DSpace at VNU: Syntheses, structures and biological evaluation of some transition metal complexes with a tetradentate benzamidine thiosemicarbazone ligand

Accepted Manuscript Syntheses, Structures and Biological Evaluation of some Transition Metal Complexes with a Tetradentate Benzamidine/Thiosemicarbazone Ligand Thi Bao Yen Nguyen, Chien Thang Pham, Thi Nguyet Trieu, Ulrich Abram, Hung Huy Nguyen PII: DOI: Reference: S0277-5387(15)00223-5 http://dx.doi.org/10.1016/j.poly.2015.04.026 POLY 11290 To appear in: Polyhedron Received Date: Accepted Date: March 2015 21 April 2015 Please cite this article as: T.B.Y Nguyen, C.T Pham, T.N Trieu, U Abram, H.H Nguyen, Syntheses, Structures and Biological Evaluation of some Transition Metal Complexes with a Tetradentate Benzamidine/ Thiosemicarbazone Ligand, Polyhedron (2015), doi: http://dx.doi.org/10.1016/j.poly.2015.04.026 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain 1 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Syntheses, Structures and Biological Evaluation of some Transition Metal Complexes with a Tetradentate Benzamidine/Thiosemicarbazone Ligand Thi Bao Yen Nguyen,a) Chien Thang Pham,a,b) Thi Nguyet Trieu,a) Ulrich Abram,b)* Hung Huy Nguyena)* a) Department of Chemistry, Hanoi University of Science, 19 Le Thanh Tong, Hanoi, Vietnam b) Freie Universität Berlin, Institute of Chemistry and Biochemistry, Fabeckstr 34-36, D- 14195 Berlin, Germany Abstract The potentially tetradentate benzamidine/thiosemicarbazone ligand, Et2N-(C=S)NH-C(Ph)=N-(o-C4H6)-C(Me)=N-NH-(C=S)-NH-Me (H2L) readily reacts with Ni(CH3COO)2, [PdCl2(CH3CN)2], [PtCl2(PPh3)2] and (NBu4)[ReOCl4] under formation of complexes of the compositions [M(L)] (M= Ni (1), Pd (2), Pt (3)) and [ReO(L)(OMe)] (4) In all complexes, H2L is doubly deprotonated and bonded to the central meal ion via its N2S2 donor set Complexes 1, and have distorted square-planar coordination spheres, while the rhenium compound is an octahedral trans oxido/methoxido complex The H2L proligand shows a medium cytotoxicity with an IC50 value of 21.1 M While the rhenium complex exhibits a stronger antiproliferative effect (IC50 = 5.52 M), the nickel, palladium and platinum complexes are almost inactive Keywords: Transition Metals, Benzamidines, Thiosemicarbazones, X-ray structure, Cytotoxicity Corresponding Authors: ulrich.abram@fu-berlin.de (Ulrich Abram) nguyenhunghuy@hus.edu.vn (Hung Huy Nguyen) 1 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Introduction Thiosemicarbazones, which form stable complexes with many main group and transition metals[1,2], constantly attract the interest of chemists and pharmacists due to their remarkable biological and pharmacological properties such as antibacterial, antiviral, antineoplastic, or antimalarial activity[3-5] Modifications of the thiosemicarbazone framework, in order to find new compounds with higher activity and/or to tune their biological activity, have been extensively studied, and relationships between the biological activity and chelate formation are evident in a number of cases[6-8] Recently we reported the synthesis and structural characterization of a series of tridentate benzamidine/thiosemicarbazide ligands (H2L’), which were prepared by reactions of N[N’,N’-dialkylamino(thiocarbonyl)]benzimidoyl