of the compone d angles of r to a small ex mains same. As mination revea ving syn arran in solid state ordinated by tw a slightly disto he Pd‐C8 and are much short nds [2.3883(16 cis‐influence o g is coordinated ular to its cis‐im a dihedral angle mplex units l⋅⋅⋅HCHCl2 (3.4 2CCl2 (2.859 Å) etwork. icancer results ssful formation plexes, we w r potentials of ts precursor s distinct comp studies differ m of the metal cen aque / European J he units of trinucle (A) nts A and B of the these struct xtent; whereas s depicted in als complex 5 to gement of the [20]. The palla wo NHC ligand orted square p The Pd‐C19 b ter than that of 6) and 2.3573(1 of the coordin d to palladium c midazole ring pa e of 79.3(5) °. are connected 408 Å), ClCH2Cl ) hydrogen bon s of imidazolium were intereste f cis‐platin ana ilver complexe pounds tested mainly in counte nter(s). Journal of Chemi ear silver‐NHC com cis‐palladium‐NHC turally their these o be a e NHC adium ds and planar bonds f their 12) Å], nating center arallel In the d by l⋅⋅⋅Himi nds to m salts ed in alogue es and d for er ions 1‐5 usin pot test rev with mu mor of u Figu com istry 7 (1) (2016) mplex 3with displa (B) C complex 5with d The in vitro an 5 against HCT11 ng 5‐fluorourac tential of these ted compounds ealed weak an h IC50 value o ch even after rphology was c untreated cells ( ure 4. MTT assa mplexes vs. the HCT 6) 115‐120 acement ellipsoids displacement ellips nticancer activit 16 cell lines bas cil (5‐FU) as an complexes as a s, silver comple nticancer poten f >200 µM. Th r 72 h of in changed to a le (Figure 4). ay results of imi 116 cell lines. drawn at 50% pro soids drawn at 50% ties of the carb sed on the MTT n internal stand anticancer agen ex 4 and pallad ntial against HC he cell growth ncubation, wh esser extent com dazolium salts an 119 obability. % probability. bene complexes T assay method dard reveal the nts. Among the ium complex 5 CT116 cell line did not affect hereas cellular mpared to that nd their carbene s d e e 5 e t r t e 120 Fi Surprisin complex 3 d values 8.32, (Figure 5) demonstrate compared w Similar antib for the analo Cells treated and morpho respect to th cells treated debris can be 4. Conclusio Two Ag( imidazole‐ba compounds formation of that the choi a range of st arrangement and intramo trinuclear co connected by mononuclear these struct prepare palla different targ the complex which is cha precursors anticancer p complex 3 HCT116 canc Supplement Crystallo Cambridge deposition n 3 and 5, resp Acknowledg Abbas W for the Res Rosenani An igure 5. Images of ngly, compoun displayed poten 0.19 and 0.40 µ of the cells ed the strong with the standa bacterial and an ogues mono‐NH d with compou ology of the ce hat of the negati d with complex e seen in the ph ons (I)‐NHC comple ased NHC precu differ in the f different silv ice of counterio tructural archit t of NHC ligan olecular interac ompound in w y a triply bridge r entity crystal turally differen adium‐NHC com gets by transme xes formed sam aracterized by X and carbene potential, where displayed hig cer cell line. tary materials ographic data Crystallograph numbers CCDC pectively. gements Washeel Salman search Univers nwarul Haque Salma f the control HCT11 nds 1, 2 an nt anticancer po µM, respectively treated with cytotoxic effi rd reference 5 nticancer poten HC silver acetate nds 1‐3 showe ells were comp ive control. Esp x 3, except a hotomicrograph exes 3 and 4 we ursors 1 and 2 counterion, w ver complexes. ons is very cruci tectures, includ nds around the ctions and so which each of t ed chloride, wh lized along wit nt NHC compl mplexes, expec etallation techn me cis‐palladiu X‐ray diffraction complexes 3‐ e both of the N gher anticance are available hic Data Centr 866504 and 85 n thanks Unive sity Grant 10 thanks Unive an and Haque / E 16 cells (A), cells tr d trinuclear otential with th y. Photomicrog