Through-Space Paramagnetic NMR Effects in Host–Guest Complexes

6 days ago - The potential of paramagnetic ruthenium(III) compounds for use as anticancer metallodrugs has been investigated extensively during the pa...
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Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

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Through-Space Paramagnetic NMR Effects in Host−Guest Complexes: Potential Ruthenium(III) Metallodrugs with Macrocyclic Carriers Jan Chyba,† Martin Novák,†,‡ Petra Munzarová,†,§ Jan Novotný,†,‡ and Radek Marek*,†,‡,§ †

Central European Institute of Technology (CEITEC), ‡National Center for Biomolecular Research, Faculty of Science, and Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, Brno CZ-62500, Czech Republic

§

S Supporting Information *

ABSTRACT: The potential of paramagnetic ruthenium(III) compounds for use as anticancer metallodrugs has been investigated extensively during the past several decades. However, the means by which these ruthenium compounds are transported and distributed in living bodies remain relatively unexplored. In this work, we prepared several novel ruthenium(III) compounds with the general structure Na+[trans-RuIIICl4(DMSO)(L)]− (DMSO = dimethyl sulfoxide), where L stands for pyridine or imidazole linked with adamantane, a hydrophobic chemophore. The supramolecular interactions of these compounds with macrocyclic carriers of the cyclodextrin (CD) and cucurbit[n]uril (CB) families were investigated by NMR spectroscopy, X-ray diffraction analysis, isothermal titration calorimetry, and relativistic DFT methods. The long-range hyperfine NMR effects of the paramagnetic guest on the host macrocycle are related to the distance between them and their relative orientation in the host−guest complex. The CD and CB macrocyclic carriers being studied in this account can be attached to a vector that attracts the drug-carrier system to a specific biological target and our investigation thus introduces a new possibility in the field of targeted delivery of anticancer metallodrugs based on ruthenium(III) compounds.

1. INTRODUCTION Anticancer metallodrugs have been explored and brought into clinical use following the discovery of the biological effects of cisplatin.1 However, not many metal-based compounds have passed individual trials and been approved for clinical use in anticancer therapy. In fact, only cisplatin and its two derivatives, oxaliplatin and carboplatin,2 are currently used in cancer treatment worldwide, with some other platinum(II) and platinum(IV) analogs approved and used in specific countries.3 The discovery of the biological effects of cisplatin initiated an explosion of investigations in the field of bioinorganic medicinal chemistry involving transition-metal complexes.4 Rutheniumcontaining compounds represent one class of these complexes.5 There was great hope for the anticancer potential of metallodrugs derived from ruthenium(III) compounds of the Na+[transRuIIICl4(DMSO)(Im)]− (NAMI; DMSO = dimethyl sulfoxide and Im = imidazole) and KP (e.g., Na+[trans-RuIIICl4(1Hindazole)2]−) types.6−9 However, the results of a recent phase I/ II therapeutic study employing the combination of [ImH]+[trans-RuIIICl4(DMSO)(Im)]− (NAMI-A) with gemcitabine in patients with non-small-cell lung cancer failed to show convincing efficacy.10 These disappointing results can be related to the fact that NAMI-A was not designed to be applied to these types of cancer cells and in this specific combination of drugs.11 Clearly, controlled drug delivery combined with selective transport to the particular biological target is essential in © XXXX American Chemical Society

developing new anticancer agents and formulating novel selective therapies. One of the crucial points in the ruthenium-based approach is a relatively fast ligand exchange dictated by the nature of the individual ligands and the presence and concentration of competing ligands in liquid environments such as body fluids.12−15 In this respect, a somewhat more controlled transport and ligand exchange would contribute greatly to increasing knowledge and development in the field. In this contribution, we prepared some direct analogs of a NAMI compound using novel pyridine- or imidazole-based ligands with adamantane chemophore designed to increase the lipophilicity of the system and potentially result in a greater affinity for (or penetration through) biological membranes. The structures of the compounds investigated are shown in Figure 1. Altering the lipophilicity is assumed to contribute to the known effects of NAMI-based compounds on the mobility of cancer cells involved in metastasis. The introduction of lipophilic adamant-1-yl-containing groups decreases the solubility of these compounds somewhat, but it can be further increased by binding them with supramolecular macrocyclic carriers.16−18 In this study, we investigate two groups of biocompatible carriers based on the cyclodextrin (CD)19−21 and cucurbit[n]uril (CBn)22−25 Received: December 22, 2017

A

DOI: 10.1021/acs.inorgchem.7b03233 Inorg. Chem. XXXX, XXX, XXX−XXX

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a completely new possibility in the field of targeted delivery of ruthenium-based anticancer metallodrugs.

2. METHODS 2.1. Synthesis. Materials. The starting compounds RuCl3·xH2O, RhCl3·xH2O (Alfa Aesar), pyridine-3-carboxylic acid, pyridine-4carboxylic acid, 1-adamantanol, 1-adamantanemethanol, 1-adamantylamine, 1-adamantanemethylamine, 1-(adamant-1-yl)ethylamine, 3,5dimethyl-1-adamantanamine, cyclohexylamine (TCI) were used as obtained from our suppliers. β-cyclodextrin (β-CD; Sigma-Aldrich) was dried in vacuo at 50 °C before use, and the exact concentration of cucurbit[7]uril (CB7; Strem Chemicals) solution was determined by standardization (ITC analysis) with L-phenylalanine. Solvents of p.a. grade were used without further purification. Na + [transRuCl4(DMSO)2]− and Na+[trans-RhCl4(DMSO)2]− were prepared according to previously reported procedures.27,28 Similarly, the ligands (esters and amides) containing pyridine or imidazole and adamantane or cyclohexane units (Figure 1) were prepared as reported previously.29−31 General Synthetic Procedure for Preparing Compounds 1−6. Octahedral ruthenium(III) and rhodium(III) coordination compounds with pyridine- or imidazole-based ligands were prepared using slightly modified forms of the synthetic procedures previously reported by Webb et al.32 and Mestroni et al.33 A solution of the selected pyridine or imidazole derivative (90 mmol) in acetone (2 mL) was added to Na+[trans-MCl4(DMSO)2]− (60 mmol; M represents the metal, Ru or Rh) mixed with 5 mL of acetone. The reaction mixture was stirred at room temperature for 2 h, during which time the solution became clear yellow-orange (Ru) or purple-pink (Rh). It was then evaporated to dryness (vacuum, laboratory temperature), and the crude product was washed sequentially with small amounts of dichloromethane and diethyl ether and subsequently dried in vacuo at room temperature. 2.2. Characterization of the Structure and Determination of the Binding Constants: Diffraction, Spectroscopy, and Calorimetry. X-ray Diffraction. Diffraction data for the ruthenium(III) compounds were collected on a Rigaku MicroMax-007 HF rotatinganode four-circle diffractometer with Mo Kα radiation. The data were collected at a temperature of 120(2) K. The structures were solved by direct methods and refined by standard methods using the software package ShelXTL.34 Crystallographic data and structural refinement parameters are listed in Table 1. NMR Spectroscopy. The 1H, 13C, and 2D NMR spectra of ruthenium(III) compounds 1−6 and their supramolecular assemblies with carriers were measured on a Bruker Avance III HD 700 MHz spectrometer. The NMR samples were prepared by dissolving 1−10 mg of the ruthenium(III) compound in 0.5 mL of N,N-dimethylformamide (DMF)-d7, D2O, or a 50 mM solution of NaCl in D2O. The signals of the DMF solvent (8.03 ppm for 1H and 163.2 ppm for 13C) or (trimethylsilyl)propanoic acid (TSPA) in D2O (0 ppm)35 served to reference the temperature-dependent NMR spectra. 1H-coupled 13C NMR spectra were used to distinguish between the NMR resonances of the protonated (C−H) and quaternary (Cq) carbon atoms. Single-bond 1 H−X chemical shift correlation experiments (namely, 1H−13C HSQC)36 were employed to unambiguously assign the organic ligand in the rhodium(III) diamagnetic compounds 4−6 and the atoms of the adamantane chemophore distant from the Ru center in compounds 1−3 (for signal assignments, see the Supporting Information, SI). The interactions between the individual components in supramolecular host−guest assemblies of the ruthenium(III) coordination compounds and β-CD were detected by using a 2D ROESY experiment (rotatingframe nuclear Overhauser spectroscopy).37 Mass Spectrometry (MS). MS spectra were measured on a Q-TOF Impact II (Bruker Daltonics, Germany) mass spectrometer using electrospray ionization and operating in negative mode. Samples were dissolved in Milli-Q water (Merck Millipore, USA) to a concentration of 1 μg μL−1 and eventually mixed with a solution of the macrocyclic cavitand in an equimolar ratio. The samples were subsequently diluted 10-fold to get a 50% acetonitrile solution (acidified with 1% formic acid) and injected into the instrument at a flow rate 300 μL h−1. The parameters of the electrospray ion source were set as follows: end-plate

