Tricarbonylrhenium(I) complexes with the N-methylpyridine-2-carbothioamide ligand – Synthesis, characterization and cytotoxicity studies

Accepted Manuscript Tricarbonylrhenium(I) complexes with the N-methylpyridine-2-carbothioamide ligand – Synthesis, characterization and cytotoxicity studies Krzysztof Lyczko, Monika Lyczko, Sylwia Meczynska-Wielgosz, Marcin Kruszewski, Józef Mieczkowski PII:

S0022-328X(18)30238-9

DOI:

10.1016/j.jorganchem.2018.04.008

Reference:

JOM 20400

To appear in:

Journal of Organometallic Chemistry

Received Date: 25 January 2018 Revised Date:

6 April 2018

Accepted Date: 7 April 2018

Please cite this article as: K. Lyczko, M. Lyczko, S. Meczynska-Wielgosz, M. Kruszewski, Jó. Mieczkowski, Tricarbonylrhenium(I) complexes with the N-methylpyridine-2-carbothioamide ligand – Synthesis, characterization and cytotoxicity studies, Journal of Organometallic Chemistry (2018), doi: 10.1016/j.jorganchem.2018.04.008. 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.

ACCEPTED MANUSCRIPT

Tricarbonylrhenium(I) complexes with the N-methylpyridine-2carbothioamide ligand – synthesis, characterization and cytotoxicity studies Krzysztof Lyczko,a,* Monika Lyczko,a Sylwia Meczynska-Wielgosz,a Marcin

a

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Kruszewski,a,b,c Józef Mieczkowskid

Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland

b

Faculty of Medicine, University of Information Technology and Management, Sucharskiego

c

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2, 35-225 Rzeszów, Poland

Department of Molecular Biology and Translational Research, Institute of Rural Health,

Jaczewskiego 2, 20-090 Lublin, Poland

Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland

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d

*Corresponding author. E-mail: [email protected]

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Abstract

A new series of tricarbonyl complexes of rhenium(I) in the ‘2+1’ system with the bidentate ligand

N-methylpyridine-2-carbothioamide

(NC5H4-CS-NH-CH3,

LH(Me)NS)

and

a

monodentate ligand, being either an anion (Cl, Br, I or SCN) or a neutral molecule (3,5-

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dimethylpyrazole (Hdmpz) or imidazole (Him)), was synthesized. The use of mixed ligands leads to the formation of neutral or cationic (in the form of PF6− salts) tricarbonylrhenium(I)

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complexes: [Re(CO)3(LH(Me)NS)X] (X = Cl, Br, I, NCS) (complexes 1−4) and [Re(CO)3(LH(Me)NS)Y]+ (Y = Hdmpz, Him) (5 and 6), respectively. In case of the [Re(CO)3(LH(Me)NS)NCS] complex two polymorphic forms (4a and 4b) have been distinguished. Crystal structure of all complexes was determined by single-crystal X-ray diffraction method and the results were compared with the molecular structures obtained from DFT calculations. The compounds were characterized by FT-IR, NMR, UV-Vis and HPLC techniques. IR and UV-Vis spectra were also simulated by DFT and TD-DFT methods. Cytotoxicity of the complexes was estimated using human ovarian cancer cell line (A2780), its cisplatin resistant cell line (A2780cis) and non-cancerous human embryonic kidney cells (Hek-293). The toxicity of newly synthesized complexes was comparable to cisplatin when 1

ACCEPTED MANUSCRIPT tested against both cancerous cell lines (IC50 = 2−49 µM), but lower than cisplatin towards non-cancerous cells (IC50 = 6−63 µM). Among them, the complexes with chloride and iodide anions exhibit remarkable cytotoxicities.

structure, DFT calculations, Cytotoxicity, IC50

1.

Introduction

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Keywords: Tricarbonylrhenium(I) complexes, N-methylpyridine-2-carbothioamide, Crystal

Tricarbonylrhenium(I) compounds with one bidentate and one monodentate ligand (the so called ‘2+1’ system) still remain a very interesting field to explore [1−11]. 188

Re(CO)3 core in radiotherapy [12,13], the

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Besides the possible applications of the

tricarbonyl complexes of natural rhenium isotope are considered as potential anticancer agents in conventional chemotherapy [14−16] and photodynamic therapy [17−19]. They may also be used in some therapeutic processes as carbon monoxide releasing molecules at the biological targets upon illumination with light (photoCORMs) [20,21]. Moreover, Re(I) organometallic

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compounds can be toxic for microorganisms [22]. In addition, these species are widely studied because of their excellent photophysical and photochemical properties [23−28]. The rhenium(I) tricarbonyl complexes in a ‘2+1’ layout can be applied as photosensitizers, photocatalysts and luminescence probes [24−26]. They can become a promising material for

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production of organic light emitting devices (OLEDs) [27,28]. The rhenium(I) compounds are still studied and compared with the technetium(I) analogues as their structural model [29,30]. Continuing our research on the tricarbonylrhenium(I) compounds in the ‘2+1’ system

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[31], we have chosen herein N-methylpyridine-2-carbothioamide as the bidentate ligand, in order to investigate the influence of the sixth monodentate ligand on the formation of the final rhenium(I) complexes. N-methylpyridine-2-carbothioamide (NC5H4-CS-NH-CH3, LH(Me)NS) is an amide derivative of thiopicolinic acid containing three potential donor atoms: a nitrogen atom from the aromatic ring, a sulfur atom from the thiocarbonyl group and a nitrogen atom from the amide part. However, only the bidentate way of complexation of metal ions is possible for this ligand. The synthesis, structures, and spectroscopic characterization of a series of tricarbonylrhenium(I) complexes with the bidentate N,S-donor ligand Nmethylpyridine-2-carbothioamide and with different monodentate ligands being either an 2

ACCEPTED MANUSCRIPT anion (Cl−, Br−, I− and SCN−) or a neutral molecule (imidazole (Him) and 3,5dimethylpyrazole (Hdmpz)) are presented in this work. It must be noted that the formation and molecular structure of the complex with a chloride ion was briefly published earlier [32]. In the previous work we also characterized a series of tricarbonylrhenium(I) complexes with the N,O-donor derivative of LH(Me)NS ligand [31].

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Moreover, the presented studies are enriched by the in vitro cytotoxicity measurements towards two types of human ovarian cancer cell lines (A2780 and A2780cis) and noncancerous human embryonic kidney cells (Hek-293). The search for novel anticancer organometallic compounds, other than platinum drugs, is of great interest in chemistry [33]. A

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growing number of investigations revealed the potential anticancer effect of the tricarbonylrhenium(I) complexes in the ‘2+1’ mixed ligand system, even better than a commonly used cisplatin or carboplatin [14,34−38]. The most attention has been paid for

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cytotoxicity studies of such complexes with the N,N-bidentate ligands towards various human cancer cell lines including cervical, colon, breast, pancreatic, prostate, liver, lung and glioblastoma cells [14,35−43]. As far as we know, the biological activity of the rhenium(I) species with the N,S-donor ligands has not yet been reported.

Experimental

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2.

2.1. Materials and methods

The N-methylpyridine-2-carbothioamide ligand was synthesized according to the published

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method involving conversion of picolinic acid into the secondary thioamide [32]. All other chemicals were used as purchased from commercial sources. Elemental analysis was performed on an Elementar Vario EL III analyzer. Infrared absorption spectra in the range

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400−4000 cm−1 were recorded with a Thermo Scientific Nicolet iS10 FT-IR spectrometer using KBr pellets. UV-vis spectra of methanol solutions were recorded in the range 200−900 nm with a Thermo Scientific Evolution 600 spectrometer. The ESI mass spectroscopy measurements were performed with an Agilent Technologies 6530 Accurate-Mass Q-TOF LC/MS device. 1H,

13

C and

19

F NMR spectra of DMSO-d6 or MeOD-d4 solutions were

measured on a Varian Unity Plus 500 MHz spectrometer. High-performance liquid chromatography (HPLC) was performed using the ELITE LaChrom (VWR-Hitachi) system with L-2310 pump coupled to L-2455 diode array detector and L-2350 column oven. An Aeris Peptide column (4.6 x 150 mm, 3.6 µm) and a flow rate of 1 mL/min were used. The 3

ACCEPTED MANUSCRIPT gradient elution system consisted of deionized water containing 0.1% (v/v) TFA (A) and MeOH (B). Gradient started with 95% A / 5% B for 3 min; then was increased to 100% B over the next 12 min and held at 100% B for 5 min, after which the gradient parameters were returned to the initial conditions during the next 5 min. For biological studies the following materials were used: RPMI-1640 medium, L-

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glutamine, cisplatin, phosphate-buffered saline (PBS), dimethylsulfoxide (DMSO) and 3-(4,5dimetyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) - all from Sigma Aldrich, eagle's minimum essential medium (EMEM) from American Type Culture Collection (ATCC, Rockville, MD) and fetal calf serum (FCS) from Biological Industries (Israel).

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Human ovarian carcinoma cell line (A2780) and its cisplatin resistant derivative (A2780cis) were purchased from Sigma Aldrich. Human embryonic kidney cell line (Hek-293) were purchased from the ATCC. A2780 cells were cultured in RPMI-1640 medium supplemented

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with 10% FCS and 2 mM L-glutamine. A2780cis cells were cultured in the same medium, but 1 µM cisplatin was added every 2-3 passage to keep cisplatin resistance. Hek-293 cells were cultured in EMEM medium supplemented with 10% FCS. The cells were incubated in a 5% CO2 atmosphere at 37oC.

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2.2. Synthesis of the complexes 2.2.1. [Re(CO)3(LH(Me)NS)Cl] (1)

The preparation of the title complex has been reported before in the literature [32] but in this study the respective crystals of 1 were obtained in an even simpler manner described below.