these compo icacies that ca ‐FU (IC50 = 5.2 ntials were obs e complexes [2 ed growth inhi pletely changed pecially, in the c few dead cells h. ere synthesized , respectively. which leads t This finding s ial, which can le ding their nucle e metal center, on. Complex 3 the metal cent hereas complex h KPF6 unit. Fu lexes were us ting two struct nique. However um‐NHC comp n method. Both 5, were teste NHC precursor er potential a e on request re on quoting 55688 for comp ersiti Sains Ma 01/PKIMIA/84 rsiti Sains Ma European Journa reated with 5‐FU ( silver he IC50 graphs ounds an be 2 µM). served 1‐23]. bition d with case of s only d from Latter o the shows ead to earity, , inter 3 is a ters is x 4 is a urther, ed to turally r, both lex 5, h, NHC ed for rs and gainst from g the plexes alaysia 43090. alaysia (US the Ref [1]. [2]. [3]. [4]. [5]. [6]. [7]. [8]. [9]. [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] al of Chemistry 7 B) and compounds SM) for the sho Research Univ ferences Budagumpi, S.; Eur. J. Inorg. Ch Gautier, A.; Cisn Budagumpi, S.; 256, 1787‐1830 Budagumpi, S.; Liu, W.; Gust, R Broekemier, N. Chem. 2014, 5( Hartinger, C. G. Hindi, K. M.; Pa Chem. Rev. 200 Ray, S.; Mohan Panda, D.; Ghos . Gao, E. J.; Liu, Agents Med. Che . Haque, R. A.; S Majid, A. M. S. M . Haque, R. A.; Mudaris, Z. A. 2013, 27, 465‐4 . Haque, R. A.; Sa 365‐370. . Haque, R. A.; S Cryst. E 2011, 6 . Baker, M. V.; Br Incl. Phenom. M . Warsink, S.; de Lutz, M.; Spek, A . Dastgir, S.; C Organometallic . Magill, A. M.; M V. C.; White, A Organomet. Che . Wang, X.; Liu, 3565‐3569. . Hsiao, T‐H.; Wu Bianchini, C.; O 4024. . Patil, S.; Deall Paradisi, F.; Tac . Patil, S.; Deally Tacke, M. Metal . Patil, S.; Claffey Müller‐Bunz, H 1020‐1031. 7 (1) (2016) 115‐ s 1 (C) and 3 (D) a ort term grant ersity grant 10 Haque, R. A.; End em. 2013, 4367‐4 netti, F. Metallomic Haque, R. A.; Salm 0. Kim, K.; Kim, I. Coo R. Chem. Soc. Rev. 20 . W.; Broekemier, (1), 162‐166. ; Dyson, P. J. Chem. anzner, M. J.; Tessi 09, 109, 3859‐3884 n, R.; Singh, J. K.; sh, P. J. Am. Chem. S C.; Zhu, M. C.; Lin em. 2009, 9, 356‐3 Salman, A. W.; Bu Metallomics, 2013, Salman, A. W.; B A.; Abdul Majid, 473. alman, A. W.; Guan alman, A. W.; Wha 67, m97‐m98. rown, D. H.; Haque Macrocycl. Chem. 20 Boer, S. Y.; Jongen A. L.; Elsevier, C. J. Coleman, K. S.; cs 2006, 25, 300‐30 McGuinness, D. S.; C A. J. P.; Williams, em. 2001, 617‐618 S.; Weng, L‐H.; J u, T‐L.; Chatterjee, Oberhauser, W. J. O y, A.; Gleeson, B. cke, M. Z. Anorg. Al y, A.; Hackenberg llomics 2011, 3, 74 y, J.; Deally, A.; Hog H.; Paradisi, F.; Ta 120 fter 72 h of incuba (203/PKIMIA/ 01/PKIMIA/81 ud, S.; Ur‐Rehman 388. cs 2012, 4, 23‐32. man, A. W. Coord. or. Chem. Rev. 201 013, 42, 755‐773. N. C.; Short, R. T.; . Soc. Rev. 2009, 38 ier, C. A.; Cannon, C 4. Samantaray, M. Soc. 2007, 129, 150 n, H. K.; Wu, Q.; L 368. dagumpi, S.; Abdu 5, 760‐769. Budagumpi, S.; Ab A. M. S. Appl. Or n, T. S. Aust. J. B. Ap ai, C. K.; Quah, C. K e, R. A.; Skelton, B. 009, 65, 97‐109. ns, L. M.; Fu, C‐F.; L Dalton Trans. 200 Cowley, A. R.; 06. Cavell, K. J.; Britovs D. J.; White A. H. 8, 546‐560. Jin, G‐X. Organom S.; Chiu, C‐Y.; Lee, Organomet. Chem. .; Hackenberg, F.; llg. Chem. 2011, 63 g, F.; Müller‐Bunz 4‐88. gan, M.; Gleeson, B. acke, M. Eur. J. In ation. /6311123) and 11217. n, G.; Salman, A. W. Chem. Rev. 2012, 1, 255, 278‐2809. Palencia, H. Eur. J. 8, 391‐401. C. L.; Youngs, W. J. K.; Shaikh, M. M.; 042‐15053. Liu, L. Anti‐Cancer ullah, A. A.; Abdul bdullah, A. A.; Al‐ rganometal. Chem. ppl. Sci. 2011, 5(9), K.; Fun, H. K. Acta . W.; White, A. H. J. Liu, S‐T.; Chen, J‐T.; 09, 7080‐7086. Green, M. L. H. sek, G. J. P.; Gibson, ; Skelton, B. W. J. etallics 2006, 25, H. M.; Bettucci, L.; 2009, 694, 4014‐ Müller‐Bunz, H.; 37, 386‐396. z, H.; Paradisi, F.; ; Méndez, L. M. M.; norg. Chem. 2010, d . , . . ; r l ‐ . , a . ; . , . , ; ‐ ; ; ; ,