Figure 1. Structures and numbering schemes of compounds 1−6 (guests) with the general formula Na+[trans-MIIICl4(DMSO)L]−, where M = Ru or Rh.

families, specifically β-CD and CB7 (Figure 2). We report the first X-ray structures of supramolecular assemblies between

Figure 2. Schematic visualization of the macrocyclic carriers (hosts) with the H-atom numbering schemes used for β-CD and CB7.

octahedral paramagnetic ruthenium(III)-based anions and CB7. The supramolecular binding between ruthenium coordination compounds and carriers (cavitands) is characterized by using NMR spectroscopy and includes detailed analysis of the hyperfine (HF) NMR effects of the guest molecule (ruthenium compound) on the NMR resonances of the host (cavitand) in these host−guest assemblies. The host−guest binding constants in water were determined by isothermal titration calorimetry (ITC). Both types of carriers (hosts) can be attached to vector(s) for specific tumor tissue,26 and our investigation thus introduces B

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Table 1. Crystallographic Data for Ruthenium(III) Compounds 1a, 1c, 1e, 2a, and 3g, Supramolecular Host−Guest Complexes of 1c and 2c with CB7, and Supramolecular Host−Guest Complex of Hydrolyzed 2c (2ch@CB7) CCDC chemical formula fw cryst syst space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z Dcalcd (g cm−3) F(000) μ (mm−1) measd/unique reflns data/param R1, wR2 [I > 2σ(I)] R1, wR2 (all data) GOF Δρmax/Δρmin (e Å−3) CCDC chemical formula fw cryst syst space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z Dcalcd (g cm−3) F(000) μ (mm−1) measd/unique reflns data/param R1, wR2 [I > 2σ(I)] R1, wR2 (all data) GOF Δρmax/Δρmin (e Å−3) Flack parameter

1a

1c

1e

2a

1585576 C42H66Cl8N2Na2O10Ru2S2 1354.80 monoclinic P21/c 7.6031(1) 27.5459(5) 13.1599(3) 90 96.303(2) 90 2739.47(9) 2 1.642 1380 1.09 17588/5182 5182/317 0.0285, 0.0618 0.0386, 0.0656 1.040 0.42/−0.40 3g

1585583 C18H28Cl4N2NaO4.25RuS 638.34 monoclinic C2/c 46.4150(8) 17.1379(2) 31.1704(5) 90 103.292(2) 90 24130.4(7) 32 1.406 10336 0.98 116102/22864 22864/1280 0.0289, 0.0718 0.0336, 0.0744 1.022 1.47/−1.27 1c@CB7

1585581 C20H32Cl4N2NaO3RuS 646.39 monoclinic P21/c 26.3765(3) 30.5760(2) 13.2166(2) 90 92.813(1) 90 10646.2(2) 16 1.613 5264 1.11 87836/20196 20196/1208 0.0334, 0.0793 0.0450, 0.0849 1.030 1.42/−0.90 2c@CB7

1585577 C18H29Cl4NNaO5RuS 637.34 triclinic P1̅ 7.8231(1) 17.2649(3) 18.6624(2) 93.987(1) 93.996(1) 91.870(1) 2506.65(6) 4 1.689 1292 1.18 23368/9436 9436/587 0.0294, 0.0738 0.0326, 0.0761 1.052 1.49/−0.93 2ch@CB7

1585578 C60H68Cl4N30O16RuS 1740.37 orthorhombic Pca21 37.6127(15) 13.1951(6) 15.9523(5) 90 90 90 7917.2(5) 4 1.460 3576 0.44 30198/14801 14801/1011 0.0545, 0.1398 0.0651, 0.1477 1.037 1.66/−1.00 −0.026(13)

1585579 C60H68Cl4N30O16RuS 1740.37 orthorhombic P212121 12.9983(1) 16.2634(2) 39.9920(5) 90 90 90 8454.17(16) 4 1.367 3576 0.41 50801/15954 15954/1120 0.0389, 0.1059 0.0404, 0.1072 1.026 1.36/−0.35 −0.022(5)

1585582 C58H62Cl4N30O16Ru 1678.24 monoclinic P21 13.4260(2) 21.0717(3) 15.6379(2) 90 91.296(1) 90 4422.97(11) 2 1.260 1720 0.37 54691/16672 16672/982 0.0969, 0.2603 0.1003, 0.2657 1.021 1.78/−1.08 0.10(4)

1585580 C42H72Cl8N4Na2O6Ru2S2 1324.87 triclinic P1̅ 10.7640(3) 11.8152(2) 22.6738(5) 81.758(2) 80.095(2) 80.806(2) 2784.17(11) 2 1.580 1356 1.06 34644/10484 10484/802 0.0466, 0.1197 0.0504, 0.1223 1.074 1.90/−1.21

analyzed using MicroCal PEAQ-ITC software. The data were fitted to a theoretical titration curve using a model with a single binding site. 2.3. Quantum Chemical Calculations. Geometry. The structures were optimized using density functional theory (DFT) with the TPSS38 or PBE0 functional,39,40 augmented by a D3 dispersion correction41 and BJ damping.42 The def2-TZVPPD43,44 basis set was used for all of the atoms of the ruthenium(III) coordination compounds and the smaller def2-SVP basis set for the supramolecular systems (if not otherwise stated), with corresponding relativistic effective core potentials (def2ECPs)45 for the metal centers (ECP substituting 28 electrons for Ru and Rh), as implemented in the program TURBOMOLE 7.00.46 The structures were optimized either in a vacuum or by using the COSMO (conductor-like screening model)47 solvent model (for Cartesian

offset of 500 V with a capillary voltage of 4500 V, nebulizing nitrogen gas of 0.4 bar, drying nitrogen gas of 4 L min−1, and drying-gas temperature of 180 °C. MS spectra were acquired in the range m/z 100−2800. ITC. ITC measurements to determine the binding affinity and thermodynamic parameters of interaction between the ruthenium(III) compounds and the macrocyclic cavitands were performed using an automated isothermal microcalorimeter (Malvern AutoITC200) and VP-ITC MicroCal. The samples were dissolved in Milli-Q water, and the ITC measurements were carried out at 25 °C using a stirring speed of 750 (310) rpm. After an initial delay of 60 (120) s, 20−40 injections (2.0/10.0 μL each) of the solution were added from the microsyringe to the solution in the cell every 120−300 s. The raw experimental data were C

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Figure 3. Molecular structures of compounds 1a, 2a, and 3g as determined by X-ray diffraction with the atom numbering scheme used (the Na+ cation is typically found in the highly negative ESP region close to the equatorial chlorides and the O atom of the DMSO ligand; Figure S1). Thermal ellipsoids are drawn at the 30% probability level. For the crystallographic data, see Table 1.

