The lipophilicity of ten ruthenium(II)-arene complexes was assessed by reversed-phase thin-layer chromatography (RP-TLC) on octadecyl silica stationary phase. The binary solvent systems composed of water and acetonitrile were used as mobile phase in order to determine chromatographic descriptors for lipophilicity estimation. Octanol-water partition coefficient,
Apart from being important in material science and catalysis, metal ions and their complexes play a significant role in the vital functions of living organisms. Numerous applications of metal-based compounds as both therapeutic and diagnostic agents as well as mineral supplements were studied in scope of relatively young but rapidly developing research discipline named medicinal inorganic chemistry [
In addition to the widely used platinum-based chemotherapeutic drugs such as cisplatin or carboplatin, numerous non-platinum-based compounds were investigated as anticancer agents [
Our previous studies have been focused on syntheses, characterization, and cytotoxic activity of series of ruthenium(II)-arene compounds [
Since the lipophilicity is one of the major parameters affecting important biological processes that follow drug intake such as adsorption, passage through membranes, drug-receptor interactions, metabolism, and toxicity of molecules [
Octanol-water partition coefficient
While considerable effort has been devoted to studying the
However, despite its numerous advantages and long history of successful application for lipophilicity determination of small organic molecules, modern high-performance thin-layer chromatography is rarely used for
On the other hand, modern computational approach to the estimation of lipophilicity of metal complexes mostly relies on quantitative structure property relationship studies (QSPR) that establish quantitative models based on experimentally determined
In the present work the attention was focused on the application of RP-TLC as a simple, fast, and reliable tool to determine
Being simple, fast and reliable RP-TLC provides retention data in the form of
The first parameter
Slope,
The last descriptor, the first principal component, PC1, is derived from principal component analysis (PCA), that is, principal component regression (PCR), multivariate chemometric methods often applied on chromatographic data. It has been demonstrated that the scores of the principal components (usually the PC1 scores are sufficient) are better correlated with
All reagents and solvents, including standard substances, were of analytical or HPLC purity grade. They are purchased from commercial suppliers: Aldrich (Milwaukee, WI, USA), Fluka (Buchs, Switzerland), and Merck (Darmstadt, Germany), and used as received. Ruthenium(II)-arene complex compounds (Figure
Structures of studied ruthenium(II)-arene complexes.
In the present work a set of 28 standard solutes, mainly mono- and polysubstituted phenols, aromatic carboxylic acids, ketones, amines, esters, and few polyaromatic hydrocarbons, of known
Calibration set of standard compounds with experimentally determined
No. | Compound |
|
|
|
---|---|---|---|---|
1 | 1,2,3-Benzotriazole | 1.44 | 8.37 | 0.42 |
2 | 4-Chlorobenzoic acid | 2.65 | 3.98 | 99.05 |