chlorides (Bzm-Cl) and thiosemi- carbazides [9,10] They form stable complexes with various transition metals [9-12] Additionally, the organic ligands as well as their oxorhenium(V) and gold(III) complexes show a promising cytotoxicity on breast cancer cell lines [10-12] The reaction of 2aminoacetophenone-N-(4-methylthiosemicarbazone) with Bzm-Cl results in the formation of a tetradentate hybrid thiosemicarbazone/benzamidine ligand, H2L [13] This ligand has hitherto only been used for reactions with nitridotechnetium and –rhenium complexes, which resulted in stable, neutral TcVN and ReVN complexes 13 With respect to the stability of these products, H2L should also be suitable for the coordination of other metal ions and the obtained products may possibly show interesting biological properties Here, we report about reactions of H2L with Ni(CH3COO)2, PdCl2(CH3CN)2, PtCl2(PPh3)2 and (NBu4)ReOCl4, the structures of the obtained products as well as their cytotoxicity against human MCF-7 breast cancer cells 2 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Results and Discussion 2.1 Syntheses and structures of the nickel, palladium and platinum complexes H2L readily reacts with Ni(CH3COO)2, [PdCl2(CH3CN)2] or [PtCl2(PPh3)2] under formation of complexes of the composition [M(L)] (Scheme 1) Depending on the solubility of the starting materials, the reactions were carried out in MeOH for Ni(CH3COO)2 or in a MeOH/CH2Cl2 mixture (v/v: 1/1) for [PdCl2(CH3CN)2] and [PtCl2(PPh3)2] While the first reaction proceeds very quickly, the two latter reactions require more time The addition of a supporting base such as Et3N accelerates the formation of the complexes and allows the syntheses to be carried out at ambient temperature with good yields The products are only sparingly soluble in alcohols, but well soluble in CH2Cl2 or CHCl3 and can be recrystallized from CH2Cl2/MeOH mixtures Ni(CH 3COO) MeOH, Et 3N N - Et 3NHCH 3COO H 2L + [Pd(MeCN) 2Cl 2] CH 2Cl / MeOH, Et 3N N CH 2Cl / MeOH, Et 3N - Et 3NHCl, - PPh S M - Et 3NHCl, - MeCN [Pt(PPh 3) 2Cl2] N N S N HN 1: M = Ni, 3: M = Pd; 3: M = Pt Scheme The IR spectra of all three compounds show a moderate absorption at about 3400 cm-1, which is assigned to the N-H stretch of the MeNH-CS group The absorption band of theC=N vibration is observed as a very intense band around 1550 cm-1 This corresponds to a strong bathochromic shift of the corresponding band in H2L by about 170 cm-1 Such shifts are commonly explained by a chelate formation with a large degree of π-electron delocalization within the benzamidine chelate rings [9-12] Expectedly, the 1H NMR spectra of the complexes no longer show resonances at 12.62 ppm and 8.41 ppm, which are assigned to the NH protons 3 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 of the benzamidine and thiocarbazone moieties in the proligand Additionally, a high field shift of the signal of the NH proton of the CS-NHMe residue from 7.64 ppm in the proligand [13] to the region around 5.0 ppm in the spectra of the complexes 1, and is observed, which confirms that the organic ligand is doubly deprotonated and chelated to the central metal ions A hindered rotation around the C–NEt2 bond is observed and results in two magnetically nonequivalent ethyl groups Thus, two triplet signals of the