δ tot = δ orb + δ HF

coordinates, see the SI) and an approach calibrated in our previous studies of transition-metal complexes.48−50 Electron Paramagnetic Resonance (EPR) Parameters and HF Contributions to the NMR Chemical Shifts..51−55 The EPR parameters along with the HF contributions to the 1H NMR shifts were calculated by using the ADF 2016 program.56,57 Calculations were performed at the two-component level of theory using the zeroth-order regular approximation incorporating spin−orbit coupling (SO-ZORA), with the PBE0 functional, the TZ2P basis set, and the COSMO solvent model, as implemented in ADF 2016. Relativistic unrestricted calculations used a collinear approximation. Because the current twocomponent implementation of the NMR calculations in the ADF 2016 program is limited to closed-shell systems, the one-component ZORA approach was used to calculate the orbital contributions (δorb) to the total NMR chemical shifts for open-shell ruthenium compounds. The HF NMR contributions for supramolecular host−guest complexes were calculated at the scalar-relativistic ZORA level with the PBE0/TZP method in a COSMO environment. However, because the g tensor is fully isotropic at the one-component level of theory, it was calculated for an isolated guest molecule (using its geometry in the host−guest complex) at the SO-ZORA level (see section 3.3.2). The NMR shifts obtained from the one-component (ZORA) HF coupling tensors and two-component (SO-ZORA) electronic g tensor are compared with those obtained from the two-component A and g (SO-ZORA) in the SI. The performance of the method used in this work and the effect of a countercation were evaluated in our recent study.48 The NMR chemical shifts for rhodium(III) compounds and the orbital contributions to the NMR chemical shifts for ruthenium(III) compounds were calculated by using tetramethylsilane (TMS) as the reference compound for 1H and 13C (eq 1):

δi = σref − σi

(2)

The value of the HF NMR shift (δ ) was obtained as the sum of δHFi (the traditional contact term, δcon), calculated from the isotropic value of the HF coupling constant (Aiso) and the g factor, and δHFa (the traditional pseudocontact term, δpc), calculated from the anisotropy of the HF coupling tensor and the g tensor (eq 3).48,55,58 For further discussion, see ref 58: HF

δ HF = δ HFi + δ HFa

(3)

Visualization of the Spin Density and Point-Dipole (PD) and HF Contributions to the NMR Chemical Shifts. The spatial distribution of the total spin density in ruthenium(III) compound 1c discussed in the main text (for 2c and 3g, see the SI) was calculated at the scalarrelativistic (ZORA/PBE0/TZ2P) level either in a vacuum or by using the COSMO solvent model (DMF).48 The HF contributions to the NMR chemical shifts (see above) calculated from the anisotropies of the A and g tensors (δHFa = δpc) are analyzed and discussed in section 3. The spatial distribution of δPD and δHFa was visualized by using the programs VMD 1.959 and Pymol 1.8.60

3. RESULTS AND DISCUSSION 3.1. Synthesis and Structures of the Ruthenium(III) Coordination Compounds. 3.1.1. Preparation and Characterization: X-ray Diffraction and MS. The starting compound Na+[trans-RuIIICl4(DMSO)2]− was prepared from the parent [DMSOH]+[trans-RuIIICl4(DMSO)2]− by substituting Na+ for [DMSOH]+ according to a previously reported procedure.27 Ruthenium(III) compounds 1−3 were obtained by reacting Na+[trans-RuIIICl4(DMSO)2]− with the appropriate substituted pyridine or imidazole base,29−31 as shown in Figure 1. The preparation of the pyridine- and imidazole-based ligands is described in section 2. The resulting products were obtained as yellow-orange (pyridine-based) or orange (imidazole-based) powders in yields of 70−80%. Crystals suitable for single-crystal X-ray diffraction experiments were obtained by slowly

(1)

where δi is the NMR chemical shift of interest and σref and σi are the NMR shielding constants of the respective atoms in the reference compound (TMS) and the molecule being investigated, respectively. The NMR chemical shifts (δtot) were each calculated as the sum of the orbital (δorb, temperature-independent) and hyperfine (δHF, temperature-dependent) contributions (eq 2): D

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Table 2. Total Experimental 1H and 13C NMR Chemical Shifts (δtot) for Ruthenium(III) Compounds 1c, 2c, and 3g Measured in DMF-d7 at 298 K and Their Separate Orbital (δorb, Temperature-Independent) and HF (δHF, Temperature-Dependent) Componentsa 1

13

H NMR

atom H2

H3

H4

H5

H6

H8

H10−H12

H13−H15

H16a−H18a

H16b−H18b

H19, H20

δorb δHF δtot δorb δHF δtot δorb δHF δtot δorb δHF δtot δorb δHF δtot δorb δHF δtot δorb δHF δtot δorb δHF δtot δorb δHF δtot δorb δHF δtot δorb δHF δtot

C NMR

1c

2c

3g

+6.3 −12.8 −5.9 +7.8 −9.1 −1.3

+7.2b −13.1b −5.9b

+5.7 −9.1 −3.4

+7.8 −9.1 −1.3 +6.3 −12.2 −5.9 +6.7 −1.1 +5.6 +2.4 −1.3 +1.07 +2.3 −0.8 +1.48 +2.0 −0.9 +1.12 +2.0 −0.8 +1.24 +3.4 −15.8 −12.4

atom C2

C3

+7.8 −1.4 +6.4 +7.4 −5.8 −1.6 +7.2b −13.1b −5.9b +6.2 −0.9 +5.3 +2.6 −1.3 +1.34 +2.5 −0.8 +1.74 +2.1 −0.7 +1.36 +2.1 −0.7 +1.45 +3.9 −16.2 −12.3

+6.7 −8.9 −2.2 +7.2 −13.3 −6.1

C4

C5

C6

C7

+2.3 −3.2 −0.88 +2.5 −1.5 +0.98 +2.1 −1.5 +0.57 +2.1 −1.3 +0.82 +3.8 −16.8 −13.0

C9

C10−C12

C13−C15

C16−C18

1c

2c

+162.7 −72.8 +89.9 +118.0 −19.8 +98.2 +147.6 −30.3 +117.3 +118.0 −19.8 +98.2 +162.7 −72.8 +89.9 +165.3 +3.4 +168.7 +54.6 −2.5 +52.1 +43.6 −3.1 +40.5 +31.0 −1.2 +29.8 +38.9 −2.1 +36.8

+162.6 −74.9 +87.7 +133.6 −22.1 +111.5 +139.5 −28.0 +111.5 +120.5 −21.7 +98.8 +164.6 −70.9 +93.7 +166.8 −12.1 +154.7 +54.8 −3.1 +51.7 +43.9 −2.5 +41.4 d d +30.1d +39.1 −2.1 +37.0

3g

+14.3c

+114.2 −35.7 +78.5 +135.0 −69.0 +66.0

+57.8 −5.7 +52.1 +47.4 −7.6 +39.8 +32.4 −3.7 +28.7 +38.8 −3.5 +35.3

C19, C20e

a

The NMR chemical shifts are given in ppm. bThe H2 and H6 resonances in compound 2c are indistinguishable and produced a single very broad line. cThe signal for C2 in compound 3g was observed at 248 K, but at other experimental temperatures, it overlapped with the signal of the methyl group of the DMF solvent. dThe signal overlapped with the signal of the methyl group of the DMF solvent. eNot observed.

terized by using NMR spectroscopy. However, because of the paramagnetic nature of these compounds, the assignment of the signals was not straightforward. We performed a systematic study of the 1H and 13C NMR chemical shifts of selected compounds at several temperatures to break down the total NMR chemical shifts into the approximately temperature-independent orbital shifts (δorb L )neglecting rovibrational contributions and any associations in solutionand the highly temperature-dependent 61 Further discussion is presented in HF NMR shifts (δHF L ). section 2. The corresponding orbital and HF terms (Table 2) were extracted from Curie plots (NMR chemical shift as a function of 1/T, where T is the absolute temperature). The orbital 1H and 13C NMR shifts are compared with those of the corresponding rhodium(III) analogs in Figures S3−S7 and Tables S3−S5. The 1H and 13C NMR spectra of compound 1c were measured at several temperatures, with selected portions of the spectra shown in parts a and b of Figure 4, respectively. The orbital and HF contributions to the NMR chemical shift extracted from the corresponding Curie plots are shown in parts c (1H) and d (13C) of Figure 4.

evaporating the solvent from concentrated solutions of the ruthenium(III) compounds in acetone. The complexes were characterized by using NMR spectroscopy, MS, and X-ray diffraction (see section 2). The molecular structures of compounds 1a, 2a, and 3g are shown in Figure 3 as examples (for additional structures and structural data, see Figure S1). The geometries of several complexes determined by X-ray diffraction were used to further validate the DFT optimizations of the geometry (Table S1). The ruthenium(III) and rhodium(III) coordination compounds Na+[trans-MCl4(DMSO)L]− were characterized by electrospray ionization mass spectrometry (ESI-MS) in the negative mode (for details, see section 2): signals corresponding to the molecular ions [M]− were observed in the spectra. The m/ z values of the individual signals and the isotopic patterns are in very good agreement with the calculated models of the anions of the corresponding ruthenium(III) compounds (Table S2 and Figure S2). 3.1.2. NMR Spectroscopy: HF NMR Shifts for the Ligand Atoms (δHF L ). The coordination compounds were also characE

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Figure 4. (above) Portions of the (a) 1H and (b) 13C NMR spectra of compound 1c plotted at 258, 278, and 298 K. (below) Curie plots of the (c) 1H and (d) 13C NMR chemical shifts for compound 1c with the estimated values of δorb and temperature prefactor (slope given by δHF). For the Curie plots for compounds 2c and 3g, see Figures S6 and S7.