3 | 2-Nitrobenzaldehyde | 1.74 | — | — |
4 | 4-Bromoaniline* | 2.26 | 3.86 | 99.28* |
5 | Phenol | 1.46 | 10.09 | 0.01 |
6 | Benzophenone | 3.18 | — | — |
7 | 3-Nitrobenzaldehyde | 1.46 | — | — |
8 | 4-Aminobenzoic acid | 0.83 | 4.65 | 95.72 |
9 | Phthalimide* | 1.15 | 100.00* | |
10 | 1,4-Benzoquinone | 0.20 | — | — |
11 | 4-Nitrophenol | 1.91 | 7.15 | 6.61 |
12 | 3-Nitrophenol | 2.00 | 8.28 | 0.52 |
13 | Benzyl alcohol | 1.10 | — | — |
14 | Naphthylamine* | 2.25 | 3.92 | 99.18* |
15 | 2-Naphthol | 2.85 | 9.67 | 0.02 |
16 | 4-Fluoroaniline* | 1.15 | 4.70 | 95.23* |
17 | 1-Naphthol | 2.85 | 9.34 | 0.05 |
18 | 4-Hydroxybenzaldehyde | 1.35 | — | — |
19 | 3-Chloronitrobenzene | 2.46 | — | — |
20 | 2,4-Dichlorophenol | 3.06 | 7.85 | 1.39 |
21 | 4-Methylphenol | 1.94 | 10.09 | 0.01 |
22 | 4-Chlorophenol | 2.39 | 9.38 | 0.04 |
23 | Anthracene | 4.45 | — | — |
24 | Acetophenone | 1.58 | — | — |
25 | 2-Aminophenol | 0.62 | 9.44 | 0.04 |
26 | 4-t-Butylphenol | 3.31 | 10.31 | 0.00 |
27 | 1,3,5-Trihydroxybenzene | 0.16 | 9.40 | 0.04 |
28 | 2,6-Dimethylphenol | 2.36 | 10.59 | 0.00 |
For all chromatographic experiments solutions of standard substances, as well as of studied ruthenium complex compounds, were prepared by dissolving appropriate amount of substance in acetone in concentration of 0.1 mg/mL. Commercially available octadecyl modified silica aluminum sheets (Art. number 5559, Merck, Darmstadt, Germany) were cut into
The following chromatographic descriptors:
Retention of standard compounds and studied ruthenium complexes given as
Number | Compound | Volume fraction of acetonitrile (%) | ||||||
---|---|---|---|---|---|---|---|---|
30 | 35 | 40 | 45 | 50 | 55 | 60 | ||
1 | 1,2,3-Benzotriazole | — | — | 0.31 | 0.39 | 0.48 | 0.51 | 0.53 |
2 | 4-Chlorobenzoic acid | — | — | 0.13 | 0.16 | 0.22 | 0.24 | 0.38 |
3 | 2-Nitrobenzaldehyde | — | — | 0.11 | 0.14 | 0.21 | 0.24 | 0.30 |
4 | 4-Bromoaniline | — | — | 0.06 | 0.08 | 0.15 | 0.18 | 0.25 |
5 | Phenol | — | — | 0.26 | 0.33 | 0.40 | 0.50 | 0.57 |
6 | Benzophenone | — | — | 0.03 | 0.05 | 0.07 | 0.09 | 0.15 |
7 | 3-Nitrobenzaldehyde | — | — | 0.11 | 0.14 | 0.23 | 0.24 | 0.30 |
8 | 4-Aminobenzoic acid | — | — | 0.44 | 0.48 | 0.54 | 0.56 | 0.60 |
9 | Phthalimide | — | — | 0.24 | 0.30 | 0.41 | 0.43 | 0.48 |
10 | 1,4-Benzoquinone | — | — | 0.40 | 0.43 | 0.49 | 0.50 | 0.52 |
11 | 4-Nitrophenol | — | — | 0.24 | 0.28 | 0.33 | 0.46 | 0.52 |
12 | 3-Nitrophenol | — | — | 0.16 | 0.20 | 0.27 | 0.41 | 0.49 |
13 | Benzyl alcohol | — | — | 0.42 | 0.50 | 0.53 | 0.59 | 0.64 |
14 | Naphthylamine | — | — | 0.12 | 0.16 | 0.22 | 0.33 | 0.41 |
15 | 2-Naphthol | — | — | 0.13 | 0.18 | 0.27 | 0.37 | 0.43 |
16 | 4-Fluoroaniline | — | — | 0.26 | 0.28 | 0.36 | 0.48 | 0.52 |
17 | 1-Naphthol | — | — | 0.12 | 0.13 | 0.19 | 0.33 | 0.39 |
18 | 4-Hydroxybenzaldehyde | — | — | 0.41 | 0.39 | 0.48 | 0.61 | 0.63 |
19 | 3-Chloronitrobenzene | — | — | 0.07 | 0.09 | 0.11 | 0.22 | 0.28 |
20 | 2,4-Dichlorophenol | — | — | 0.09 | 0.12 | 0.27 | 0.33 | 0.40 |
21 | 4-Methylphenol | — | — | 0.26 | 0.30 | 0.36 | 0.48 | 0.54 |
22 | 4-Chlorophenol | — | — | 0.17 | 0.24 | 0.30 | 0.39 | 0.51 |
23 | Anthracene | — | — | 0.01 | 0.02 | 0.02 | 0.09 | 0.15 |
24 | Acetophenone | — | — | 0.23 | 0.26 | 0.31 | 0.41 | 0.51 |