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Re(CO)5Cl (0.050 g, 0.138 mmol) and N-methylpyridine-2-carbothioamide (0.026 g, 0.171 mmol) were stirred and refluxed for 12 h in methanol (4.0 mL). Next, a clear dark orange

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solution was stored at room temperature for approximately 3 weeks which resulted in the formation of orange crystals. Yield: 0.039 g (61.9%). Anal. Calc. for C10H8ClN2O3ReS: C, 26.23; H, 1.76; N, 6.12; S, 7.00. Found: C, 26.29; H, 1.92; N, 6.18; S, 6.98%. UV-Vis λmax(MeOH)/nm (ε/dm3·mol−1·cm−1) 273 (14809), 394 (4309). IR νmax(KBr)/cm−1 3248w,br (NH), 2016vs, 1919vs (CO), 1567w (CN). ESI-MS m/z = 422.9812 [M – Cl]+ (calc. 422.9802). 1H NMR (500.20 MHz, DMSO-d6) δ/ppm = 11.73 (1H, s, H2), 9.15 (1H, dd, J = 5.5, 1.0 Hz, H4), 8.44 (1H, d, J = 7.5 Hz, H7), 8.40 (1H, ddd, J = 7.9, 7.9, 1.7 Hz, H5), 7.85 (1H, ddd, J = 7.4, 5.6, 1.6 Hz, H6), 3.35 (3H, s, H10A-C). 13C NMR (125.79 MHz, DMSO-d6)

4

ACCEPTED MANUSCRIPT δ/ppm = 196.92, 194.43, 193.59, 190.28, 156.35, 152.38, 140.16, 129.82, 124.01, 34.53 (C10, CH3). 2.2.2. [Re(CO)3(LH(Me)NS)Br] (2) Re(CO)5Br (0.071 g, 0.175 mmol) and N-methylpyridine-2-carbothioamide (0.035 g, 0.230

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mmol) were stirred and refluxed for about 10 h in methanol (5.0 mL) and a clear dark orange solution was obtained. Storing this solution at room temperature for approximately 3 weeks resulted in the formation of orange crystals. Yield: 0.040 g (45.4%). Anal. Calc. for C10H8BrN2O3ReS: C, 23.91; H, 1.61; N, 5.58; S, 6.38. Found: C, 24.10; H, 1.85; N, 5.67; S, 6.33%. UV-Vis λmax(MeOH)/nm (ε/dm3·mol−1·cm−1) 273 (11845), 395 (3091). IR

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νmax(KBr)/cm−1 3259w,br (NH), 2016vs, 1921vs (CO), 1564w (CN). ESI-MS m/z = 422.9815 [M–Br]+ (calc. 422.9802). 1H NMR (500.20 MHz, DMSO-d6) δ/ppm = 11.72 (1H, s, H2), 9.17

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(1H, dd, J = 5.5, 1.0 Hz, H4), 8.45 (1H, ddd, J = 8.1, 1.4, 0.6 Hz, H7), 8.39 (1H, ddd, J = 8.0, 8.0, 1.5 Hz, H5), 7.85 (1H, ddd, J = 7.4, 5.6, 1.1 Hz, H6), 3.36 (3H, s, H10A-C).

13

C NMR

(125.79 MHz, DMSO-d6) δ/ppm = 196.38, 193.96, 193.28, 189.80, 156.59, 152.48, 140.14, 129.81, 124.05, 34.46 (C10, CH3).

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2.2.3. [Re(CO)3(LH(Me)NS)I] (3)

Re(CO)5Cl (0.040 g, 0.111 mmol) was dissolved in methanol (3.0 mL) under reflux. Then, AgNO3 (0.019 g, 0.112 mmol) dissolved in hot methanol (1.0 mL) was added to the clear solution and the mixture was stirred for 1 h. After separation of AgCl precipitate through a

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syringe filter with 0.45 µm PTFE membrane, a mixture of KI (0.028 g, 0.169 mmol) and Nmethylpyridine-2-carbothioamide (0.022 g, 0.144 mmol) in methanol (1.0 mL) was added.

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Next, the entire mixture was stirred and refluxed (65 °C) for 12 h. The resulting solution was stored in a refrigerator and after approximately 5 weeks orange crystals were obtained. Yield: 0.024 g (39.3%). Anal. Calc. for C10H8IN2O3ReS: C, 21.86; H, 1.47; N, 5.10; S, 5.84. Found: C, 21.88; H, 1.66; N, 5.29; S, 5.81%. UV-Vis λmax(MeOH)/nm (ε/dm3·mol−1·cm−1) 274 (13510), 398 (3290). IR νmax(KBr)/cm−1 3236w,br (NH), 2020vs, 1924vs (CO), 1558w (CN). ESI-MS m/z = 422.9812 [M – I]+ (calc. 422.9802). 1H NMR (500.20 MHz, DMSO-d6) δ/ppm = 11.70 (1H, s, H2), 9.21 (1H, dd, J = 5.8, 1.0 Hz, H4), 8.46 (1H, d, J = 8.0 Hz, H7), 8.38 (1H, ddd, J = 8.0, 8.0, 1.5 Hz, H5), 7.82 (1H, ddd, J = 7.4, 6.2, 1.4 Hz, H6), 3.36 (3H, s, H10A-C). 13

C NMR (125.79 MHz, DMSO-d6) δ/ppm = 196.38, 193.96, 193.28, 189.80, 156.59, 152.48,

140.14, 129.81, 124.05, 34.46 (C10, CH3). 5

ACCEPTED MANUSCRIPT 2.2.4. [Re(CO)3(LH(Me)NS)NCS] (4a and 4b) The clear solution of Re(CO)5Cl (0.040 g, 0.111 mmol) in methanol (3.0 mL) was prepared as described above for 3. Next AgPF6 (0.028 g, 0.111 mmol) dissolved in methanol (0.5 mL) was added to the solution and the precipitate that formed was separated by means of a syringe

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filter with 0.45 µm PTFE membrane. To this clear solution a mixture of N-methylpyridine-2carbothioamide (0.023 g, 0.151 mmol) and KSCN (0.015 g, 0.154 mmol) in methanol (1.0 mL) was added. The resulting mixture was stirred and refluxed for 20 h. The volume of the obtained solution was reduced by about a half in a desiccator under vacuum. The orange

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crystals of 4a were separated after its subsequent storing at room temperature for approximately 3 weeks. Yield: 0.018 g (34.0%). The remaining solution was stored for additional 6 weeks at room temperature giving reddish crystalline material of 4b. Yield: 0.013

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g (24.5%). A much smaller amount of orange crystals of 4a was also obtained. Anal. Calc. for C11H8N3O3ReS2: C, 27.49; H, 1.68; N, 8.74; S, 13.35. Found: C, 27.49; H, 1.82; N, 8.72; S, 13.21%. UV-Vis λmax(MeOH)/nm (ε/dm3·mol−1·cm−1) 269 (11847), 405 (2527). IR νmax(KBr)/cm−1 3182w,br (NH), 2119m (NCS), 2019vs, 1912vs (CO), 1577w (CN) for 4a, 3272w,br (NH), 2113m (NCS), 2039s, 1942vs, 1912vs (CO), 1555w (CN) for 4b. ESI-MS

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m/z = 422.9799 [M – NCS]+ (calc. 422.9806). 1H NMR (500.20 MHz, DMSO-d6) δ/ppm = 11.97 (1H, s, H2), 9.18 (1H, dd, J = 4.8, 0.8 Hz, H4), 8.50-8.44 (2H, m, H7, H5), 7.91 (1H, ddd, J = 7.1, 5.4, 1.9 Hz, H6), 3.40 (3H, s, H10A-C). 13C NMR (125.79 MHz, DMSO-d6) δ/ppm = 194.77, 193.32, 192.31, 192.15, 156.73, 152.41, 140.74, 134.33 (C11, NCS), 130.43, 124.30,

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34.82 (C10, CH3).

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2.2.5. [Re(CO)3(LH(Me)NS)Hdmpz]PF6 (5) Complex 1 (0.025 g, 0.055 mmol) was dissolved in methanol (7.0 mL) under reflux. The precipitate of AgCl was separated from this solution after addition of AgPF6 (0.014 g, 0.055 mmol) in methanol (1.0 mL) and then Hdmpz (0.006 g, 0.062 mmol) was added as a solid. The resultant mixture was stirred and refluxed for 6 h. The volume of orange solution was reduced to about 0.5 mL in a desiccator under reduced pressure. An orange material was obtained during storage in a refrigerator after approximately 4 months. This product was recrystallized in methanol giving suitable crystals. Yield: 0.010 g (27.8%). Anal. Calc. for C15H16F6N4O3PReS: C, 27.15; H, 2.43; N, 8.44; S, 4.83. Found: C, 27.14; H, 2.51; N, 8.34; S, 4.96%. UV-Vis λmax(MeOH)/nm (ε/dm3·mol−1·cm−1) 268 (10 450), 392 (2564). IR 6

ACCEPTED MANUSCRIPT νmax(KBr)/cm−1 3382m, 3251w,br (NH), 2030m, 1922vs (CO), 1582w (CN), 855m, 556w (PF). ESI-MS m/z = 519.0498 [M–PF6]+ (calc. 519.0494). 1H NMR (500.20 MHz, MeOD-d4) δ/ppm = 9.47 (1H, d, J = 5.5 Hz, H4), 8.35 (1H, ddd, J = 8.0, 8.0, 1.6 Hz, H7), 8.27 (1H, d, J = 8.0 Hz, H5), 7.85 (1H, ddd, J = 7.5, 5.5, 1.4 Hz, H6), 5.89 (1H, s, H12 (Hdmpz)), 3.44 (3H, s, H10A-C), 2.19 (3H, s, CH3 (Hdmpz)), 2.03 (3H, s, CH3 (Hdmpz)).

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C NMR (125.79 MHz,

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MeOD-d4) δ/ppm = 195.22, 194.91, 193.60, 193.15, 159.06, 155.24, 154.84, 145.00, 142.15, 130.82, 125.40, 107.77, 35.35 (C10, CH3), 15.14 (CH3 (Hdmpz)), 10.30 (CH3 (Hdmpz)). NMR (420.63 MHz, MeOD-d4) δ/ppm = −74.08, −75.59.

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2.2.6. [Re(CO)3(LH(Me)NS)Him]PF6 (6)

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From the clear solution of Re(CO)5Cl (0.057 g, 0.158 mmol) prepared in the same way as for 2, AgCl was precipitated and separated after adding an equimolar amount of AgPF6 (0.040 g,

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0.158 mmol) in methanol (1.0 mL). Next, to the clear solution a mixture of N-methylpyridine2-carbothioamide (0.027 g, 0.177 mmol) and Him (0.012 g, 0.176 mmol) in methanol (1.0 mL) was added and the whole solution was stirred and warmed at 55 °C for 20 h. Both the syntheses for 5 and 6 were carried out in a PFA flask to avoid possible contamination with SiF62‾ anions caused by dissolution of a glass material via the presence of PF6‾ ions [44]. The

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volume of the solution was decreased to about 0.5 mL in a desiccator under reduced pressure and orange crystals were obtained. Yield: 0.072 g (72.0%). Anal. Calc. for C13H12F6N4O3PReS: C, 24.57; H, 1.90; N, 8.82; S, 5.05. Found: C, 24.77; H, 2.04; N, 8.86; S, 5.19%. UV-Vis λmax(MeOH)/nm (ε/dm3·mol−1·cm−1) 266 (12460), 397 (3027). IR

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νmax(KBr)/cm−1 3464w, 3378w (NH), 2026vs, 1904vs (CO), 1568w (CN), 843m, 558w (PF). ESI-MS m/z = 491.0207 [M–PF6]+ (calc. 491.0181). 1H NMR (500.20 MHz, MeOD-d4)

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δ/ppm = 9.33 (1H, dm, Hz, H4), 8.32 (1H, ddd, J = 8.0, 8.0, 1.6 Hz, H7), 8.25 (1H, dm, Hz, H5), 7.85 (2H, m, H6 and CH (Him)), 7.06 (1H, dd, J = 1.6, 1.2, CH (Him)), 6.91 (1H, dd, J = 1.6, 1.6, CH (Him)), 3.47 (3H, s, H10A-C).