Table 3. Experimental Binding Constants (Ka in M−1) of the Ruthenium Compounds 1c, 2c, and 3g with the Macrocyclic Carriers β-CD and CB7 in Milli-Q Water As Determined by ITC Experiments at 298 Ka

The HF NMR shifts (δHF) of H atoms close to the paramagnetic Ru center (e.g., H2, H3) are influenced by all of the HF mechanisms: Fermi contact (FC), spin-dipole (SD), and paramagnetic spin−orbit (PSO).58 However, the FC contribution diminishes rapidly with the number of chemical bonds from the Ru center, and the HF NMR shifts of more distant H atoms (e.g., the adamantane chemophore) are therefore governed by the SD and PSO mechanisms. For a more detailed discussion about the role of the SD term in HF NMR shifts in host−guest complexes, see section 3. 3.2. Binding to Macrocyclic Carriers. 3.2.1. Binding Constants Determined by ITC. ITC was performed to determine the binding constants between selected compounds 1−3 (guest) and the macrocyclic cavitands β-CD and CB7 (host). For ITC analysis of the binding between the ruthenium compound and β-CD, the reverse titration mode was employed. A solution of β-CD with a concentration of 1.3 mM was added stepwise to a solution of the guest ruthenium compound at a concentration of 0.1 mM. The binding constants between selected guests 1c, 2c, and 3g and CB7 were determined by a multistep titration method using L-phenylalanine (Ka = 9.48 × 105 M−1) as a competitor.62 A solution of the ruthenium complex in a syringe was added stepwise to a solution containing a mixture of the CB7 host and the competitor in the measuring cell. The observed binding constants spanned the range of 104−105 M−1 for the β-CD host, and higher binding affinities of about 109 M−1 were determined for the CB7 carrier (Table 3). 3.2.2. Supramolecular Structures in Vacuo: MS. ESI-MS was used to detect the formation of supramolecular assemblies composed of the guest ruthenium(III) compounds and host macrocyclic cavitands. A solution containing a ruthenium(III) compound mixed with its molar equivalent of a macrocyclic cavitand (β-CD or CB7) in solution and then subjected to MS analysis in the negative mode generally produced m/z signals with the isotopic patterns corresponding to [RuCl4(DMSO)L + β-CD]− or [RuCl4(DMSO)L + CB7]− host−guest assemblies. The ESI-MS spectra of 1a@β-CD and 1a@CB7, which demonstrate the most interesting and significant features of the

binding constant (M−1) compound

β-CD

1c 2c 3g

(4.86 ± 0.34) × 10 (4.92 ± 0.19) × 104 (4.29 ± 0.07) × 104

CB7b 4

(1.03 ± 0.07) × 109 (1.47 ± 0.13) × 109 (9.91 ± 0.50) × 108

For additional data with β-CD, see Table S6. bThe values for CB7 were determined with the use of L-phenylalanine as a binding competitor. a

systems being analyzed, are shown in Figure 5 as examples. The ESI-MS spectra (in the negative mode) of all of the other compounds, with the characteristic isotopic patterns, are shown in Figure S2. The detection of the host−guest complexes in vacuo left open the question of their arrangement in the solid state and in solution. 3.2.3. Supramolecular Structure in the Solid State: X-ray Diffraction Analysis. Characterizing the inclusion complexes of the ruthenium(III) compounds with macrocyclic carriers by Xray diffraction required that several crystallization experiments be carried out to prepare suitable single crystals. Crystallizing compounds 1c and 2c with CB7 from water afforded such crystals of the host−guest complexes (for crystallographic data, see Table 1). Although we were not able to localize the countercation in the crystal structure, the system was assumed to be neutral possibly because of the presence of the proton (not localized in the electron-density map) that compensated for the negative charge of the ruthenium(III) compound. Crystals of the systems 1c@CB7 and 2c@CB7 were obtained, but only when the crystallization medium also included 10% DMSO. The DMSO ligand from 2c was easily hydrolyzed during crystallization from pure water, resulting in the formation of 2ch@CB7 (Figure 6 and Table 1). F

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Hguest−1Hhost interactions in complexes with β-CD. We also monitored changes of the guest and host 1H NMR resonances induced by complexation and paramagnetism, respectively. The interpretation of these observations is described in the following sections. ROESY: Supramolecular 1H−1H Interactions in the Complex between Compound 1c and β-CD. 2D NMR spectroscopy was used to characterize the supramolecular structure of the host− guest complexes between anionic coordination compounds and β-CD in solution. The NMR samples were prepared by dissolving the ruthenium(III) coordination compound in a solution containing 50 mM NaCl in a mixture of D2O and DMSO (95:5) to slow down the hydrolysis and substitution of the DMSO and Cl− ligands. Portions of the 2D ROESY spectrum37 of the supramolecular complex 1c@β-CD are shown in Figure 7 with the supramolecular 1H−1H interactions highlighted. “Through-space” nuclear spin−spin interactions between the H atoms of the guest adamant-1-yl moiety (H13 and H16, in green) and the interior of the host β-CD cavity (H3′ and H5′, in magenta) are clearly shown on the left panel. These data suggest that the guest molecule 1c is bound via the wider secondary portal of the β-CD host. Analysis of the NMR Shielding of the Adamantane Moiety Induced by CB7 and the HF NMR Shielding of CB7 Caused by the Paramagnetic Ruthenium(III) Compound: Supramolecular Host−Guest Complex between 1c and CB7. The 1H NMR signals of guest molecules encapsulated in the internal cavity of the CB7 host are significantly more shielded68 than those in the unbound state. The effects of the CB7 host on the 1H NMR resonances of the adamantane moiety in the diamagnetic rhodium(III) compound 4c (Figure 8a) and the paramagnetic ruthenium(III) compound 1c (Figure 8b) caused by supramolecular host−guest binding are shown on the left side of Figure 8. In parallel, the paramagnetic nature of the ruthenium complex, significantly altering the ligand NMR chemical shifts in the ruthenium(III) compound itself (see section 3.1 and Table 2), affects also the NMR resonance frequencies of the macrocyclic carriers upon formation of the host−guest assembly, as shown for 1c@CB7 as an example in Figure 8b, right. The effect of the unpaired electron density (magnetization), predominantly found in the singly occupied molecular orbital (SOMO; metal dxy1

Figure 5. ESI-MS spectra (in the negative mode) of the supramolecular host−guest complexes (a) 1a@β-CD and (b) 1a@CB7.

The supramolecular host−guest structure is formed by the stabilizing hydrophobic interaction63−66 of the adamantane chemophore with the cavity of CB7 and is further stabilized by hydrogen bonding between the amidic proton of compounds 1c or 2c and the carbonyl portal of CB7 (Figure 6).67 3.2.4. Structure of Supramolecular Host−Guest Systems in Solution: NMR Spectroscopy. The formation of supramolecular host−guest assemblies between ruthenium(III) compounds and macrocyclic cavitands was monitored by using NMR spectroscopy. We performed 2D NOE experiments to detect dipolar

Figure 6. Supramolecular structures (side view) of the host−guest complexes 1c@CB7 and 2c@CB7 and the hydrolysis product 2ch@CB7 as determined by single-crystal X-ray diffraction. Thermal ellipsoids are drawn at the 30% probability level. For the crystallographic data, see Table 1. G

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Figure 7. Portions of the 2D ROESY spectrum (mixing time of 300 ms) of a mixture (2:1) of guest 1c (green) and host β-CD (magenta) in a 50 mM solution of NaCl in D2O/DMSO (95:5) at 298 K. The DFT-optimized host−guest complex 1c@β-CD is also shown.