methyl groups of the –NEt2 residues are observed in the 1H NMR spectra of the complexes The signals of the two methylene groups appear as four well separated multiplet resonances This pattern has previously been rationalized by the rigid structure of the tertiary amine group, which makes ethylene protons magnetically nonequivalent with respect to their axial and equatorial positions [9,10] Single crystals suitable for X-ray studies were obtained by slow evaporation of CH2Cl2/MeOH mixtures for the nickel and palladium compounds Figure illustrates the Figure about here molecular structure of as a representative for this class of compounds The structure of the analogous palladium compound is virtually identical and, thus, no extra Figure is shown Selected bond lengths and angles of and are compared in Table The atomic labeling scheme of the palladium complex has been adopted from that of the nickel complex Both metal ions are coordinated by the S2N2 donor set of the organic ligand in a distorted squareplanar coordination environment The molecular planes defined by the metal atoms and the four donor atoms S1, N5, N8 and S11 are slightly distorted with maximum deviations from the mean least-squares planes of 0.215(1) Å for N8 (in 1) and of 0.098(1) Å for N5 (in 2) 2.1 Synthesis and structures of the oxidorhenium(V) complex H2L reacts with (NBu4)[ReOCl4] in MeOH in the presence of the supporting base Et3N under formation of a red crystalline solid of the composition [ReO(OMe)(L)] (4) in high Table about here 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 yields (Scheme 2) The reaction can be carried out at room temperature or under reflux N NH (NBu 4)[ReOCl 4] S + N N N S MeOH, Et 3N - NBu 4Cl, HNEt 3Cl N N S Re N HN HN H 2L O OMe S N HN Scheme without significant change in the yield The IR spectrum of is similar to those discussed for the complexes - with a sharp medium absorption band of the N-H stretch at 3387 cm-1 and a strong bathochromic shift of the C=N band with respect to the corresponding vibration in the spectrum of H2L The strong absorption at 941 cm-1 is assigned to the Re=O vibration This wavenumber is slightly lower than those, which are normally reported for common six-coordinate oxidorhenium(V) complexes [14], but within the typical range for octahedral trans oxido/alkoxido rhenium(V) complexes [15,16] The 1H NMR spectrum of shows the same features as those of the nickel, palladium and platinum compounds: the absence of two N-H resonances and a high field shift of the N-H signal of the CS-NHMe moiety to 5.26 ppm The chelate formation also leads to a strong downfield shift of about 1.1 ppm of the MeC=N signal The presence of a methoxy group in is clearly indicated by an additional singlet at 3.04 ppm The +ESI mass spectrum of show no molecular ion peak, but an intense peak at m/z = 641.11, which can be assigned to the fragment [M - OMe]+ The X-ray diffraction data of are in a good agreement with the spectroscopic results Figure about here Figure shows the molecular structure of the complex The environment of the rhenium atom is best described as a distorted octahedron with an oxido and a methoxido ligand arranged in trans positions to each other The L2- ligand is expectedly coordinated to the metal via its N2S2 donor set The Re atom