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C NMR (125.79 MHz, MeOD-d4) δ/ppm =

196.10, 195.73, 194.18, 193.25, 158.17, 154.40, 141.87, 140.55, 131.66, 130.17, 125.15, 119.32, 35.18 (C10, CH3). 19F NMR (420.63 MHz, MeOD-d4) δ/ppm = −73.89, −75.39. 2.3. X-ray crystallography Diffraction data for all the studied complexes were collected at 100 K on a Rigaku SuperNova (dual source) four circle diffractometer equipped with an Eos CCD detector using mirrormonochromated Mo Kα radiation (λ = 0.7107 Å) from a micro-focus Mova X-ray source. A 7

ACCEPTED MANUSCRIPT suitable crystal of each complex was mounted on a nylon loop with help of paratone-N cryoprotectant oil. The crystal structure of the [Re(CO)3(LH(Me)NS)Cl] complex, which was already measured at room temperature [32], was re-determined at low temperature for the exact comparison with other similar compounds disclosed in this work. Data collection (ωscans) and processing (cell refinement, data reduction and empirical absorption correction)

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were performed using CrysAlis PRO software. The structures were solved by direct methods and refined by the full matrix least-squares method on F2 data. All non-hydrogen atoms were refined with anisotropic atomic displacement parameters. Hydrogen atoms bonded to carbon atoms were placed into geometrically idealized positions with C−H equal to 0.98 (methyl) or

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0.95 Å (all other) and refined isotropically using riding model with Uiso(H) set to 1.5 or 1.2Ueq(C), respectively. In turn, hydrogen atoms bonded to nitrogen atoms were freely refined (4b, 5 and 6) or located from difference Fourier maps and then only their positions were

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freely refined with Uiso(H) set to 1.2Ueq(N) (1−3, 4a). All calculations were performed with the SHELXTL programs [45]. SHELXTL and MERCURY [46] programs were applied for graphical representation of the crystal structures. Selected crystallographic parameters and

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refinement details are presented in Table 1.

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ACCEPTED MANUSCRIPT Table

1.

Crystallographic

data

and

structure

refinement

parameters

for

the

tricarbonylrhenium(I) complexes 1−6. 1

2

3

4a

4b

5

6

Chemical formula Formula weight Temperature (K) λ [Mo Kα] (Å) Crystal system Space group a (Å) b (Å) c (Å) α (°) β (°) γ (°) Volume (Å) Z Dcalc (g·cm-3) µ (mm-1) F (000) Crystal size (mm) θ (°) Reflections collected Independent reflections Rint Data/ restraints/ parameters GOF(F2) Final R indices [I > 2σ(I)] R indices (all data)

C10H8ClN2O3ReS 457.89 100(2) 0.71073 Triclinic P -1 7.8988(2) 7.9739(3) 10.5889(4) 77.348(3) 84.290(2) 89.288(2) 647.48(4) 2 2.349 9.751 428 0.22x0.18x0.06 3.42−25.00 8063

C10H8BrN2O3ReS 502.35 100(2) 0.71073 Triclinic P -1 7.8683(5) 8.0800(4) 10.8061(4) 82.860(4) 79.020(4) 89.917(5) 669.03(6) 2 2.494 12.223 464 0.18x0.10x0.06 2.99−24.99 4363

C10H8IN2O3ReS 549.34 100(2) 0.71073 monoclinic P 21/n 7.7660(4) 8.2577(3) 21.8740(9) 90.00 99.624(4) 90.00 1383.03(10) 4 2.638 11.169 1000 0.25x0.20x0.12 3.11−25.00 5397

C11H8N3O3ReS2 480.52 100(2) 0.71073 monoclinic P 21/c 12.09943(19) 12.75448(18) 9.38381(12) 90.00 90.4553(13) 90.00 1448.08(4) 4 2.204 8.688 904 0.20x0.18x0.06 3.17−26.99 21067

C11H8N3O3ReS2 480.52 100(2) 0.71073 monoclinic P 21/c 15.62961(8) 6.43847(3) 14.32245(7) 90.00 101.8860(5) 90.00 1410.376(13) 4 2.263 8.920 904 0.10x0.08x0.06 2.91−30.00 79046

C15H16F6N4O3PReS 663.55 100(2) 0.71073 triclinic P -1 8.47774(12) 10.37628(16) 12.7202(2) 80.6014(13) 87.8998(12) 74.7383(13) 1064.99(3) 2 2.069 5.955 636 0.12x0.06x0.03 2.98−27.50 30253

C13H12F6N4O3PReS 635.50 100(2) 0.71073 monoclinic P 21/c 6.80537(5) 9.77808(7) 28.8374(2) 90.00 91.3979(7) 90.00 1918.37(2) 4 2.200 6.606 1208 0.20x0.15x0.12 2.97−25.00 55667

2280

2360

2424

3148

4091

4872

3353

0.0740 2280/1/155

0.0327 2360/0/161

0.0285 2424/0/161

0.0293 3148/0/185

0.0342 4091/1/186

0.0287 4872/0/291

0.0256 3353/0/271

1.059 R1 = 0.0216 wR2 = 0.0499 R1 = 0.0227 wR2 = 0.0506 1.698/-1.431

1.044 R1 = 0.0249 wR2 = 0.0538 R1 = 0.0270 wR2 = 0.0553 1.205/-1.368

1.227 R1 = 0.0336 wR2 = 0.0665 R1 = 0.0369 wR2 = 0.0676 1.341/-1.292

1.129 R1 = 0.0153 wR2 = 0.0325 R1 = 0.0169 wR2 = 0.0330 0.799/-0.893

1.078 R1 = 0.0113 wR2 = 0.0252 R1 = 0.0125 wR2 = 0.0256 0.543/-0.561

1.056 R1 = 0.0136 wR2 = 0.0315 R1 = 0.0149 wR2 = 0.0321 0.544/-0.550

1.195 R1 = 0.0163 wR2 = 0.0366 R1 = 0.0165 wR2 = 0.0367 1.472/-0.733

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Largest difference in peak/hole(e·Å-3)

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Compound

2.4. Cytotoxicity measurements

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The impact of the tricarbonylrhenium(I) complexes and cisplatin on cellular metabolic activity was measured with MTT assay. Cells were seeded in 96-well microplates (TPP, Switzerland) at a density of 1x104 cells/well in 100 µL of culture medium. Twenty four hours after cell seeding cells were treated for 24 h with increasing concentrations of the rhenium(I) compounds and cisplatin (0.02−150 µg/mL). Cisplatin was prepared as a 0.3 mM solution in 0.9% NaCl and diluted using culture media. The rhenium(I) complexes were prepared as 0.3 M solutions in DMSO and diluted using culture media. The final concentration of DMSO in each well was 0.1%. After the described treatment, cell culture medium was removed and 100 µL of 3 mg/mL MTT solution was added to each well. After 3 h incubation at 37°C the MTT 9

ACCEPTED MANUSCRIPT solution was removed. Remaining insoluble formazan crystals were dissolved in 100 µL DMSO and absorbance of the solution was measured at 570 nm in a plate reader spectrometer Infinite M200 (Tecan, Austria). IC50 values were interpolated from the resulting dosedependent curves and calculated using GraphPad Prism Software. The reported IC50 values are the average from at least three independent experiments in six replicates per concentration

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level.

2.5. Computational methodology

Computational calculations were obtained using the Gaussian 09 program package [47]. DFT

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calculations were performed at the B3LYP level of theory with the LANL2DZ basis set for rhenium and iodine atoms and the 6-31G(d,p) basis set for the remaining lighter elements. The 6-31G++(d,p) and 6-311G++(d,p) basis sets were also compared in structural

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calculations. The geometries obtained from the X-ray structural data of the respective complexes were used as the initial geometries in the optimization of the molecular structures. All geometries were fully optimized and then evaluated through calculation of the vibrational frequencies to verify the states with minimum energy. The calculated harmonic frequencies were scaled by the factor 0.95. Time-dependent DFT calculations with the CAM-B3LYP

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functional were applied to obtain absorption spectra. In addition, the solvent effect was modeled using the polarizable continuum model (IEFPCM). For visualization of the molecular orbitals and extraction of the percent contributions of atom groups to each of the

3.

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MOs the GaussView 5.0 [47] and GaussSum 3.0 [48] programs were employed.

Results and discussion

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3.1. Synthesis

A series of the complexes was synthesized in quite good yields. The refluxing methanol solutions of the commercially available Re(CO)5X (X = Cl, Br) compounds were predominantly used as a starting step for the synthesis of the tricarbonylrhenium(I) complexes. The neutral complexes 1 and 2 were obtained in the reaction of the chloro and bromo precursors with the N-methylpyridine-2-carbothioamide ligand. The same process carried out with previous removal of halide ions and subsequent addition of another anion (iodide and thiocyanate) resulted in the formation of neutral complexes 3 and 4. In turn, during the reaction of the neutral complex (i.e. 1) or Re(CO)5Cl and LH(Me)NS with a 10

ACCEPTED MANUSCRIPT heterocyclic ligand (3,5-dimethylpyrazole (Hdmpz) or imidazole (Him)), after earlier precipitation of chloride ions, cationic compounds 5 and 6 were obtained. Simplified reaction paths used for the preparation of all the studied complexes are presented in Scheme 1. Complexes 1−6 were verified by elemental analyses and ESI-MS measurements (Fig. S1,

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Supplementary data) and characterized by the methods described below.

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Scheme 1. Simple scheme for the synthesis of the studied tricarbonylrhenium(I) complexes.

3.2. Description of the crystal structures

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For all the studied complexes (1−6), selected bond lengths and angles derived from measurements and calculations are shown in Table 2. The crystal and molecular structures of

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the studied compounds are described below. The complexes presented herein are divided into three groups, depending on the nature of the monodentate ligand and the charge of the formed complex. The crystal structure of compound 1, shown in earlier work [32], was re-determined at low temperature for exact comparison with other similar structures of both heavier halogen atoms.