Figure 8. Portions of the experimental 1H NMR spectra of two host−guest complexes: (a) diamagnetic 4c@CB7 in D2O and (b) paramagnetic 1c@ CB7 in a 50 mM solution of NaCl in D2O, both measured at 298 K. The 1H NMR signals of the adamantane chemophore in free and bound guest are shown on the left-hand side and those of the CB7 host on the right-hand side.

Figure 9. Visualization of the scalar-relativistic (ZORA) spin density for compound 1c at isovalues (a) 10−3 au, (b) 10−4 au, and (c) 10−5 au, along with (d) the scalar-relativistic spin density for the host−guest complex 1c@CB7 at isovalues 10−5 au, which shows a vanishingly small spin density at the adamantane chemophore as well as the CB7 host. Positive and negative values are shown in blue and red, respectively. For the spin densities in compounds 2c and 3g, see Figures S8 and S9.

based; section 3.3) at the Ru center, on the NMR chemical shifts of Ha−Hc atoms of the macrocyclic carrier is clearly identified. 3.3. Relativistic DFT Calculations: Modeling the Supramolecular Structure in Solution and Interpreting the Experimental HF NMR Shifts. Relativistic DFT was used to optimize the geometry and calculate the NMR parameters so that experimental NMR observations of the ruthenium(III) coordi-

nation compounds and the supramolecular host−guest systems could be interpreted. The geometries were preoptimized by using the TPSS-D3(BJ) functional with the def2-TZVPPD (for the host−guest complexes, all atoms with def2-SVP) basis set and the corresponding relativistic ECP. In the subsequent step, the geometry was reoptimized by using the PBE0-D3(BJ) H

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Inorganic Chemistry functional and the above-mentioned basis sets (for details, see section 2.3 and the technical discussion in SI). 3.3.1. FC Contributions to the Isotropic HF NMR Shifts of the Ligand and the Distribution of the Spin Density in Ruthenium(III) Coordination Compounds. The optimized geometries were used to calculate the EPR parameters (g and A tensors) and HF NMR shifts (Tables S7−S9). The temperature-dependent HF shift (δHF) was calculated as the sum of the corresponding contact term (δcon = δHFi) and the pseudocontact term (δpc = δHFa). The δHFi term, typically dominated at short distances by the FC interaction and linked to the distribution of the spin density,69 governs the HF NMR chemical shifts for the pyridine or imidazole part of ruthenium compounds 1−3 (see Figure 9 for visualization of the spin density in compound 1c). However, the spin distribution is vanishingly small at the distant adamantane part and also at the hosting macrocycle because of the very inefficient propagation of spin polarization from the Ru center to these distant parts of the system (Figure 9c,d). The HF NMR shifts at the adamantane and cavitand parts of the supramolecular host−guest systems are therefore dominated by the SD and PSO contributions (see section 2 and ref 58). The SD contribution, which typically dominates δHFa (the traditional pseudocontact term), is related to the distance and orientation arrangement of the adamantane chemophore and the carrier relative to the paramagnetic center (dxy type of unpaired molecular spin orbital, SOMO; cf. Figure 9a).48 3.3.2. Anisotropic HF Contributions to the Isotropic NMR Shifts, δHFa (Pseudocontact), of the Macrocycles in Host− Guest Complexes. The HF δHFa contribution calculated from the anisotropy of the HF coupling tensor (A) and the electronic g tensor (traditionally also termed δpc; see section 2 and ref 58) is typically dominated at long distances by the SD mechanism (related to the anisotropy of ASD).58 It can therefore be used to estimate the relative positions and orientation of the host and guest in the supramolecular host−guest complex.70 In the simple form of a PD approximation,71 this PD shift contribution is operating as shown graphically in Figure 10a. In this approach, the magnetic susceptibility, χ, derived from the electronic g tensor (Figure 10b) according to eq 472 is converted to the PD shift, δPD, using the relationship defined approximately by eq 5 in the general Cartesian system (r refers to the position vector of the space element relative to the paramagnetic center and x, y, and z are the components of r). χ≈

μ0 μB 2 ge 4kT

g

Figure 10. (a) Schematic representation of the relative distance (d) between and orientation (angle θ) of the main magnetization (spin density) at the Ru center (SOMO; cf. Figure 9a) and the O portal of CB7 in the host−guest assembly. (b) Orientation of the principal components of the g tensor in compound 2c, as an example. (c) Visualization of the isosurfaces for the anisotropic HF contributions to the isotropic 1H NMR chemical shifts in 1c@CB7 (left), 2c@CB7 (middle), and 3g@CB7 (right), calculated from the electronic g tensors using a PD approximation (δPD isovalues at ±0.3 ppm). (d) Visualization of the HF 1H NMR shifts (δHF) for the individual atoms of the host macrocycle in 1c@CB7 (left), 2c@CB7 (middle), and 3g@ CB7 (right), calculated from the full tensors g (calculated for the guest at the SO-ZORA level) and A (calculated for the host−guest complex at the ZORA level); for details of the relativistic DFT calculations, see section 2. Red stands for shielding (δHF < 0) and blue for deshielding (δHF > 0). The total HF effect on the individual 1H NMR resonances depends on the distribution of the spin density (vanishingly small for the host system) and the relative orientation of the ruthenium guest vis-à-vis macrocyclic host. Note the significant HF NMR effects for 3g@CB7 (right), which are, however, dynamically averaged for seven equivalent atoms to a very small total δHF contribution (cf. Table 4 and the SI).

(4)

is calculated from the electronic g tensor and the full HF coupling tensor, A. Using a semirigorous approach, we calculated the δHF values for the individual H atoms of the CB7 host in the host− guest complexes 1c@CB7, 2c@CB7, and 3g@CB7 from scalarrelativistic (ZORA) A tensors and spin−orbit (SO-ZORA) g tensors (see section 2.3). The results are shown schematically by the color coding of the individual atoms of CB7 in Figure 10d (see also Figure S10). This semirigorous approach nicely reflects the trends in the PD approximation of the long-range δHF values. Note that the more rigorous spin−orbit ZORA approach to both A and g provides δHF values very close to the experimental HF NMR data (Table S10). The experimental HF 1H NMR shifts (averaged because of the 7-fold dynamic symmetry) for the host−guest complexes 1c@ CB7, 2c@CB7, and 3g@CB7, along with the distance between the Ru atom and the center of the upper O portal as well as the

δ PD = f (χ , r, x , y , z) 2z 2 − x 2 − y 2 1 ⎡ ⎢(χzz − χ ̅ ) = + (χxx − χyy ) 3 4πr ⎣ 2r 2 x2 − y2 2r 2

+ χxy

2xy r2

+ χxz

2yz ⎤ 2xz ⎥ + χ yz 2 r2 r ⎦

(5)

Figure 10c shows the distribution of the PD HF NMR shift in real space around the RuCl4 corecontaining the major portion of the magnetization (spin density)plotted as isosurfaces at ±0.3 ppm for host−guest complexes 1c@CB7, 2c@CB7, and 3g@ CB7. In rigorous paramagnetic NMR theory, the HF NMR contribution for a doublet system (a single unpaired electron) I

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spectrum in Figure 11). The pattern is more complicated for 3g@CB7. The distance between Ha′ and the Ru center (see the centroid−Ru distances in Table 4) is somewhat shorter in 3g@ CB7 than in 1c@CB7, and the HF shielding effect on Ha′ is therefore more pronounced (bottom spectrum in Figure 11). Because this shorter distance partially compensates for the dependence on the orientation, the HF effects on Hb′ are very similar for these two host−guest complexes. However, the HF deshielding effect of magnetization in the RuCl4 plane (blue surface in Figure 10c) starts to play an important role for the Hc atoms, resulting in the attenuated-average value δHF = −0.22 ppm for 3g@CB7 (δHF = −0.25 ppm for Hc in 1c@CB7). This HF shielding−deshielding averaging is even more pronounced for Hb and especially for Ha in 3g@CB7 (Table 4). Twisting of the guest in the host cavity causes dynamic averaging of the shielding and deshielding contributions visualized in Figure 10d, and this, in turn, results in relatively small experimental HF NMR shifts, as demonstrated for 3g@CB7 in Figure 11. However, the nearness of Hb and particularly Ha to the Ru center in this host−guest assembly is accompanied by fast electron−nuclear spin relaxation, which causes significant NMR line broadening (bottom spectrum in Figure 11). Clearly, HF NMR shifts can be used to characterize the mutual orientation of the host and guest in supramolecular complexes in detail as demonstrated above. This provides an indispensable tool for studying supramolecular host−guest systems formed by paramagnetic ruthenium(III) metallodrugs with macrocyclic carriers, cages, or capsules. Further investigations in this direction are underway in our laboratory.