is located only 0.151(2) Å above the mean leastsquare plane formed by the four donor atoms of L2- towards the oxido ligand The Re–O20 Table about here 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 bond length of 1.917(4) Å is shorter than a typical rhenium–oxygen single bond and reflects some double bond character The required electron density is transferred from the double bond of the oxido ligand Consequently, the Re-O10 bond length of 1.707(4) Å is slightly longer than those in five-coordinate or other octahedral oxidorhenium(V) complexes This is in a good agreement with the relatively low wavenumber of the Re=O absorption in the IR spectrum of 2.3 In vitro cell tests We investigated the antiproliferative effects of the ligand H2L and its complexes on human MCF-7 breast cancer cells in a concentration response assay This allows the determination of their IC50 values The uncoordinated H2L shows an IC50 value of 21.1(9) M reflecting a medium antiproliferative effect The complexation of H2L with Ni2+, Pd2+ and Pt2+ ions dramatically decreases the cytotoxicity of the compound Thus, complex only causes a very weak reduction of the growth of human MCF-7 breast cancer cells (IC50 = 258(10)M), while complexes and show almost no antiproliferative effect The low cytotoxicity of the square-planar complexes reflects their limited dissociation inside the cell and the stable metal chelates themselves exhibit no antiproliferative effects This can be understood by the rigid tetradentate N2S2 coordination of the ligand, which is expected to form stable complexes with Ni2+, Pd2+ and Pt2+ Additionally, no labile coordination site is available, as they are present in all metal complexes of the previously studied tridentate thiosemicarbazone/benzamidine hybrid ligands, for which promising antiproliferative effects have been found [10-12] Such a potentially labile ligand is present in the rhenium complex 4, where the methoxo ligand can readily be hydrolyzed, which enables the resulting complex fragment for interactions with biological targets In fact, compound exhibits an IC50 value of 5.52(14) mM, which is markedly lower than that of 6 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 H2L The cytotoxicity of is in the magnitude of those reported for oxidorhenium(V) and gold(III) complexes with tridentate H2L’ ligands [10,12], which also possess a labile (chlorido) ligand in their coordination spheres, and it is almost equal to that of cisplatin (IC50 = 7.10) determined under the same experimental conditions [17] Conclusions In the present communication, we could show that the benzamidine/thiosemicarbazone hybrid ligand H2L forms stable complexes with Ni2+, Pd2+ and Pt2+ and ReO3+ metal centers The proligand H2L and its oxidorhenium(V) complex show some antiproliferative effects on human MCF-7 breast cancer cells Since H2L is the hitherto only representative of this new class of potentially bioactive hybrid ligands, studies with other derivatives of this class are recommended and are in preparation in our laboratories Experimental 4.1 Materials All reagents used in this study were reagent grade and used without further purification H2L was prepared as reported previously 13 4.2 Physical Measurements Infrared spectra were measured from KBr pellets on a Shimadzu