11

ACCEPTED MANUSCRIPT Table 2. Selected bond lengths (Å) and angles (°) for complexes 1−6 obtained from experiment and DFT calculations (B3LYP/LANL2DZ,6-31G(d,p)) (X = Cl1 (for 1), Br1 (for 2), I1 (for 3), N3 (for 4a, 4b, 5 and 6)). 1

2

3

Bond lengths Exp. 1.913(6) 1.909(5) 1.912(5) 2.214(4) 2.4524(14) 2.6265(6) 1.678(6) 1.317(7) 1.455(7)

Calc. 1.936 1.922 1.920 2.217 2.539 2.674 1.689 1.338 1.458

Exp. 1.906(7) 1.925(9) 1.961(9) 2.207(6) 2.450(2) 2.8124(6) 1.684(8) 1.318(10) 1.459(10)

79.46(10) 82.91(9) 86.26(4) 172.45(16) 173.91(13) 175.96(13) 89.69(19) 89.39(18) 89.52(19) 94.02(13) 88.33(13) 177.9(4) 179.3(4) 177.7(4)

78.34 81.91 83.39 170.98 172.01 175.81 90.29 91.70 92.04 91.90 90.08 178.17 177.93 179.32

79.06(11) 83.93(10) 86.71(4) 172.21(18) 174.34(15) 176.00(15) 89.1(2) 90.7(2) 89.7(2) 92.76(16) 88.25(15) 176.9(5) 178.4(4) 178.4(5)

78.31 82.81 84.11 171.01 171.93 176.56 90.44 91.80 92.18 91.28 89.34 178.16 177.92 179.40

79.55(17) 84.06(16) 87.41(5) 172.2(3) 175.0(2) 176.0(2) 89.3(3) 90.3(3) 90.1(3) 93.2(2) 88.1(2) 177.1(7) 178.8(7) 178.7(7)

Calc. 1.936 1.926 1.917 2.225 2.513 2.910 1.684 1.343 1.457

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Calc. 1.936 1.921 1.919 2.216 2.544 2.532 1.690 1.337 1.458

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Exp. 1.907(4) 1.912(5) 1.905(4) 2.206(3) 2.4531(12) 2.4842(10) 1.687(4) 1.308(5) 1.446(6)

78.32 85.10 86.15 171.35 171.99 178.46 90.45 91.63 92.11 89.86 87.46 178.28 177.83 179.36

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Re1-C1 Re1-C2 Re1-C3 Re1-N1 Re1-S1 Re1-X C9-S1 C9-N2 C10-N2 Angles N1-Re1-S1 N1-Re1-X S1-Re1-X N1-Re1-C1 S1-Re1-C2 X-Re1-C3 C1-Re1-C2 C1-Re1-C3 C2-Re1-C3 X-Re1-C1 X-Re1-C2 O1-C1-Re1 O2-C2-Re1 O3-C3-Re1

12

ACCEPTED MANUSCRIPT Table 2. contd. 5

6

4a

4b

Exp. 1.923(3) 1.920(3) 1.920(3) 2.192(2) 2.4913(6) 2.124(2) 1.697(2) 1.309(3) 1.458(3)

Exp. 1.9279(17) 1.9269(16) 1.9315(16) 2.1963(13) 2.4670(4) 2.1315(16) 1.6891(16) 1.322(2) 1.456(2)

Calc. 1.937 1.919 1.932 2.234 2.589 2.147 1.703 1.329 1.461

Exp. 1.929(2) 1.930(2) 1.911(2) 2.2026(16) 2.4966(5) 2.2037(16) 1.7064(19) 1.302(3) 1.464(2)

Calc. 1.934 1.928 1.938 2.252 2.521 2.258 1.696 1.332 1.461

Exp. 1.928(4) 1.923(3) 1.919(3) 2.198(3) 2.4656(8) 2.192(3) 1.692(3) 1.312(4) 1.458(4)

Calc. 1.936 1.925 1.938 2.250 2.518 2.250 1.693 1.334 1.461

79.48(6) 82.16(8) 81.16(8) 174.19(9) 173.85(8) 174.40(9) 88.18(11) 89.25(11) 89.37(11) 95.78(9) 93.22(10) 178.6(2) 178.8(2) 179.0(2)

78.99(4) 83.83(5) 82.51(4) 174.76(6) 173.80(5) 175.40(6) 88.16(7) 89.46(7) 90.78(7) 93.32(6) 92.96(6) 179.40(15) 178.70(14) 179.38(16)

77.98 80.10 82.71 171.04 173.39 173.10 90.30 91.52 91.52 93.94 92.66 178.37 178.05 178.65

79.15(4) 85.08(6) 83.79(4) 172.96(7) 176.52(6) 177.44(7) 87.96(9) 89.37(8) 88.33(9) 92.69(7) 93.25(8) 179.14(18) 177.17(19) 179.16(19)

78.17 89.20 85.46 173.44 174.51 177.59 89.56 90.23 90.42 90.17 91.96 178.08 178.15 179.46

79.37(7) 82.08(9) 89.30(9) 170.75(11) 176.32(9) 178.27(11) 88.02(13) 90.66(13) 88.10(12) 90.95(11) 92.59(11) 178.0(3) 177.0(3) 179.3(3)

78.27 85.74 88.62 172.47 174.58 178.30 90.18 90.89 90.63 90.41 90.94 177.96 177.38 179.31

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Re1-C1 Re1-C2 Re1-C3 Re1-N1 Re1-S1 Re1-X C9-S1 C9-N2 C10-N2 Angles N1-Re1-S1 N1-Re1-X S1-Re1-X N1-Re1-C1 S1-Re1-C2 X-Re1-C3 C1-Re1-C2 C1-Re1-C3 C2-Re1-C3 X-Re1-C1 X-Re1-C2 O1-C1-Re1 O2-C2-Re1 O3-C3-Re1

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Bond lengths

3.2.1. Complexes of the [Re(CO)3(LH(Me)NS)X’] type (X’ = Cl, Br and I) The structure of tricarbonylrhenium(I) complexes with the bidentate ligand (LH(Me)NS) and with halide anions (complexes 1-3) are presented in Figs 1 and 2 and Fig. S2. The metal ion is

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surrounded by six donor atoms, including three carbon atoms, one nitrogen, one sulfur and one halogen atom, in a slightly distorted octahedral geometry. The three CO ligands are

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directed into the facial positions of the octahedron. The Re−C bond distances are in the range 1.90−1.96 Å. N-methylpyridine-2-carbothioamide behaves in 1−3 as a neutral ligand, which chelates the rhenium(I) ion by means of sulfur and nitrogen atoms, with average bond lengths of 2.45 and 2.21 Å, respectively, forming a five-membered ring. The N1−Re1−S1 bite angles (average value of 79.4°) are typical for that type of chelate ring and are about 5° higher than the respective N−Re−O bite angles in the analogous complexes with the LH(Me)NO ligand [31]. The sixth coordination position of the metal ion is occupied by the halide anion, which makes all the complexes of the [Re(CO)3(LH(Me)NS)X] type neutral. The Re−Cl bond length in 1 is about 0.14 and 0.33 Å shorter than the Re−Br and Re−I distances in 2 and 3, respectively (see Table 2). In the crystal structure of the [Re(CO)3(LH(Me)NS)Cl] complex (1) 13

ACCEPTED MANUSCRIPT the molecules are held together by two N2−H2···Cl1 hydrogen bonds (3.218(4) and 3.281(4) Å) (Fig. S2b) and two other interactions (C4−H4···O2, 3.186(6) Å and C6−H6···O1, 3.385(6) Å). Similarly to 1, the molecular packing in 2 is stabilized through two N2−H2···Br1 (3.361(5) and 3.436(5) Å) intermolecular hydrogen bonds (Fig. 1b). In turn, the molecular packing in the complex with the iodine atom is different from these complexes obtained with

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both lighter halogen atoms. The crystal structure of 3 is stabilized by intermolecular N2−H2···I1 and C10−H10C···S1 hydrogen bonds of 3.532(7) and 3.501(8) Å, respectively (Fig. 2b). The shortest distance between neighboring I atoms (4.754(1) Å) in 3 is much longer than the respective Cl···Cl (3.438(1) Å) and Br···Br (3.703(1) Å) contacts in two other

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compounds of the [Re(CO)3(LH(Me)NS)X’] type.

In the Cambridge Structural Database there are structures of several other complexes with the bidentate N,S-donor ligands, which form the octahedral Re(CO)3(NS)Br core around

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the metal center. Some of them has been described recently [30,49−51]. An analogous core with a chlorine atom instead of a bromine atom has been reported earlier for a few complexes [50,52−57]. In turn, there are only two other crystal structures for rhenium(I) complexes in

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which the Re(CO)3INS core can be distinguished [58].

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Figure 1. (a) Molecular structure of [Re(CO)3(LH(Me)NS)Br] (2) with the atom numbering scheme, plotted with 50% probability of displacement ellipsoids and (b) fragment of the

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crystal structure of 2 showing some intermolecular interactions.

15

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Figure 2. (a) Molecular structure of [Re(CO)3(LH(Me)NS)I] (3) with the atom numbering

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scheme, plotted with 50% probability of displacement ellipsoids and (b) fragment of the crystal structure of 3 showing some intermolecular interactions.

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3.2.2. Complex of the [Re(CO)3(LH(Me)NS)X”] type (X” = NCS) Besides halide ions, the thiocyanate anion was successfully incorporated into the sixth

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coordination place of the fac-[Re(CO)3]+ core bound to the bidentate LH(Me)NS ligand (Figs 3 and 4). This pseudohalide ion, which can interact with a metal center in two modes - either by the nitrogen or sulfur atom (ambidentate ligand), is coordinated in the title complex through the N atom, which is generally typical for hard metal ions using the ‘hard and soft acids and bases’ (HSAB) concept. Surprisingly, two types of crystals, orange (4a) and reddish (4b), were

distinguished

from

the

solution

for

one

complex

of

the

formula

[Re(CO)3(LH(Me)NS)NCS] (see Experimental part). The molecular structures of these both polymorphs have similar bond lengths between atoms (Table 2). A clear difference between them can be observed in a location of the NCS− ion relative to the rest part of molecule (see Fig. 5). In the case of 4a the thiocyanate anion is clearly bent towards of S=C−N(H)−CH3 part 16

ACCEPTED MANUSCRIPT of the bidentate ligand, while for 4b it is less distinct. This causes that the N2···S2 and N2···C11 distances of 4.145(2) and 3.789(2) Å, respectively for the orange polymorph are much shorter than those of 5.308(2) and 4.531(2) Å, respectively found for the reddish form. Moreover, the Re1−N3−C11 angle is about 9° lower in 4a than in 4b. In contrast to analogous complexes with halide ions discussed above, these two polymorphs with the NCS− group have

the remaining atoms for 4a and 4b, respectively.

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a non-planar chelate ring, wherein the S atom is about 0.57 and 0.38 Å out of plane formed by

The molecular packing in the crystal structure of 4a is stabilized through intermolecular N−H···S and C−H···S hydrogen bonds (Fig. 3b). The shortest interaction of this type between

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neighboring molecules is equal to 3.338(2) Å (N2−H2···S2). Besides, two longer distances of 3.628(3) Å (C7−H7···S2) and 3.687(3) Å (C10−H10···S1) can be distinguished. In turn, in the extended crystal structure of 4b the S atoms are involved in the formation of hydrogen

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bonds of 3.430(1) (N2−H2···S2), 3.475(2) (C7−H7···S2) and 3.492(2) Å (C6−H6···S1) between adjacent molecules. Some other weaker intermolecular contacts for both polymorphs are shown on Figs 3b and 4b.