angle between the Ru−N bond and the plane of the O portal, are summarized in Table 4. Table 4. Experimental Distance, Angle, and HF 1H NMR Shiftsa for the Atoms of CB7 in the Host−Guest Complexes 1c@CB7, 2c@CB7, and 3g@CB7b d θ Ha Hb Hc Hb′ Ha′

1c@CB7

2c@CB7

3g@CB7

763 26 −0.70 −0.32 −0.25 −0.22 −0.25

664 37 −0.26 −0.11 −0.11 −0.11 −0.13

469c 37c −0.09 −0.08 −0.22 −0.26 −0.35

a Distance (d) in picometers, angle (θ) in degrees, and HF NMR shift in parts per million. bHF 1H NMR obtained as the difference between the 1H NMR chemical shift in the host−guest complex and free CB7. c Calculated for the DFT-optimized structure (no X-ray structure is available).

The HF NMR shifts predicted by the DFT approach and shown schematically in Figure 10d can be used to interpret the experimental NMR data that are summarized in Table 4. The HF NMR shielding effects on the H atoms of the CB7 host are demonstrated by comparing the NMR spectrum of the diamagnetic rhodium(III) complex 4c@CB7 with that of the paramagnetic ruthenium(III) complex 1c@CB7 in Figure 8. The effect of guest 4c on the 1H NMR resonances of the host CB7 in 4c@CB7 is vanishingly small because the same pattern is observed when the NMR spectra of 1c@CB7 are compared with those of the free host CB7 (Figure 11). Because of the mutual host−guest orientation in 1c@CB7, the effect of the paramagnetic center on the individual 1H resonances in the host CB7 decreases approximately uniformly with the distance from the Ru center in the order Ha > Hb > Hc (middle

4. CONCLUSIONS In this contribution, we analyzed newly designed and developed paramagnetic ruthenium(III) coordination compounds containing the adamantane chemophore and their binding with the macrocyclic cavitands β-CD and CB7. The structures of the coordination compounds and their supramolecular host−guest assemblies with cavitands were characterized by MS and NMR spectroscopy, including 2D ROESY experiments. The molecular and crystal structures of the inclusion complexes of paramagnetic ruthenium(III) compounds with CB7 in the solid state were determined by X-ray diffraction for the first time. The host− guest binding constants were measured in aqueous solution by using ITC. The paramagnetic nature of the ruthenium(III) systems was investigated by using temperature-dependent NMR spectra supported by relativistic DFT calculations. The distribution of the spin density in the ruthenium(III) coordination compounds is shown to correlate well with the isotropic FC contributions to the temperature-dependent HF NMR shifts. For the cavitand molecule in the host−guest complex, anisotropic HF contributions are shown to dominate the isotropic HF NMR shift, which is used to estimate the relative distance and orientation between the ruthenium(III) octahedral core (with concentrated spin density) and the CB7 macrocyclic cavitand. Our present case study opens new horizons for the use of NMR spectroscopy in solution to characterize paramagnetic host−guest complexes, including metallodrug−carrier systems.



Figure 11. Portions of the experimental 1H NMR spectra of CB7 (top), 1c@CB7 (middle), and 3g@CB7 (bottom) in a 50 mM solution of NaCl in D2O demonstrating the HF effects of the Ru center on the NMR resonances of Ha−Hc atoms. The atom-labeling and color-coding schemes are also shown for convenience.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b03233. J

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(9) Sava, G.; Bergamo, A.; Dyson, P. J. Metal-Based Antitumour Drugs in the Post-Genomic Era: What Comes Next? Dalton Trans. 2011, 40 (36), 9069−9075. (10) Leijen, S.; Burgers, S. A.; Baas, P.; Pluim, D.; Tibben, M.; van Werkhoven, E.; Alessio, E.; Sava, G.; Beijnen, J. H.; Schellens, J. H. M. Phase I/II Study with Ruthenium Compound NAMI-A and Gemcitabine in Patients with Non-Small Cell Lung Cancer after First Line Therapy. Invest. New Drugs 2015, 33 (1), 201−214. (11) Allardyce, C. S.; Dyson, P. J. Metal-Based Drugs That Break the Rules. Dalton Trans 2016, 45 (8), 3201−3209. (12) Bacac, M.; Hotze, A. C. G.; van der Schilden, K.; Haasnoot, J. G.; Pacor, S.; Alessio, E.; Sava, G.; Reedijk, J. The Hydrolysis of the AntiCancer Ruthenium Complex NAMI-A Affects Its DNA Binding and Antimetastatic Activity: An NMR Evaluation. J. Inorg. Biochem. 2004, 98 (2), 402−412. (13) Groessl, M.; Reisner, E.; Hartinger, C. G.; Eichinger, R.; Semenova, O.; Timerbaev, A. R.; Jakupec, M. A.; Arion, V. B.; Keppler, B. K. Structure-Activity Relationships for NAMI-A-Type Complexes (HL) [trans-RuCl4L(S-DMSO)ruthenate(III)] (L = Imidazole, Indazole, 1,2,4-Triazole, 4-Amino-1,2,4-triazole, and 1Methyl-1,2,4-triazole): Aquation, Redox Properties, Protein Binding, and Antiproliferative Activity. J. Med. Chem. 2007, 50 (9), 2185−2193. (14) Groessl, M.; Hartinger, C. G.; Polec-Pawlak, K.; Jarosz, M.; Keppler, B. K. Capillary Electrophoresis Hyphenated to Inductively Coupled Plasma-Mass Spectrometry: A Novel Approach for the Analysis of Anticancer Metallodrugs in Human Serum and Plasma. Electrophoresis 2008, 29 (10), 2224−2232. (15) Webb, M. I.; Walsby, C. J. Control of Ligand-Exchange Processes and the Oxidation State of the Antimetastatic Ru(III) Complex NAMIA by Interactions with Human Serum Albumin. Dalton Trans. 2011, 40 (6), 1322. (16) Yu, G.; Jie, K.; Huang, F. Supramolecular Amphiphiles Based on Host−Guest Molecular Recognition Motifs. Chem. Rev. 2015, 115 (15), 7240−7303. (17) Ma, X.; Zhao, Y. Biomedical Applications of Supramolecular Systems Based on Host−Guest Interactions. Chem. Rev. 2015, 115 (15), 7794−7839. (18) Yang, R.; Wei, T.; Goldberg, H.; Wang, W.; Cullion, K.; Kohane, D. S. Getting Drugs Across Biological Barriers. Adv. Mater. 2017, 29, 1606596. (19) Uekama, K.; Hirayama, F.; Irie, T. Cyclodextrin Drug Carrier Systems. Chem. Rev. 1998, 98 (5), 2045−2076. (20) Del Valle, E. M. M. Cyclodextrins and Their Uses: A Review. Process Biochem. 2004, 39 (9), 1033−1046. (21) Crini, G. Review: A History of Cyclodextrins. Chem. Rev. 2014, 114 (21), 10940−10975. (22) Walker, S.; Oun, R.; McInnes, F. J.; Wheate, N. J. The Potential of Cucurbit[n]Urils in Drug Delivery. Isr. J. Chem. 2011, 51 (5−6), 616− 624. (23) Macartney, D. H. Encapsulation of Drug Molecules by Cucurbiturils: Effects on Their Chemical Properties in Aqueous Solution. Isr. J. Chem. 2011, 51 (5−6), 600−615. (24) Uzunova, V. D.; Cullinane, C.; Brix, K.; Nau, W. M.; Day, A. I. Toxicity of Cucurbit[7]Uril and Cucurbit[8]Uril: An Exploratory in Vitro and in Vivo Study. Org. Biomol. Chem. 2010, 8 (9), 2037. (25) Koner, A. L.; Ghosh, I.; Saleh, N.; Nau, W. M. Supramolecular Encapsulation of Benzimidazole-Derived Drugs by Cucurbit[7]Uril. Can. J. Chem. 2011, 89 (2), 139−147. (26) Cao, L.; Hettiarachchi, G.; Briken, V.; Isaacs, L. Cucurbit[7]Uril Containers for Targeted Delivery of Oxaliplatin to Cancer Cells. Angew. Chem., Int. Ed. 2013, 52 (46), 12033−12037. (27) Alessio, E.; Balducci, G.; Calligaris, M.; Costa, G.; Attia, W.; Mestroni, G. Synthesis, Molecular-Structure, and Chemical Behavior of Hydrogen trans-Bis(dimethyl sulfoxide)tetrachlororuthenate(III) and mer-Trichlorotris(dimethyl sulfoxide)ruthenium(III): The First Fully Characterized Chloride Dimethyl-Sulfoxide Ruthenium(III) Complexes. Inorg. Chem. 1991, 30 (4), 609−618. (28) Alessio, E.; Sessanta o Santi, A.; Faleschini, P.; Calligaris, M.; Mestroni, G. New Aspects of Rhodium(III) Dimethyl-Sulfoxide