IRAffinity - 1S FTIR spectrometer between 400 and 4000 cm-1 ESI mass spectra were measured with an Agilent 6210 ESI-TOF (Agilent Technologies) All MS results are given in the form: m/z, assignment Elemental analysis of carbon, hydrogen, nitrogen, and sulphur were determined using a Heraeus Vario EL elemental analyzer NMR-spectra were taken with a JEOL 400 MHz spectrometer or a BRUKER 500 MHz spectrometer 4.3 Syntheses 7 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 4.3.1 Synthesis of Ni(L), Ni(CH3COO)2  H2O (25 mg, 0.1 mmol) was added to a solution of H2L (44 mg, 0.1 mmol) in mL of MeOH A deep red solution was obtained after the addition of three drops of Et3N, and a dark red solid deposited within a few minutes The mixture was stirred for additional h at room temperature and then the precipitate was filtered off, washed with MeOH and dried in vacuum Single crystals of were obtained by slow evaporation of a CH2Cl2/MeOH (v/v: 1/1) solution Yield 84% (42 mg) Elemental analysis: Calcd for C22H26N6S2Ni: C, 53.13; H, 5.27; N, 16.90; S, 12.90% Found: C, 53.01; H, 5.14; N, 16.95; S, 12.63% IR (KBr, cm-1): 3407 (m), 3086 (w), 2923 (m), 1547 (vs), 1502 (vs), 1486 (s), 1424 (s), 1361 (s), 1230 (m), 1022 (m), 810 (w), 702 (m), 630 (m) 1H NMR (500 MHz, CDCl3, ppm): 1.30 (t, J = 7.0 Hz, 3H, CH3), 1.31 (t, J = 7.0 Hz, 3H, CH3), 2.70 (s, 3H, N=C-CH3), 2.97 (d, J = 5.0, 3H, NCH3), 3.69 (m, 1H, NCH2), 3.74 (m, 1H, NCH2), 3.86 (m, 1H, NCH2), 4.09 (m, 1H, NCH2), 4.84 (s, br, NH), 6.41 (d, J = 8.0 Hz, 1H, C6H4), 6.78 (t, J = 7.7 Hz, 1H, C6H4), 6.86 (t, J = 7.7 Hz, 1H, C6H4), 7.12 (t, J = 7.5 Hz, 2H, Ph), 7.20 (t, J = 7.3 Hz, 1H, Ph), 7.32 (d, J = 7.0 Hz, 2H, Ph), 7.52 (d, J = 8.0 Hz, 1H, C6H4) +ESI MS (m/z): 497.09, 100%, [M + H]+ 4.3.2 Synthesis of Pd(L), [PdCl2(CH3CN)2] (26 mg, 0.1 mmol) was added to a solution of H2L (44 mg, 0.1 mmol) in mL of a CH2Cl2/MeOH (v/v 1/1) mixture, and then three drops of Et3N were added The mixture was stirred for h at room temperature to obtain a clear yellow solution Slow evaporation of the solvents gave light yellow crystals of The product was filtered off, washed with MeOH and dried in vacuum Yield 65% ( 35 mg) Elemental analysis: Calcd for C22H26N6S2Pd: C, 48.48; H, 4.81; N, 15.42; S, 11.77% Found: C, 48.21; H, 4.85; N, 15.35; S, 11.60% IR (KBr, cm-1): 3434 (m), 3052 (w), 2967 (m), 1547 (vs), 1503 (vs), 1467 (s), 1420 (s), 1379 (s), 1223 (m), 1089 (m), 749 (m), 618 (m) 1H NMR (500 MHz, CDCl3, ppm): 1.33 (t, J = 7.0 Hz, 3H, CH3), 1.36 (t, J = 7.0 Hz, 3H, CH3), 2.78 (s, 3H, N=C-CH3), 3.03 (d, J = 5.0, 3H, 8 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 NCH3), 3.65 (m, 1H, NCH2), 3.74 (m, 1H, NCH2), 4.04 (m, 1H, NCH2), 4.24 (m, 1H, NCH2), 4.95 (s, br, NH), 6.53 (d, J = 8.0 Hz, 1H, C6H4), 6.83 (t, J = 7.7 Hz, 1H, C6H4), 6.86 (t, J = 7.6 Hz, 1H, C6H4), 7.15 (t, J = 7.5 Hz, 2H, Ph), 7.21 (t, J = 7.2 Hz, 1H, Ph), 7.37 (d, J = 7.4 Hz, 2H, Ph), 7.59 (d, J = 8.0 Hz, 1H, C6H4) +ESI MS (m/z): 544.98, 100%, [M + H]+ 4.3.2 Synthesis of Pt(L), The compound was prepared as described for complex 2, but starting from [PtCl2(PPh3)2] (79 mg, 0.1 mmol) to obtain yellow crystals Yield 62% ( 39 mg) Elemental analysis: Calcd for C22H26N6S2Pt: C, 41.70; H, 4.14; N, 13.26; S, 10.12% Found: C, 41.63; H, 4.05; N, 13.32; S, 10.10% IR (KBr, cm-1): 