Only a few papers have reported structural data on complexes containing the SCN‾ ion connected to the [Re(CO)3]+ core [31,59−64]. In all these compounds the thiocyanato groups

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are coordinated to the metal center by the N atom. The Re−N(NCS) bond lengths of 2.124(2) and 2.132(2) Å in both polymorphs of the title complex are similar to the other such distances found in [Re(CO)3(LH(Me)NO)NCS] (2.117(3) and 2.127(1) Å), [31,59] [Re(CO)3(tBuDAB)NCS] (2.115(1) Å) [60], [Re(CO)3(bipy-PdTPP)NCS] (2.132(9) Å) [61], 1[Re(CO)3(Pr-

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DAB)NCS] (2.115(7) Å) and [Re(CO)3(bipy)NCS] (2.123(4) and 2.129(4) Å) [62], [Re(CO)3(NCS)3](NEt4)2 (2.112−2.145(10) Å) [63] and [Re(CO)3(bipy(CH3)(COOH))NCS] (2.125(3) Å) [64]. The molecular structure of the tricarbonylrhenium(I) complex with the

4b.

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corresponding N,O-donor ligand reported previously in [31] resembles that of the polymorph

17

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Figure 3. Molecular structure of [Re(CO)3(LH(Me)NS)NCS] (4a) with the atom numbering scheme, plotted with 50% probability of displacement ellipsoids and (b) fragment of the

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crystal structure of 4a showing some intermolecular interactions.

18

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Figure 4. (a) Molecular structure of [Re(CO)3(LH(Me)NS)NCS] (4b) with the atom numbering scheme, plotted with 50% probability of displacement ellipsoids and (b) fragment

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of the crystal structure of 4b showing some intermolecular interactions.

Figure 5. Imposition of two molecular structures 4a (orange) and 4b (red) formed by the [Re(CO)3(LH(Me)NS)NCS] complex showing the differences between them. 19

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3.2.3. Complexes of the [Re(CO)3(LH(Me)NS)Y]PF6 type (Y = Hdmpz and Him) During the reaction of [Re(CO)3(LH(Me)NS)X’] or Re(CO)5Cl and LH(Me)NS with Hdmpz or Him,

after

earlier

precipitation

of

chloride

ions,

the

complexes

of

the

[Re(CO)3(LH(Me)NS)Y]+ type were obtained. In contrast to the previous species presented

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herein, the compounds 5 and 6 form cationic metal complexes (Figs 6 and 7), neutralized by the hexafluorophosphate ion. Similarly to all other presented compounds, N-methylpyridine2-carbothioamide in 5 and 6 behaves as a neutral ligand. The crystal structure of 5 is stabilized by the formation of intermolecular hydrogen bonds of 2.875(2) Å (N4−H8···F5),

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2.895(2) Å (N2−H2···F1) and 3.038(2) Å (N2−H2···F2), caused by the presence of hexafluorophosphate anions in the crystal lattice (Fig. 6b). Some other weaker C−H···F

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interactions can also be found (i.e. C4−H4···F3, 3.100(7) Å and C4−H4···F6, 3.155(3) Å). Similarly to analogous complexes with pseudohalide anions presented above, the complex 5 has a non-planar five-membered chelate ring with the S atom lying about 0.78 Å out of plane formed by the remaining atoms. This deviation from planarity is caused by the orientation of Hdmpz ligand, which takes a part into the intramolecular N4−H8···S1 hydrogen bond of 3.181(2) Å. In contrast to the compound with Hdmpz ligand the [Re(CO)3(LH(Me)NS)Him]+

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complex has a planar chelate ring. The molecular packing in 6 is stabilized by the presence of intermolecular hydrogen bonds of 2.968(3) (N2−H2···F1), 3.003(3) (N4−H8···F3), 3.099(4) (N2−H2···F5) and 3.146(4) Å (C10−H10B···F5) (Fig. 7b). A few crystal structures with one Him molecule coordinated to a tricarbonylrhenium(I)

Re−N(Him)

bond

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core together with some bidentate ligand have been reported to date [17,31,65−71]. The lengths

Me

about

[66],

and

2.18

Å

in

[Re(CO)3(phen)Him]+

[Re(CO)3(L(Me)NN)Him]

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[Re(CO)3(H2B(tim )2Him]

of

[31],

2.19

[65], Å

in

+

[Re(CO)3(Me2NCS2)(Him)] [68], [Re(CO)3(bipy)Him] [69], [Re(CO)3(acac)Him] [70] and [Re(CO)3(PhN2C11H5NO)Him] [71] and 2.20 Å in [Re(CO)3(HO2C-C6H3N-CO2)Him] [67], [Re(CO)3(C24H14N3O2)Him] [17] and [Re(CO)3(LH(Me)NO)Him]PF6 [31] are in coherence with the respective distance presented for compounds 6 (see Table 2). Previously, the Re(CO)3Hdmpz core with an additional bidentate ligand was [Re(CO)3(L(Me)NN)Hdmpz],

[Re(CO)3(LH(Me)NO)Hdmpz]PF6

found only for

[31]

and

the

[Re(CO)3(HN=C(CH3)dmpz)Hdmpz]+ cationic complex with perchlorate and chloride ions as counterions [72]. 20

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Figure 6. (a) Molecular structure of [Re(CO)3(LH(Me)NS)Hdmpz]+ (in 5) with the atom numbering scheme, plotted with 50% probability displacement ellipsoids and (b) fragment of

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the crystal structure of 5 showing some intermolecular interactions.

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Figure 7. (a) Molecular structure of [Re(CO)3(LH(Me)NS)Him]+ (in 6) with the atom numbering scheme, plotted with 50% probability displacement ellipsoids and (b) fragment of

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the crystal structure of 6 showing some intermolecular interactions.

3.3. DFT optimized structures

The geometric parameters of the studied complexes were optimized using three different basis

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sets for the lighter elements. Better correlation between calculated and experimental structures was achieved for the 6-31G(d,p) basis set as presented by the smallest mean absolute

S7).

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deviation (MAD) values determined for the chosen bond lengths and angles (see Tables S1–

In summary, the bond distances for the presented tricarbonylrhenium(I) complexes originating from the crystal structure determinations remain in agreement with quantum mechanical calculations (see Table 2). In most cases the differences between the experimental and theoretical distances are no larger than 0.06 Å, with a clear tendency for slightly shorter experimental bond lengths. The larger difference being even about 0.10 Å can be observed for the Re1−S1 distances in all neutral complexes (1–4) and the Re1−I1 bond length in 3. This good agreement obtained between the DFT optimized and experimental structures is 22

ACCEPTED MANUSCRIPT illustrated in Fig. 8. In the case of compounds 5 and 6 the molecular structures of [Re(CO)3(LH(Me)NS)Hdmpz]+ and [Re(CO)3(LH(Me)NS)Him]+ ions were included in the calculations. For complexes with halide ions a difference can be noticed between experimental and calculated structures with regard to the chelate ring which is found to be planar for X-ray measurements and non-planar for DFT optimizations. It can be seen through

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the experimentally determined and the calculated N1−C8−C9−S1 torsion angles which are equal to −0.9(5) and −21.6° for 1, −0.5(7) and −20.4° for 2, and −1.4(9) and −14.0° for 3, respectively. For two polymorphs of the [Re(CO)3(LH(Me)NS)NCS] complex a better agreement in the molecular structures obtained from X-ray measurements and DFT

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calculations can be found for 4a than 4b. It is especially evident in the arrangement of the thiocyanato group of both crystallographic forms in comparison to the modeled structure. The experimentally determined Re1−N3−C11 angles are equal to 162.6(2) and 171.3(1)°, for 4a

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and 4b respectively, while the calculated value is 161.8°. In addition, for both the polymorphic complexes a non-planar chelate ring is observed, and this distortion is larger for the modeled structure. As a result of that the experimentally determined N1−C8−C9−S1 torsion angles are equal to 23.2(3)° for 4a and 9.9(2)° for 4b, while the corresponding calculated value is −29.7°. In the case of cationic complexes with heterocyclic ligands the

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simulated geometries exhibit non-planar chelate ring while for the experimentally determined structures the similar distortion can only be found for compound with the Hdmpz molecule. For both these complexes the N1−C8−C9−S1 torsion angles in the structure and in the modeled molecule are −33.0(2) and 14.5° for 5, and −3.0(4) and 11.4° for 6, respectively. A

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significant difference between experimental and calculated structures for 6 can be observed

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with regard to the arrangement of a heterocyclic molecule.

23

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Figure 8. Graphical pictures showing the overlay of the molecular structures obtained from experiment (blue) and DFT optimization (red) for (a) [Re(CO)3(LH(Me)NS)Cl] (RMSD = 0.3922 Å), (b) [Re(CO)3(LH(Me)NS)Br] (RMSD = 0.3557 Å), (c) [Re(CO)3(LH(Me)NS)I] (RMSD = 0.2408 Å), (d) [Re(CO)3(LH(Me)NS)NCS] (4a) (RMSD = 0.2586 Å), (e)

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[Re(CO)3(LH(Me)NS)NCS] (4b) (RMSD = 0.4766 Å), (f) [Re(CO)3(LH(Me)NS)Hdmpz]+

3.4. Spectroscopic analysis

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(RMSD = 0.4832 Å) and (g) [Re(CO)3(LH(Me)NS)Him]+ (RMSD = 0.3040 Å).