ITC data, ESI-MS data, experimental and calculated NMR data, and additional figures (PDF) Cartesian coordinates and calculated HF NMR data (ZIP) Accession Codes

CCDC 1585576−1585583 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jan Chyba: 0000-0002-1273-5632 Martin Novák: 0000-0001-5067-1994 Jan Novotný: 0000-0002-1203-9549 Radek Marek: 0000-0002-3668-3523 Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS This work has received funding from the Czech Science Foundation (Grants 15-09381S and 18-05421S). The results of this work have been acquired within Project CEITEC 2020 (LQ1601) with a financial contribution made by the Ministry of Education, Youth and Sports of the Czech Republic within the special support paid from the National Program for Sustainability II funds. The CIISB research infrastructure Project LM2015043 funded by MEYS CR is gratefully acknowledged for financial support of the NMR, X-ray, ITC, and MS measurements. The authors thank Dr. M. Babiak and Prof. M. Nečas for their help with the collection and analysis of X-ray diffraction data and J. Ž dánská and Dr. Z. Prucková for their help with the ITC experiments. Computational resources were provided by CESNET (LM2015042) and CERIT Scientific Cloud (LM2015085).



REFERENCES

(1) Rosenberg, B.; Van Camp, L.; Krigas, T. Inhibition of Cell Division in Escherichia Coli by Electrolysis Products from a Platinum Electrode. Nature 1965, 205 (4972), 698−699. (2) Kelland, L. R.; Farrell, N. Platinum-Based Drugs in Cancer Therapy; Humana Press: Totowa, NJ, 2000. (3) Johnstone, T. C.; Suntharalingam, K.; Lippard, S. J. The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs. Chem. Rev. 2016, 116 (5), 3436−3486. (4) Bioinorganic Medicinal Chemistry; Alessio, E., Ed.; Wiley-VCH Verlag GmbH: Weinheim, Germany, 2011. (5) Bergamo, A.; Sava, G. Linking the Future of Anticancer MetalComplexes to the Therapy of Tumour Metastases. Chem. Soc. Rev. 2015, 44 (24), 8818−8835. (6) Sava, G.; Pacor, S.; Mestroni, G.; Alessio, E. Na[transRuCl4(DMSO)Im], a Metal Complex of Ruthenium with Antimetastatic Properties. Clin. Exp. Metastasis 1992, 10 (4), 273−280. (7) Sava, G.; Pacor, S.; Mestroni, G.; Alessio, E. Effects of the Ru(III) Complexes [mer-RuCl3(DMSO)2Im]° and Na[trans-RuCl4(DMSO)Im] on Solid Mouse Tumors. Anti-Cancer Drugs 1992, 3 (1), 25−31. (8) Mestroni, G.; Alessio, E.; Sava, G.; Pacor, S.; Coluccia, M.; Boccarelli, A. Water-Soluble Ruthenium(III)-Dimethyl Sulfoxide Complexes: Chemical Behaviour and Pharmaceutical Properties. Met.Based Drugs 1994, 1 (1), 41−63. K

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Inorganic Chemistry

Screening Energy and Its Gradient. J. Chem. Soc., Perkin Trans. 2 1993, 0 (5), 799−805. (48) Novotný, J.; Sojka, M.; Komorovsky, S.; Nečas, M.; Marek, R. Interpreting the Paramagnetic NMR Spectra of Potential Ru(III) Metallodrugs: Synergy between Experiment and Relativistic DFT Calculations. J. Am. Chem. Soc. 2016, 138 (27), 8432−8445. (49) Vícha, J.; Patzschke, M.; Marek, R. A Relativistic DFT Methodology for Calculating the Structures and NMR Chemical Shifts of Octahedral Platinum and Iridium Complexes. Phys. Chem. Chem. Phys. 2013, 15 (20), 7740−7754. (50) Vícha, J.; Novotný, J.; Straka, M.; Repisky, M.; Ruud, K.; Komorovsky, S.; Marek, R. Structure, Solvent, and Relativistic Effects on the NMR Chemical Shifts in Square-Planar Transition-Metal Complexes: Assessment of DFT Approaches. Phys. Chem. Chem. Phys. 2015, 17 (38), 24944−24955. (51) Moon, S.; Patchkovskii, S. First-Principles Calculations of Paramagnetic NMR Shifts. In Calculation of NMR and EPR Parameters; Kaupp, M., Bühl, M., Malkin, V. G., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2004; pp 325−338. (52) Autschbach, J. NMR Calculations for Paramagnetic Molecules and Metal Complexes. Annual Reports in Computational Chemistry; Elsevier, 2015; Vol. 11, pp 3−36. (53) Vaara, J. Chemical Shift in Paramagnetic Systems. Science and Technology of Atomic, Molecular, Condensed Matter & Biological Systems; Elsevier, 2013; Vol. 3, pp 41−67. (54) Van den Heuvel, W.; Soncini, A. NMR Chemical Shift in an Electronic State with Arbitrary Degeneracy. Phys. Rev. Lett. 2012, 109, 7. (55) Komorovsky, S.; Repisky, M.; Ruud, K.; Malkina, O. L.; Malkin, V. G. Four-Component Relativistic Density Functional Theory Calculations of NMR Shielding Tensors for Paramagnetic Systems. J. Phys. Chem. A 2013, 117 (51), 14209−14219. (56) te Velde, G.; Bickelhaupt, F. M.; Baerends, E. J.; Fonseca Guerra, C.; Van Gisbergen, S. J. A.; Snijders, J. G.; Ziegler, T. Chemistry with ADF. J. Comput. Chem. 2001, 22 (9), 931−967. (57) ADF2016, SCM, Theoretical Chemistry; Vrije Universiteit: Amsterdam, The Netherlands, 2016. (58) Novotný, J.; Přichystal, D.; Sojka, M.; Komorovsky, S.; Nečas, M.; Marek, R. Hyperfine Effects in Ligand NMR: Paramagnetic Ru(III) Complexes with 3-Substituted Pyridines. Inorg. Chem. 2018, 57 (2), 641−652. (59) Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual Molecular Dynamics. J. Mol. Graphics 1996, 14 (1), 33−38. (60) PyMOL Molecular Graphics System, version 1.8.6.2; Schrödinger, LLC, New York, 2017. (61) La Mar, G. N.; Horrocks, W. D.; Holm, R. H. NMR of Paramagnetic Molecules: Principles and Applications; Elsevier Science: Burlington, VT, 2013. (62) Rekharsky, M. V.; Mori, T.; Yang, C.; Ko, Y. H.; Selvapalam, N.; Kim, H.; Sobransingh, D.; Kaifer, A. E.; Liu, S.; Isaacs, L.; et al. A Synthetic Host-Guest System Achieves Avidin-Biotin Affinity by Overcoming Enthalpy−entropy Compensation. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (52), 20737−20742. (63) Moghaddam, S.; Yang, C.; Rekharsky, M.; Ko, Y. H.; Kim, K.; Inoue, Y.; Gilson, M. K. New Ultrahigh Affinity Host−Guest Complexes of Cucurbit[7]Uril with Bicyclo[2.2.2]Octane and Adamantane Guests: Thermodynamic Analysis and Evaluation of M2 Affinity Calculations. J. Am. Chem. Soc. 2011, 133 (10), 3570−3581. (64) Nau, W. M.; Florea, M.; Assaf, K. I. Deep Inside Cucurbiturils: Physical Properties and Volumes of Their Inner Cavity Determine the Hydrophobic Driving Force for Host-Guest Complexation. Isr. J. Chem. 2011, 51 (5−6), 559−577. (65) Kaifer, A. E. Toward Reversible Control of Cucurbit[n]Uril Complexes. Acc. Chem. Res. 2014, 47 (7), 2160−2167. (66) Tootoonchi, M. H.; Yi, S.; Kaifer, A. E. Detection of Isomeric Microscopic Host−Guest Complexes. A Time-Evolving Cucurbit[7]Uril Complex. J. Am. Chem. Soc. 2013, 135 (29), 10804−10809. (67) Senler, S.; Li, W.; Tootoonchi, M. H.; Yi, S.; Kaifer, A. E. The Cucurbituril ‘Portal’ Effect. Supramol. Chem. 2014, 26 (9), 677−683.