3415 (m), 3058 (w), 2966 (m), 1548 (vs), 1502 (vs), 1467 (s), 1421 (s), 1375 (s), 1230 (m), 1081 (m), 747 (m), 623 (m) 1H NMR (500 MHz, CDCl3, ppm): 1.32 (t, J = 7.0 Hz, 3H, CH3), 1.36 (t, J = 7.0 Hz, 3H, CH3), 2.80 (s, 3H, N=C-CH3), 3.01 (d, J = 5.0, 3H, NCH3), 3.63 (m, 1H, NCH2), 3.72 (m, 1H, NCH2), 4.03 (m, 1H, NCH2), 4.25 (m, 1H, NCH2), 4.96 (s, br, NH), 6.50 (d, J = 8.0 Hz, 1H, C6H4), 6.81 (t, J = 7.7 Hz, 1H, C6H4), 6.86 (t, J = 7.7 Hz, 1H, C6H4), 7.14 (t, J = 7.5 Hz, 2H, Ph), 7.20 (t, J = 7.3 Hz, 1H, Ph), 7.35 (d, J = 7.5 Hz, 2H, Ph), 7.60 (d, J = 8.0 Hz, 1H, C6H4) +ESI MS (m/z): 634.08, 100%, [M + H]+ 4.3.4 Synthesis of ReO(OCH3)(L), H2L (44 mg, 0.1 mmol) was dissolved in mL of CH2Cl2 and added to a stirred solution of (NBu4)[ReOCl4] (58 mg, 0.1 mmol) in mL MeOH After the addition of drops of Et3N, the reaction mixture was heated to 40 oC for 30 The solvent of the resulting clear red solution was slowly evaporated to give red crystals of Yield 60% (40 mg) Elemental analysis: Calcd for C23H29N6O2S2Re: C, 41.12; H, 4.35; N, 12.51; S, 9.55% Found: C, 40.71; H, 4.09; N, 12.56; S, 9.21% IR (KBr, cm-1): 3387 (m), 3070 (w), 2970 (m), 2924 (m), 2800 (w), 1558 (s), 1512 (s), 1425 (m), 1359 (m), 1288 (m), 1250 (m), 1227 (m), 1172 (w), 1110 (m), 942 (s), 810 (w), 771 (w) 1H NMR (400 MHz, CDCl3, ppm): 1.36 (t, J = 7.1 Hz, 3H, CH3), 1.41 (t, J = 7.2 Hz, 3H, CH3), 2.92 (s, 3H, N=C−CH3), 3.04 (s, 3H, OCH3), 3.14 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 (d, J = 5.0, 3H, NCH3), 3.74 (m, 2H, NCH2), 4.33 (m, 1H, NCH2), 4.53 (m, 1H, NCH2), 5.26 (s, br, NH), 6.56 (d, J = 7.9 Hz, 1H, C6H4), 6.82 (t, J = 7.9 Hz, 1H, C6H4), 6.91 (t, J = 8.0 Hz, 1H, C6H4), 7.15 (m, 3H, Ph), 7.52 (d, J = 7.8, 2H, Ph), 7.66 (d, J = 7.8, 1H, C6H4) +ESI MS (m/z): 641.11, 100%, [M – OMe]+ 4.4 X-ray Crystallography The intensities for the X-ray determinations were collected on a Bruker D8-QUEST (1 and 2) and a STOE IPDS 2T instrument (4) with Mo K radiation ( = 0.71073 Å) Standard procedures were applied for data reduction and absorption correction Structure solution and refinement were performed with SHELXS and SHELXL 17] Hydrogen atom positions were calculated for idealized positions and treated with the ‘riding model’ option of SHELXL More details on data collections and structure calculations are contained in Table 4.5 In vitro cell tests The cytotoxic activity of the compounds was determined using a MTT assay Human cancer cells of the cell line MCF-7 were obtained from the American Type Culture Collection (Manassas, VA) ATCC Cells were cultured in medium RPMI 1640 supplemented with 10% FBS (Fetal bovine serum) under a humidified atmosphere of 5% CO2 at 37 °C The testing substances were initially dissolved in DMSO, then diluted to the desired concentration by adding cell culture medium The samples (100 L) of the complexes with different concentrations were added to the wells on 96-well plates Cells were detached with trypsin and EDTA and seeded in each well with  104 cells per well After incubation for 48 h, a MTT solution (20 L, mg mL-1) of phosphate buffer saline (8 g NaCl, 0.2 g KCl, 1.44 g Na2HPO4 and 0.24 g KH2PO4/L) was added into each well 10 Table about here 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 The cells were further incubated for h and a purple