The infrared absorption spectra of all studied compounds have been compared with the spectrum of the free N-methylpyridine-2-carbothioamide ligand (Figs S3–S10). The presence of a few very strong bands for all the complexes in the range 1860−2050 cm‾1, originating

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from the coordinated CO ligands, is characteristic for the formation of a tricarbonyl core around the rhenium atom. The distinct C−N stretching vibration, observed at 1534 cm‾1 in the uncoordinated ligand, is found to be shifted to 1577−1555 for 1–4, 1582 for 5 and 1568 cm‾1 for 6. The IR spectra of compounds 1, 2 and 3 are very similar and only slight shifts between

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the equivalent bands can be observed. The different infrared spectra for both polymorphs of [Re(CO)3(LH(Me)NS)NCS] have been registered. The stretching frequencies derived from

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vibrations of the NCS‾ ion are found at 2119 and 2113 cm‾1 in 4a and 4b, respectively, similarly to the [Re(CO)3(LH(Me)NO)NCS] compound [31] and other typical isothiocyanato complexes [73]. In turn, the main bands belonging to the hexafluorophosphate ion are located at 855 and 556 cm‾1 in 5 and at 843 and 558 cm‾1 in 6, just as for [Re(CO)3(LH(Me)NO)Hdmpz]PF6 and other compounds containing these anions [31,74]. The experimentally observed infrared spectra of compounds 1–6 are compared with the corresponding calculated data, as shown in Figs S4–S10. In the case of 5 and 6, the theoretical IR spectra are obtained only for the cationic part of compounds, so they do not possess frequencies from the PF6‾ ion. Nevertheless, for all species quite a reasonable correlation is 24

ACCEPTED MANUSCRIPT obtained between the calculated and experimental IR spectra, particularly with regard to the carbonyl stretching frequencies. The characteristic three carbons of the facial carbonyl groups and the carbon belonging to the C=S group of the N-methylpyridine-2-carbothioamide ligand appear in the downfield region around 189–197 ppm in the 13C NMR spectra of the complexes. The resonances for the 34.3–35.4 ppm in the 1H and

13

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methyl moiety of the bidentate ligand are found for the complexes in the ranges 3.3–3.5 and C NMR spectra, respectively. The

13

C NMR spectrum of 4

also shows the signal for the isothiocyanato group at 134.3 ppm. The N2−H2 proton signal is appeared in the downfield region at about 11.7–12.0 ppm for complexes 1–4, while it was not registered for compounds 5 and 6. The reason for this deficiency is the use of deuterated

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methanol as solvent during the 1H NMR measurements in the case of both last species. All NMR spectra are collected in the Supplementary data (Figs S11–S16).

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Generally, the electronic absorption spectra of the studied compounds show intense absorptions below 300 nm. In addition, for all the complexes a band with lower intensity can also be observed in the 390−410 nm region (Fig S17). For comparison, a maximum of absorption at 312 nm can be observed for the pure N-methylpyridine-2-carbothioamide ligand. Time-dependent DFT calculations for the absorption spectra of the studied complexes

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in simulated solvent (methanol) are in good agreement with the experimental data. The results presented in Table 3 correspond to the lowest energy singlet excitations. The CAM-B3LYP method was used for all calculated systems similarly as in the case of other tricarbonylrhenium(I) complexes [31,75]. The solvent was modeled by applying the

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polarizable continuum model (IEFPCM). Calculated orbital contours (from HOMO−n (n = 6, 7 or 8) to LUMO+m (m = 9, 10 or 11)) and tables of calculated transitions for all complexes are presented in the Supplementary data (Figs S18–S29 and Tables S1–S6). The frontier

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orbitals of 3–6 chosen as representative examples for the studied complexes (1 and 2 have similar MO diagrams to 3) are shown in Fig. 9. The energy differences between the HOMO and LUMO levels are equal to 5.85, 5.77, 5.63, 5.76, 5.78 and 5.90 eV for 1−6, respectively (Figs S18–S29). Hence, the all complexes have similar calculated energy gap with the lowest one for the compound with the I− ion. For the most of presented complexes this energy gap is above 0.5 eV lower than the corresponding values for the respective complexes with similar chelating ligand having O atom instead of S atom [31]. Only in the case of 4 and the analogous compound with the LH(Me)NO ligand that difference is about 0.3 eV. Among the studied species, both cationic complexes with the heterocyclic monodentate ligand have the 25

ACCEPTED MANUSCRIPT highest energies for the HOMO and LUMO levels. As it can be seen from the respective orbital contours and calculated compositions of selected molecular orbitals (Table 4), the three highest occupied MOs of complexes of the [Re(CO)3LH(Me)NSX] type consist mainly of halide or pseudohalide π-orbitals, a metal d-orbital and CO orbitals. Some contribution from the N−C=S or C=S part of the bidentate ligand to HOMO and HOMO−2 is also visible for

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these compounds. In the case of complexes 5 and 6, the HOMO and HOMO−1 have a mixed Re/monodentate and bidentate ligands/CO character. However, the HOMO−1 for 5 and HOMO for 6 possess much smaller component from the heterocyclic ligand molecule. Both highest occupied MO levels of cationic complexes have also a distinct contribution from

SC

N−C=S moiety of the N,S-donor ligand. In turn, both lowest LUMOs of all the complexes are predominantly the π antibonding orbitals of the bidentate ligand. According to the TD-DFT data, reported in Table 3, the lowest energy transitions for complexes 1−6 involve the

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promotion of an electron, from HOMO and HOMO−1 to LUMO. In much lesser extent in the case of compounds 3 and 4 these absorptions are accompanied by the HOMO−2 → LUMO excitation. It can be concluded that the lowest-lying electronic transitions of complexes 1–6 have a mixed metal-to-ligand (Re → bidentate ligand) and ligand-to-ligand (monodentate ligand → bidentate ligand) charge transfer character (MLCT and LLCT, respectively). Within

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LLCT transitions an increase of the halide ion contribution with a simultaneous decrease of contribution from the CO groups can be observed for the complexes from 1 to 3. In addition, a weaker contribution in the lowest energy bands of studied complexes can be assigned to ligand-centered (LC) π → π* transitions involving the chelating ligand. The similar

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assignment of the absorption bands was also presented for other tricarbonylrhenium(I)

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complexes in the ‘2+1’ system [31,62,76].

26

ACCEPTED MANUSCRIPT Table 3. The highest wavelength absorption data from calculations (TD-DFT) and experiments for the studied complexes.

5

6

390.1

0.0205

370.3

0.0794

393.3

0.0280

380.1

0.0644

393.3

0.0087

365.3

0.0370

370.3

0.0948

352.3

0.0252

366.7

0.0549

352.0

0.0744

395

398

405

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0.0849

λ (nm) 394

SC

4

360.7

Main components H→L (92.5%) H-1→L (2.8%) H-1→L (93.6%) H→L (2.6%) H→L (93.0%) H-1→L (2.3%) H-1→L (94.5%) H→L (2.3%) H→L (86.7%) H-1→L (6.0%) H-2→L (3.5%) H-1→L (89.1%) H→L (7.1%) H→L (78.0%) H-2→L (8.3%) H-1→L (5.6%) H-1→L (85.2%) H→L (8.7%) H→L (80.9%) H-1→L (15.2%) H-1→L (79.8%) H→L (14.8%) H→L (75.4%) H-1→L (21.5%) H-1→L (74.2%) H→L (21.6%)

392

397

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3

Oscillator strength 0.0242

EP

2

λ (nm) 384.9

Exp.

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1

Calculated

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Complex

27

ACCEPTED MANUSCRIPT Table 4. DFT (B3LYP/IEFPCM) calculated compositions of selected highest occupied and lowest unoccupied molecular orbitals of studied complexes in methanol, expressed in terms of composing fragments (LB – bidentate ligand, LM – monodentate ligand). MO

Re

CO

LB

LM

1

LUMO+1

3

3

93

1

LUMO

2

3

94

1

HOMO

51

21

17

11

HOMO-1

55

22

5

18

6

1

LUMO

3

2

94

1

HOMO

47

19

13

21

HOMO-1

46

18

5

31

HOMO-2

44

17

18

21

LUMO+1

2

3

94

1

LUMO

3

2

93

2

HOMO

35

13

8

44

HOMO-1

31

12

2

55

HOMO-2

10

5

34

51

LUMO+1

6

7

85

2

LUMO

3

3

93

1

HOMO

33

14

4

49

HOMO-1

32

14

4

50

HOMO-2

32

13

33

22

LUMO+1

2

3

94

1

LUMO

2

2

95

1

HOMO

47

19

15

19

HOMO-1

56

21

15

8

HOMO-2

68

26

4

2

LUMO+1

2

2

96

0

LUMO

2

2

95

1

52

20

26

2

60

22

7

11

67

26

5

2

HOMO HOMO-1 HOMO-2

SC

7

93

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5

9

3

TE D

4

23

3

EP

3

61

AC C

2

HOMO-2 LUMO+1

RI PT

Complex

28

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ACCEPTED MANUSCRIPT

Figure 9. Orbital contours of the lowest energy transitions for the selected

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tricarbonylrhenium(I) complexes.

3.5. HPLC studies

The behaviour of the studied complexes in solution was studied by the HPLC technique. The measurements showed that the compounds can be divided into two groups. The compounds

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1–4 when dissolved in solution (i.e. MeOH) exist as a mixture containing the respective complex ([Re(CO)3(LH(Me)NS)X]) and its solvated form ([Re(CO)3(LH(Me)NS)MeOH]+) resulting from an exchange of the halide anion on the solvent molecule (see Fig. S30). This is demonstrated by the presence of two peaks on chromatograms. The equilibrium of the

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mentioned process is strongly shifted towards the formation of the solvated compound with the decreasing mass of the halide anion. In the case of compound with the thiocyanate anion

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only its very small part converts into the solvated form. After addition of an excess of silver ions to the solutions of 1–4, only the solvated form remains in them. The retention time of this solvated form derived from 1–4 is the same. In turn, the complexes 5 and 6 do not form the solvated species in solution – only one peak is present on chromatograms (Fig. S31).

3.6. Cytotoxicity measurements The cytotoxic activity of the rhenium(I) complexes were evaluated against cisplatin-sensitive and cisplatin-resistant human ovarian cancer cells (A2780 and A2780cis). Only a few works on biological activity of rhenium(I) species towards human ovarian tumor cells can be found 29

ACCEPTED MANUSCRIPT [37,77–80]. To evaluate the selectivity of the complexes presented herein toward cancer cells, their cytotoxicity against non-cancerous human embryonic kidney cells (Hek-293) was also determined. Cisplatin, a common chemotherapy drug, was included for comparison. The IC50 values (concentration required to inhibit observed effect to 50%, e.g. reduce cell growth to 50%) were derived from dose-effect curves (Fig. S32) and summarized in Table 5. For

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cytotoxicity measurements the complexes were dissolved in DMSO (0.1%) solution. From the HPLC studies presented above we know that the compounds with halide anions exist in solution in equilibrium with the solvated form. Because of this, the complexes 1–3 are marked further as 1’–3’. All the tricarbonylrhenium(I) complexes studied showed good or very good

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activity against the tested carcinoma cells, comparable in the most cases to that of cisplatin. Interestingly, the compounds 1’, 2’, 4 and 5 were equally active towards the cisplatinsensitive and -resistant cell lines with a resistance factor, defined by Denora et al. [81], below

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1.5 (Table 5). In the case of 3’ and 6 this factor is higher than 2. A comparable value of the resistance factor (1.8) was also obtained for another tricarbonylrhenium(I) complex in the 2+1 system [79]. In contrast to rhenium(I) complexes, cisplatin displayed higher resistance factor close to 3.6, which is similar to that of 3.1 presented earlier [81]. The compounds 1 and 3 showed an appreciable toxicity towards A2780 and A2780cis cells and were more potent than

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cisplatin. Moreover, all tested complexes exhibited lower than cisplatin toxicity against noncancerous Hek-293 cells. However, only 3’ and 6 showed lower activity towards noncancerous cells in comparison to cancer cell lines, showing their selectivity against cancer cells. This is an important property for any chemotherapeutic agent to minimize the harmful

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side effects of treatment. Among all the rhenium(I) complexes, the compound 3’ exhibited the best biological profile with high activity against both A2780 and A2780cis cell lines and low toxicity to Hek-293 cells. In addition, N-methylpyridine-2-carbothioamide ligand alone did

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not show any cytotoxicity in the range of tested concentrations (up to 150 µM) comparing to its rhenium(I) complexes.