Chemistry - Synthesis and Molecular-Structure of [NEt4][cisRhCl4{(CH3)2SO}2] and Chemical Behavior in Aqueous-Solution of [RhCln{(CH3)2SO}6−n]3−n (n = 3 or 4) Complexes. J. Chem. Soc., Dalton Trans. 1994, 13, 1849−1855. (29) Danilenko, G. I.; Votyakov, V. I.; Mokhort, N. A.; Andreeva, O. T.; Shashikhina, M. N.; Timofeeva, M. M.; Borenko, E. I.; Denisova, L. V.; Bruskova, I. V. Synthesis and Biological Activity of Adamantane Derivatives. VIII. Adamantyl Pyridinecarboxylates. Pharm. Chem. J. 1977, 11 (6), 795−797. (30) Danilenko, G. I.; Mokhort, N. A.; Trinus, F. P. Synthesis and Biological Activity of Adamantane Derivatives. VI. Antiinflammatory Action of Pyridinecarboxylic Acid Adamantylamides. Pharm. Chem. J. 1976, 10 (8), 1036−1038. (31) Martínez, R.; Torregrosa, R.; Pastor, I. M.; Yus, M. Isoprene as Lithiation Mediator: Synthesis of 2-Substituted 1-Alkylimidazole Derivatives. Synthesis 2012, 44 (16), 2630−2638. (32) Webb, M. I.; Chard, R. A.; Al-Jobory, Y. M.; Jones, M. R.; Wong, E. W. Y.; Walsby, C. J. Pyridine Analogues of the Antimetastatic Ru(III) Complex NAMI-A Targeting Non-Covalent Interactions with Albumin. Inorg. Chem. 2012, 51 (2), 954−966. (33) Mestroni, G.; Alessio, E.; Sessanta o Santi, A.; Geremia, S.; Bergamo, A.; Sava, G.; Boccarelli, A.; Schettino, A.; Coluccia, M. Rhodium(III) Analogues of Antitumour-Active Ruthenium(III) Compounds: The Crystal Structure of [ImH][trans-RhCl4(Im)2] (Im = Imidazole). Inorg. Chim. Acta 1998, 273 (1−2), 62−71. (34) Sheldrick, G. M. A Short History of SHELX. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64 (1), 112−122. (35) Pohl, L.; Eckle, M. Sodium 3-Trimethylsilyltetradeuteriopropionate, a New Water-Soluble Standard For1H-NMR. Angew. Chem., Int. Ed. Engl. 1969, 8 (5), 381−381. (36) Bodenhausen, G.; Ruben, D. J. Natural Abundance Nitrogen-15 NMR by Enhanced Heteronuclear Spectroscopy. Chem. Phys. Lett. 1980, 69 (1), 185−189. (37) Bothner-By, A. A.; Stephens, R. L.; Lee, J.; Warren, C. D.; Jeanloz, R. W. Structure Determination of a Tetrasaccharide: Transient Nuclear Overhauser Effects in the Rotating Frame. J. Am. Chem. Soc. 1984, 106 (3), 811−813. (38) Tao, J.; Perdew, J. P.; Staroverov, V. N.; Scuseria, G. E. Climbing the Density Functional Ladder: Nonempirical Meta−Generalized Gradient Approximation Designed for Molecules and Solids. Phys. Rev. Lett. 2003, 91, 14. (39) Adamo, C.; Barone, V. Toward Reliable Density Functional Methods without Adjustable Parameters: The PBE0Model. J. Chem. Phys. 1999, 110 (13), 6158−6170. (40) Adamo, C.; Scuseria, G. E.; Barone, V. Accurate Excitation Energies from Time-Dependent Density Functional Theory: Assessing the PBE0Model. J. Chem. Phys. 1999, 111 (7), 2889−2899. (41) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A Consistent and Accurate Ab Initio Parametrization of Density Functional Dispersion Correction (DFT-D) for the 94 Elements H-Pu. J. Chem. Phys. 2010, 132 (15), 154104. (42) Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the Damping Function in Dispersion Corrected Density Functional Theory. J. Comput. Chem. 2011, 32 (7), 1456−1465. (43) Rappoport, D.; Furche, F. Property-Optimized Gaussian Basis Sets for Molecular Response Calculations. J. Chem. Phys. 2010, 133 (13), 134105. (44) Schäfer, A.; Huber, C.; Ahlrichs, R. Fully Optimized Contracted Gaussian Basis Sets of Triple Zeta Valence Quality for Atoms Li to Kr. J. Chem. Phys. 1994, 100 (8), 5829−5835. (45) Andrae, D.; Häußermann, U.; Dolg, M.; Stoll, H.; Preuß, H. Energy-Adjustedab Initio Pseudopotentials for the Second and Third Row Transition Elements. Theor. Chim. Acta 1990, 77 (2), 123−141. (46) TURBOMOLE V7.0 , a Development of University of Karlsruhe and Forschungszentrum Karlsruhe GmbH, 1989−2007, TURBOMOLE GmbH, since 2007, 2015. (47) Klamt, A.; Schüürmann, G. COSMO: A New Approach to Dielectric Screening in Solvents with Explicit Expressions for the L

DOI: 10.1021/acs.inorgchem.7b03233 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry (68) Kolman, V.; Marek, R.; Strelcova, Z.; Kulhanek, P.; Necas, M.; Svec, J.; Sindelar, V. Electron Density Shift in Imidazolium Derivatives upon Complexation with Cucurbit[6]Uril. Chem. - Eur. J. 2009, 15 (28), 6926−6931. (69) Kaupp, M.; Köhler, F. H. Combining NMR Spectroscopy and Quantum Chemistry as Tools to Quantify Spin Density Distributions in Molecular Magnetic Compounds. Coord. Chem. Rev. 2009, 253 (19− 20), 2376−2386. (70) Bertini, I.; Luchinat, C.; Parigi, G.; Ravera, E. NMR of Paramagnetic Molecules: Applications to Metallobiomolecules and Models, 2nd ed..; Elsevier: Amsterdam, The Netherlands, 2017. (71) Bertini, I.; Luchinat, C.; Parigi, G. Magnetic Susceptibility in Paramagnetic NMR. Prog. Nucl. Magn. Reson. Spectrosc. 2002, 40 (3), 249−273. (72) Benda, L.; Mareš, J.; Ravera, E.; Parigi, G.; Luchinat, C.; Kaupp, M.; Vaara, J. Pseudo-Contact NMR Shifts over the Paramagnetic Metalloprotein CoMMP-12 from First Principles. Angew. Chem., Int. Ed. 2016, 55 (47), 14713−14717.

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DOI: 10.1021/acs.inorgchem.7b03233 Inorg. Chem. XXXX, XXX, XXX−XXX