formazan precipitate was formed, which was separated by centrifugation DMSO (100 µL) was added to each well to dissolve the precipitate The optical density of the solution was determined by a plate reader (TECAN) at 540 nm The inhibition ratio was calculated on the basis of the optical densities obtained from three replicate tests Acknowledgements We gratefully acknowledge financial support from NAFOSTED (Vietnam’s National Foundation for Science and Technology Development) through project 104.02-2012.76 and Ph.D grants from DAAD (Deutscher Akademischer Austauschdienst, Germany) Appendix A Supplementary data CCDC-1052213, CCDC-1052214 and CCDC-1052215 contain the supplementary crystallographic data for 1, and 4, respectively These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223336-033; or e-mail: deposit@ccdc.cam.ac.uk 11 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 References [1] M J M Campbell, Coord Chem Rev 15 (1975) 279 [2] J S Casas, M S García-Tasende, J Sordo, Coord Chem Rev 209 (2000) 49 [3] D L Klayman, J B Scovill, J F Bartosevich, J Bruce, J Med Chem 26 (1983) 39 [4] A S Dobek, D L Klayman, E T Dickson, J P Scovill, C N Oster, Arzneim.Forsch 33 (1983) 1583 [5] C J Shipman, S H Smith, J C Drach, D L Klayman, Antiviral Res (1986) 197 [6] S Miertus, P Filipovic, Eur J Med Chem 17 (1982) 145 [7] L A Saryan, K Mailer, C Krishnamurti, W Atholine, D H Petering, Biochem Pharmacol 30 (1981) 1595 [8] L P Scovill, D L Klayman, C Lambrose, G E Childs, J D Notsch, J Med Chem 27 (1984) 87 9 H H Nguyen, P I da S Maia, V M Deflon, U Abram, Inorg Chem 48 (2009) [10] H H Nguyen, J J Jegathesh, P I da S Maia, V M Deflon, R Gust, S Bergemann, U Abram, Inorg Chem 48 (2009) 9356 [11] P I da S Maia, H H Nguyen, A Hagenbach, S Bergemann, R Gust, V M Deflon, U Abram, Dalton Trans 42 (2013) 5111 [12] P I da S Maia, H H Nguyen, D Ponader, A Hagenbach, S Bergemann, R Gust, V M Deflon, U Abram Inorg Chem 51 (2012) 1604 [13] H H Nguyen, J D Castillo Gomez, U Abram Inorg Chem Commun 26 (2012) 72 14 U Abram, Rhenium, in: J A McClevery, T J Mayer (Eds.), Comprehensive Coordination Chemistry II, vol 5, Elsevier, Amsterdam, The Netherlands, 2003, p 271 [15] A Paulo, A Domingos, J Marcalo, A Pires de Matos, I Santos Inorg Chem 34 (1995) 2113 [16] H Braband, O Blatt, U Abram Z Anorg Allg Chem 632 (2006) 2251 12 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 [17] L Yan, X Wang, Y Wang, Y Zhang, Y Li, Z Guo, J Inorg Biochem 106 (2012) 46 [18] G M Sheldrick, SHELXS-97 and SHELXL-97 - A Programme Package for the Solution and Refinement of Crystal Structures, 1997, University of Göttingen, Germany 19 K Brandenburg, DIAMOND, vers 3.2i, Crystal Impact GbR, Bonn, Germany 13 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Table Selected bond lengths (Å) and angles (deg) in and M–S1 M–S11 M–N5 M–N8 S1–C2 C2–N3 2.154(1) 2.157(1) 1.878(1) 1.909(1) 1.723(1) 1.355(2) 2.252(1) 2.270(1) 2.017(1) 2.033(1) 1.729(2) 1.348(2) S1–M–N5 S1–M–N8 S1–M–S11 95.56(4) 166.46(4) 85.49(1) 94.85(4) 173.03(4) 88.64(2) N3–C4 C4–N5 S11–C10 C10–N9 N9–N8 N8–C6 1.316(2) 1.357(2) 1.739(1) 1.300(2) 1.404(2) 1.313(2) 1.318(2) 1.348(2) 1.748(2) 1.296(2) 1.397(2) 1.308(2) N5–M–N8 N5–M–S11 N8–M–S11 93.49(5) 167.64(4) 87.83(4) 91.70(6) 172.40(4) 85.14(4) 14 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Table