30

ACCEPTED MANUSCRIPT Table 5. Cytotoxicity of the studied complexes, N-methylpyridine-2-carbothioamide (ligand)

Compound

A2780

A2780cisa

Hek-293

1’

7.75 ± 0.07

8.91 ± 0.17 (1.15)

6.61 ± 0.48

2’

19.04 ± 1.12

26.61 ± 2.37 (1.40)

15.76 ± 4.74

3’

2.02 ± 0.19

4.29 ± 0.27 (2.12)

22.24 ± 1.07

4

18.34 ± 1.36

24.97 ± 0.43 (1.36)

16.67 ± 1.34

5

13.74 ± 0.53

20.40 ± 2.55 (1.48)

15.84 ± 3.31

6

18.09 ± 0.77

48.45 ± 2.02 (2.68)

63.36 ± 1.17

ligand

>150

>150

>150

cisplatin a

8.32 ± 0.88

30.2 ± 0.94 (3.63)

3.44 ± 0.48

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and cisplatin towards different cell lines. The data are expressed as IC50 ± SD (µM).

Summary and Conclusion

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4.

SC

Resistance factor, as defined in [81], is given in parentheses 1’, 2’ and 3’ denote a mixture of the respective complex with its solvated form.

A series of tricarbonylrhenium(I) complexes with the bidentate ligand N-methylpyridine-2carbothioamide and with different monodentate ligands being either an anion (Cl, Br, I and SCN) or a neutral molecule (Him and Hdmpz) was synthesized, structurally and spectroscopically characterized and tested on their biological activity. The use of selected monodentate ligands in the reaction mixture together with the bidentate ligand (Nleads

to

the

formation

of

neutral

or

cationic

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methylpyridine-2-carbothioamide)

tricarbonylrhenium(I) complexes: [Re(CO)3(LH(Me)NS)X] (X = Cl, Br, I, NCS) (complexes 1−4) or [Re(CO)3(LH(Me)NS)Y] (Y = Hdmpz, Him) (5 and 6), respectively. Interestingly, the [Re(CO)3(LH(Me)NS)NCS] complex crystallizes in the form of two polymorphs different in

EP

the position of NCS− ion. The presented complexes show a six coordinate Re atom with a distorted octahedral configuration formed by the fac-[Re(CO)3]+ core, the chelating N,S-donor

AC C

ligand and the monodentate ligand.

Very good agreement was received between the DFT optimized and experimental structures of the studied complexes. In all cases, a reasonable correlation was also observed between the measured and calculated IR spectra. Moreover, TD-DFT predictions provided a proper description of the lowest-lying electronic transitions, which resulted in a reasonable agreement between the simulated and experimental absorption spectra. Furthermore, TD-DFT calculations revealed the nature of the orbitals involved in the electronic transitions. Generally, the calculations showed that in all rhenium(I) compounds the three highest occupied MOs, cover the Re atom, CO groups and in a different degree also monodentate and 31

ACCEPTED MANUSCRIPT bidentate ligands, while the LUMO is almost only localized on the π* orbital of the bidentate ligand, which gives mixed MLCT/LLCT character to the lowest energy bands with a small contribution associated with LC transitions. HPLC studies showed that the Re(I) complexes with halide anions exist in solution in equilibrium with the solvated form.

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The cytotoxicity of the rhenium(I) complexes were evaluated against the human ovarian cancer cell lines (A2780 and A2780cis) and non-cancerous human embryonic kidney cells (Hek-293). In general, all the compounds exhibited remarkable activity towards both cancer cell lines (IC50 = 2−49 µM), with the complexes 1’ and 3’ showing even higher cytotoxicities

SC

than cisplatin. Whereas, majority of the tested compounds had similar activity against cancerous and non-cancerous cells, the compound 3’ demonstrated the best biological profile with high activity against both A2780 and A2780cis cell lines and low toxicity against Hek-

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293 cells. Taking all together, 1’ and 3’ have the best cytotoxicities among the tested complexes.

In summary, the lability of the halido ligand appears to better affect in vitro cytotoxic activity of the studied complexes. However, it is not a case for the bromido complex. From the presented results it is not possible to conclude why the cytotoxicities of complexes 1−3

necessary.

Acknowledgements

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are so different from each other. Therefore, the additional studies on similar systems are

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The authors gratefully acknowledge the Institute of Nuclear Chemistry and Technology for the financial support. This research was also supported in part by PL-Grid Infrastructure

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(grant ID: reco3kl).

Appendix A. Supplementary data CCDC-1506767 (for 1), -1506768 (for 2), -1506769 (for 3), -1506770 (for 4a), -1506771 (for 4b), -1506772 (for 5) and -1506773 (for 6) contain the supplementary crystallographic data for this paper. These data can be obtained from the Cambridge Crystallographic Data Centre (12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; e-mail: [email protected] or http://www.ccdc.cam.ac.uk). Supplementary data associated with this article can be found in the online version, at http// 32

ACCEPTED MANUSCRIPT

References [1] T. Mukuta, P.V. Simpson, J.G. Vaughan, B.W. Skelton, S. Stagni, M. Massi, K. Koike, O. Ishitani, K. Onda, Inorg. Chem. 56 (2017) 3404–3413. [2] T. Kamatsuka, H. Shinokubo, Y. Miyake, Organometallics 36 (2017) 3429–3434.

RI PT

[3] K.M. Choi, D. Kim, B. Rungtaweevoranit, C.A. Trickett, J.T.D. Barmanbek, A.S. Alshammari, P. Yang, O.M. Yaghi, J. Am. Chem. Soc. 139 (2017) 356−362.

[4] T. Klemens, K. Czerwińska, A. Szlapa-Kula, S. Kula, A. Świtlicka, S. Kotowicz, M. Siwy, K. Bednarczyk, S. Krompiec, K. Smolarek, S. Maćkowski, W. Danikiewicz, E. Schab-

SC

Balcerzak, B. Machura, Dalton Trans. 46 (2017) 9605–9620.

[5] A. Carreño, A.E. Aros, C. Otero, R. Polanco, M. Gacitúa, R. Arratia-Pérez, J.A. Fuentes,

M AN U

New J. Chem. 41 (2017) 2140–2147.

[6] W.-K. Chung, M. Ng, N. Zhu, S. Kin-Lok Siu, V. Wing-Wah Yam, J. Organomet. Chem. 847 (2017) 278–288.

[7] V. Fernández-Moreira, H. Sastre-Martín, Inorg. Chim. Acta 460 (2017) 127–133. [8] M.R. Gonçalves, K.P.M. Frin, Polyhedron 132 (2017) 20–27.

[9] M.B. Ismail, I.N. Booysen, M.P. Akerman, C. Grimmer, J. Organomet. Chem. 833 (2017)

TE D

18–27.

[10] M.M. Lee, J.-L. Lin, C.-W. Chang, C.-Y. Hung, C.-W. Chen, C.-P. Hsu, S.-S. Sun, Eur. J. Inorg. Chem. (2017) 5224–5237.

[11] M.A. Klenner, G. Pascali, B. Zhang, T.R. Sia, L.K. Spare, A.M. Krause-Heuer, J.R.

6499–6503.

EP

Aldrich-Wright, I. Greguric, A.J. Guastella, M. Massi, B.H. Fraser, Chem. Eur. J. 23 (2017)

AC C

[12] R. Torres, M. Rosales, C. Finucane, J. Foster, S.J. Mather, P.J. Blower, Bioconjugate Chem. 21 (2010) 811–815.

[13] Y. Ma, S. Liang, H. Wu, H. Wang, J. Radioanal. Nucl. Chem. 299 (2014) 1865–1870. [14] K.Y. Zhang, K.K.-S. Tso, M.-W. Louie, H.-W. Liu, K.K.-W. Lo, Organometallics 32 (2013) 5098–5102.

[15] P. Collery, A. Mohsen, A. Kermagoret, S. Corre, G. Bastian, A. Tomas, M. Wei, F. Santoni, N. Guerra, D. Desmaële, J. d’Angelo, Invest. New Drugs 33 (2015) 848–860. [16] A. Leonidova, G. Gasser, ACS Chem. Biol. 9 (2014) 2180−2193.

33

ACCEPTED MANUSCRIPT [17] K. Waehler, A. Ludewig, P. Szabo, K. Harms, E. Meggers, Eur. J. Inorg. Chem. (2014) 807–811. [18] A. Leonidova, V. Pierroz, R. Rubbiani, J. Heier, S. Ferrarib, G. Gasser, Dalton Trans. 43 (2014) 4287–4294. [19] G. Mion, T. Gianferrara, A. Bergamo, G. Gasser, V. Pierroz, R. Rubbiani, R. Vilar, A.

RI PT

Leczkowska, E. Alessio, ChemMedChem 10 (2015) 1901–1914. [20] M.A. Wright, J.A. Wright, Dalton Trans. 45 (2016) 11688–11698.

[21] I. Chakraborty, S.J. Carrington, J. Hauser, S.R.J. Oliver, P.K. Mascharak, Chem. Mater. 27 (2015) 8387–8397.

SC

[22] M. Patra, M. Wenzel, P. Prochnow, V. Pierroz, G. Gasser, J.E. Bandow, N. MetzlerNolte, Chem. Sci. 6 (2015) 214–224.

[23] W.-K. Chu, X.-G. Wei, S.-M. Yiu, C.-C. Ko, K.-C. Lau, Chem. Eur. J. 21 (2015) 2603–

M AN U

2612.

[24] E. Portenkirchner, S. Schlager, D. Apaydin, K. Oppelt, M. Himmelsbach, D.A.M. Egbe, H. Neugebauer, G. Knör, T. Yoshida, N. Serdar Sariciftci, Electrocatalysis 6 (2015) 185–197. [25] C. Matlachowski, B. Braun, S. Tschierlei, M. Schwalbe, Inorg. Chem. 54 (2015) 10351– 10360.

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[26] K. Kam-Wing Lo, Acc. Chem. Res. 48 (2015) 2985−2995.

[27] G.-W. Zhao, Y.-X. Hu, H.-J. Chi, Y. Dong, G.-Y. Xiao, X. Li, D.-Y. Zhang, Opt. Mater. 47 (2015) 173–179.

[28] T. Klemens, A. Świtlicka-Olszewska, B. Machura, M. Grucela, E. Schab-Balcerzak, K.