Selected bond lengths (Å) and angles (deg) in Re–S1 Re–S11 Re–N5 Re–N8 Re–O10 O10–Re–S1 O10–Re–N5 O10–Re–N8 O10–Re–S11 O10–Re–O20 S1–Re–N5 S1–Re–N8 S1–Re–S11 2.358(1) 2.379(1) 2.095(4) 2.127(4) 1.707(4) Re–O20 S1–C2 C2–N3 N3–C4 C4–N5 97.2(1) 91.2(2) 90.8(2) 96.0(1) 172.1(2) 93.7(1) 171.2(1) 93.5(4) 1.917(4) 1.753(5) 1.336(7) 1.311(7) 1.347(6) S1–Re–O20 N5–Re–N8 N5–Re–S11 N5–Re–O20 N8–Re–S11 N8–Re–O20 S11–Re–O20 S11–C10 C10–N9 N9–N8 N8–C6 1.753(5) 1.309(7) 1.393(6) 1.311(7) 89.5(1) 89.8(2) 169.1(1) 84.2(2) 82.0(1) 82.8(2) 87.7(1) 15 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Table X-ray structure data collection and refinement parameter Formula Mw Crystal system a/ Å b/ Å c/ Å α/o β/o γ/o V/ Å3 Space group Z Dcalc./g cm-3 µ/mm-1 Tmin Tmax Abs Corr No of refl No of indep No param R1/wR2 GOF C22H26N6S2Ni 497.32 Orthorhombic 13.0699(3) 17.3185(5) 20.1027(5) 90 90 90 4550.3(2) Pbca 1.452 1.059 0.5457 0.7457 Multiscan 85358 5422 284 0.0266 / 0.0638 1.056 C22H26N6S2Pd 545.01 Orthorhombic 13.3416(3) 16.8770(5) 20.6174(5) 90 90 90 4642.3(2) Pbca 1.560 1.001 0.6958 0.7457 Multiscan 76416 5774 284 0.0239 / 0.0539 1.081 C23H29N6O2S2Re 671.84 Triclinic 9.927(1) 10.623(1) 13.863(1) 79.89(1) 79.07(1) 64.31(1) 1286.3(2) P-1 1.735 4.918 0.3537 0.7682 Integration 23666 6895 323 0.0377 / 0.0790 1.047 16 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Figure Captions Figure Ellipsoid representation of the molecular structure of [Ni(L)] [19] Thermal ellipsoids represent 60 percent probability Hydrogen atoms bonded on carbon atoms have been omitted for clarity Figure Ellipsoid representation of the molecular structure of [ReO(OMe)(L)] [19] Thermal ellipsoids represent 50 percent probability Hydrogen atoms bonded on carbon atoms have been omitted for clarity 17 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Figure Ellipsoid representation of the molecular structure of [Ni(L)] [19] Thermal ellipsoids represent 60 percent probability Hydrogen atoms bonded on carbon atoms have been omitted for clarity 18 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Figure Ellipsoid representation of the molecular structure of [ReO(OMe)(L)] [19] Thermal ellipsoids represent 50 percent probability Hydrogen atoms bonded on carbon atoms have been omitted for clarity 19 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Graphical Abstract The potentially tetradentate benzamidine/thiosemicarbazone ligand H2L forms stable transition metal complexes of the compositions M(L) (M = Ni, Pd, Pt) and ReO(OMe)(L) H2L and the oxidorhenium(V) complex show a considerably cytotoxicity, while the nickel, palladium and platinum complexes are almost inactive 20 ... 64 65 Syntheses, Structures and Biological Evaluation of some Transition Metal Complexes with a Tetradentate Benzamidine/ Thiosemicarbazone Ligand Thi Bao Yen Nguyen ,a) Chien Thang Pham ,a, b) Thi... Introduction Thiosemicarbazones, which form stable complexes with many main group and transition metals[1,2], constantly attract the interest of chemists and pharmacists due to their remarkable biological. .. 63 64 65 Graphical Abstract The potentially tetradentate benzamidine/ thiosemicarbazone ligand H2L forms stable transition metal complexes of the compositions M(L) (M = Ni, Pd, Pt) and ReO(OMe)(L)