EP

Smolarek, S. Mackowski, A. Szlapa, S. Kula, S. Krompiec, P. Lodowski and A. Chrobok, Dalton Trans. 45 (2016) 1746–1762. [29] T.E. Kydonaki, E. Tsoukas, F. Mendes, A.G. Hatzidimitriou, A. Paulo, L.C.

AC C

Papadopoulou, D. Papagiannopoulou, G. Psomas, J. Inorg. Biochem. 160 (2016) 94–105. [30] D.K. Nayak, R. Baishya, R. Natarajan, T. Senc, M.C. Debnath, Dalton Trans. 44 (2015) 16136–16148.

[31] K. Lyczko, M. Lyczko, J. Mieczkowski, Polyhedron 87 (2015) 122–134. [32] L. Fuks, E. Gniazdowska, J. Mieczkowski, J. Narbutt, W. Starosta, M. Zasepa, J. Organomet. Chem. 689 (2004) 4751–4756. [33] P. Martins, M. Marques, L. Coito, A.J.L. Pombeiro, P.V. Baptista, A.R. Fernandes, Anticancer Agents Med. Chem. 14 (2014) 1199–1212.

34

ACCEPTED MANUSCRIPT [34] J. Ho, W.Y. Lee, K.J.T. Koh, P.P.F. Lee, Y.-K. Yan, J. Inorg. Biochem. 119 (2013) 10– 20. [35] C. Parson, V. Smith, C. Krauss, H.N. Banerjee, C. Reilly, J.A. Krause, J.M. Wachira, D. Giri, A. Winstead, S.K. Mandal, J. Bioprocess. Biotech. 4: (2013) 141. [36] A. W.-T. Choi, M.-W. Louie, S.P.-Y. Li, H.-W. Liu, B.T.-N. Chan, T.C.-Y. Lam, A.C.-

RI PT

C. Lin, S.-H. Cheng, K.K.-W. Lo, Inorg. Chem. 51 (2012) 13289–13302. [37] K.M. Knopf, B.L. Murphy, S.N. MacMillan, J.M. Baskin, M.P. Barr, E. Boros, J.J. Wilson, J. Am. Chem. Soc. 139 (2017) 14302−14314.

[38] P.V. Simpson, I. Casari, S. Paternoster, B.W. Skelton, M. Falasca, M. Massi, Chem. Eur.

SC

J. 23 (2017) 6518−6521.

[39] C.V. Garcia, G.L. Parrilha, B.L. Rodrigues, S.F. Teixeira, R.A. de Azevedo, A.K. Ferreirab, H. Beraldo, New J. Chem. 40 (2016) 7379–7387.

M AN U

[40] G. Santoro, T. Zlateva, A. Ruggi, L. Quaroni, F. Zobi, Dalton Trans. 44 (2015) 6999– 7008.

[41] I. Maisuls, E. Wolcan, O.E. Piro, E.E. Castellano, G. Petroselli, R. Erra-Balsells, F.M. Cabrerizo, G.T. Ruiz, ChemistrySelect 2 (2017) 8666–8672.

[42] M. Kaplanis, G. Stamatakis, V.D. Papakonstantinou, M. Paravatou-Petsotas, C.A.

TE D

Demopoulos, C.A. Mitsopoulou, J. Inorg. Biochem. 135 (2014) 1–9. [43] A. Leonidova, V. Pierroz, L.A. Adams, N. Barlow, S. Ferrari, B. Graham, G. Gasser, ACS Med. Chem. Lett. 5 (2014) 809−814.

[44] N. Sen Gupta, D.S. Wragg, M. Tilsetc, J.P. Omtvedt, Acta Crystallogr. E67 (2011)

EP

o1958–1959.

[45] G.M. Sheldrick. Acta Crystallogr. A64 (2008) 112–122. [46] C.F. Macrae, I.J. Bruno, J.A. Chisholm, P.R. Edgington, P. McCabe, E. Pidcock, L.

AC C

Rodriguez-Monge, R. Taylor, J. van de Streek, P.A. Wood, J. Appl. Crystallogr. 41 (2008) 466–470.

[47] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A. Montgomery Jr., J.E. Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J.M. Millam, M. Klene, J.E. 35

ACCEPTED MANUSCRIPT Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador, J.J. Dannenberg, S. Dapprich, A.D. Daniels, O. Farkas, J.B. Foresman, J.V. Ortiz, J. Cioslowski, D.J. Fox, Gaussian 09, revision C.01, Gaussian, Inc., Wallingford CT, 2010.

RI PT

[48] N.M. O'Boyle, A.L. Tenderholt, K.M. Langner, J. Comp. Chem. 29 (2008) 839–845. [49] T.I.A. Gerber, R. Betz, I.N. Booysen, K.C. Potgieter, P. Mayer, Polyhedron 30 (2011) 1739–1745.

[50] A. Núñez-Montenegro, R. Carballo, U. Abram, E.M. Vázquez-López, Polyhedron 65

SC

(2013) 221–228.

[51] G. Makris, O. Karagiorgou, D. Papagiannopoulou, A. Panagiotopoulou, C.P.

Inorg. Chem. (2012) 3132–3139.

M AN U

Raptopoulou, A. Terzis, V. Psycharis, M. Pelecanou, I. Pirmettis, M.S. Papadopoulos, Eur. J.

[52] A. Knodler, M. Wanner, W. Kaim, J. Fiedler, Z. Anorg. Allg. Chem. 628 (2002) 1132– 1139.

[53] S. Ye, W. Kaim, M. Albrecht, F. Lissner, T. Schleid, Inorg. Chim. Acta 357 (2004) 3325–3330.

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[54] A. Núñez-Montenegro, R. Carballo, E.M. Vázquez-López, Polyhedron 28 (2009) 3915– 3922.

[55] A. Núñez-Montenegro, R. Carballo, E.M. Vázquez-López, J. Inorg. Biochem. 140 (2014) 53–63.

EP

[56] P. Mondal, R. Sarkar, A. Hens, K.K. Rajak, RSC Adv. 4 (2014) 38769–38782. [57] X. Schoultz, T.I.A. Gerber, E.C. Hosten, Polyhedron 113 (2016) 55–60. [58] R.D. Adams, L. Chen, W. Wu, Organometallics 12 (1993) 3812–3818.

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[59] K. Lyczko, Acta Cryst. E72, (2016) 1386–1389. [60] A. Grupp, M. Bubrin, F. Ehret, H. Kvapilova, S. Zalis, W. Kaim, J. Organomet. Chem. 751 (2014) 678–685.

[61] J. Schneider, K.Q. Vuong, J.A. Calladine, X.-Z. Sun, A.C. Whitwood, M.W. George, R.N. Perutz, Inorg. Chem. 50 (2011) 11877–11889. [62] A.M.B. Rodriguez, A. Gabrielsson, M. Motevalli, P. Matousek, M. Towrie, J. Sebera, S. Zalis, A. Vlcek Junior, J. Phys. Chem. A 109 (2005) 5016–5025. [63] U. Abram, R. Hubener, R. Alberto, R. Schibli, Z. Anorg. Allg. Chem. 622 (1996) 813– 818. 36

ACCEPTED MANUSCRIPT [64] P. Cavigli, G. Balducci, E. Zangrando, N. Demitri, A. Amati, M.T. Indelli, E. Iengo, Inorg. Chim. Acta 439 (2016) 61–68. [65] W.B. Connick, A.J. Di Bilio, M.G. Hill, J.R. Winkler, H.B. Gray, Inorg. Chim. Acta 240 (1995) 169–173. [66] R. Garcia, A. Paulo, A. Domingos, I. Santos, K. Ortner, R. Alberto, J. Am. Chem. Soc.

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122 (2000) 11240–11241. [67] S. Mundwiler, M. Kundig, K. Ortner, R. Alberto, Dalton Trans. (2004) 1320–1328. [68] R.S. Herrick, C.J. Ziegler, S. Sripothongnak, N. Barone, R. Costa, W. Cupelo, A. Gambella, J. Organomet. Chem. 694 (2009) 3929–3934.

SC

[69] E. Gómez, M.A. Huertos, J. Pérez, L. Riera, A. Menéndez-Velázquez, Inorg. Chem. 49 (2010) 9527–9534.

[70] M. Sagnou, D. Benaki, C. Triantis, T. Tsotakos, V. Psycharis, C.P. Raptopoulou, I.

M AN U

Pirmettis, M. Papadopoulos, M. Pelecanou, Inorg. Chem. 50 (2011) 1295–1303. [71] R. Sarkar, P. Mondal, K.K. Rajak, Dalton Trans. 43 (2014) 2859–2877. [72] M. Arroyo, D. Miguel, F. Villafañe, S. Nieto, J. Pérez, L. Riera, Inorg. Chem. 45 (2006) 7018–7026.

[73] K. Nakamoto, Infrared and Raman Spectra of Inorganic and Coordination Compounds,

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fourth ed., Wiley-Interscience, New York, 1986. Parts III-14 and III-15. [74] W. Beck, K. Sunkel, Chem. Rev. 88 (1988) 1405–1421. [75] M. G. Fraser, C. A. Clark, R. Horvath, S. J. Lind, A. G. Blackman, X.-Z. Sun, M. W. George and K. C. Gordon, Inorg. Chem. 50 (2011) 6093–6106.

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[76] J.G. Vaughan, B.L. Reid, S. Ramchandani, P.J. Wright, S. Muzzioli, B.W. Skelton, P. Raiteri, D.H. Brown, S. Stagni, M. Massi, Dalton Trans. 42 (2013) 14100–14114. [77] N. Viola-Villegas, A.E. Rabideau, J. Cesnavicious, J. Zubieta, R.P. Doyle,

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ChemMedChem 3 (2008) 1387–1394. [78] N.E. Brückmann, S. Kögel, A. Hamacher, M.U. Kassack, P.C. Kunz, Eur. J. Inorg. Chem. (2010) 5063–5068.

[79] N. Margiotta, N. Denora, S. Piccinonna, V. Laquintana, F.M. Lasorsa, M. Franco, G. Natile, Dalton Trans. 43 (2014) 16252–16264. [80] L. Quental, P. Raposinho, F. Mendes, I. Santos, C. Navarro-Ranninger, A. AlvarezValdes, H. Huang, H. Chao, R. Rubbiani, G. Gasser, A.G. Quiroga, A. Paulo, Dalton Trans. 46 (2017) 14523–14536.

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Franco, G. Natile, ACS Med. Chem. Lett. 5 (2014) 685–689.

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ACCEPTED MANUSCRIPT Highlights Tricarbonyl Re(I) complexes with N-methylpyridine-2-carbothioamide were obtained.

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The structures were measured (X-ray diffraction) and optimized (DFT calculations).

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Characterization by means of experimental and DFT studies was carried out.

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The activity of complexes was tested towards A2780, A2780cis and Hek-293 cells.

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