25 | 2-Aminophenol | — | — | 0.42 | 0.42 | 0.51 | 0.62 | 0.66 |
26 | 4-t-Butylphenol | — | — | 0.07 | 0.09 | 0.16 | 0.28 | 0.39 |
27 | 1,3,5-Trihydroxybenzene | — | — | 0.73 | 0.67 | 0.77 | 0.80 | 0.84 |
28 | 2,6-Dimethylphenol | — | — | 0.11 | 0.16 | 0.23 | 0.33 | 0.41 |
29 | Ru-1 | 0.01 | 0.01 | 0.02 | 0.04 | 0.06 | 0.11 | — |
30 | Ru-2 | 0.00 | 0.01 | 0.02 | 0.04 | 0.06 | 0.12 | — |
31 | Ru-3 | 0.01 | 0.01 | 0.02 | 0.04 | 0.06 | 0.15 | — |
32 | Ru-4 | 0.01 | 0.02 | 0.05 | 0.07 | 0.10 | 0.14 | — |
33 | Ru-5 | 0.01 | 0.03 | 0.06 | 0.08 | 0.13 | 0.16 | — |
34 | Ru-6 | 0.08 | 0.13 | 0.19 | 0.24 | 0.31 | 0.37 | — |
35 | Ru-7 | 0.23 | 0.28 | 0.32 | 0.37 | 0.44 | 0.49 | — |
36 | Ru-8 | 0.11 | 0.15 | 0.23 | 0.27 | 0.33 | 0.45 | — |
37 | Ru-9 | 0.05 | 0.07 | 0.13 | 0.16 | 0.21 | 0.29 | — |
38 | Ru-10 | 0.02 | 0.04 | 0.07 | 0.11 | 0.19 | 0.24 | — |
Linear relationship between solute retention (
Compound | Chromatographic parameters | |||||
---|---|---|---|---|---|---|
|
|
|
S.D. |
|
|
|
1,2,3-Benzotriazole |
|
|
0.9642 | 0.052 | 39.65 | 5 |
4-Chlorobenzoic acid |
|
|
0.9770 | 0.056 | 62.92 | 5 |
2-Nitrobenzaldehyde |
|
|
0.9901 | 0.035 | 149.91 | 5 |
4-Bromoaniline |
|
|
0.9858 | 0.059 | 103.48 | 5 |
Phenol |
|
|
0.9981 | 0.017 | 768.73 | 5 |
Benzophenone |
|
|
0.9935 | 0.036 | 229.29 | 5 |
3-Nitrobenzaldehyde |
|
|
0.9707 | 0.062 | 48.96 | 5 |
4-Aminobenzoic acid |
|
|
0.9848 | 0.022 | 96.39 | 5 |
Phthalimide |
|
|
0.9671 | 0.056 | 43.29 | 5 |
1,4-Benzoquinone |
|
|
0.9723 | 0.024 | 51.88 | 5 |
4-Nitrophenol |
|
|
0.9886 | 0.039 | 129.19 | 5 |
3-Nitrophenol |
|
|
0.9900 | 0.048 | 147.99 | 5 |
Benzyl alcohol |
|
|
0.9924 | 0.021 | 195.84 | 5 |
Naphthylamine |
|
|
0.9976 | 0.024 | 612.44 | 5 |
2-Naphthol |
|
|
0.9954 | 0.033 | 323.64 | 5 |
4-Fluoroaniline |
|
|
0.9789 | 0.051 | 68.73 | 5 |
1-Naphthol |
|
|
0.9785 | 0.072 | 67.56 | 5 |
4-Hydroxybenzaldehyde |
|
|
0.9396 | 0.078 | 22.59 | 5 |
3-Chloronitrobenzene |
|
|
0.9747 | 0.078 | 57.07 | 5 |
2,4-Dichlorophenol |
|
|
0.9728 | 0.095 | 52.89 | 5 |
4-Methylphenol |
|
|
0.9928 | 0.031 | 207.53 | 5 |
4-Chlorophenol |
|
|
0.9969 | 0.025 | 487.62 | 5 |
Anthracene |
|
|
0.9616 | 0.155 | 36.87 | 5 |
Acetophenone |
|
|
0.9836 | 0.046 | 89.03 | 5 |
2-Aminophenol |
|
|
0.9657 | 0.059 | 41.45 | 5 |
4-t-Butylphenol |
|
|
0.9927 | 0.055 | 204.43 | 5 |
1,3,5-Trihydroxybenzene |
|
|
0.8754 | 0.090 | 9.84 | 5 |
2,6-Dimethylphenol |
|
|
0.9984 | 0.020 | 908.70 | 5 |
Ru-1 |
|
|
0.7903 | 0.155 | 6.65 | 6 |
Ru-2 |
|
|
0.8797 | 0.106 | 13.69 | 6 |
Ru-3 |
|
|
0.8263 | 0.079 | 8.61 | 6 |
Ru-4 |
|
|
0.9351 | 0.154 | 27.86 | 6 |
Ru-5 |
|
|
0.8732 | 0.145 | 12.84 | 6 |
Ru-6 |
|
|
0.9564 | 0.037 | 42.93 | 6 |
Ru-7 |
|
|
0.9875 | 0.039 | 157.10 | 6 |
Ru-8 |
|
|
0.9563 | 0.066 | 42.81 | 6 |
Ru-9 |
|
|
0.9010 | 0.084 | 17.25 | 6 |
Ru-10 |
|
|
0.9824 | 0.066 | 110.36 | 6 |
Calibration models based on individual
The common logarithm of
All the DFT calculations have been carried out with the Gaussian 09, revision C.01 electronic structure program suite [
For all studied compounds a good linearity between retention constants
All calibration models were obtained using entire set of standard compounds. Accompanying statistics and equations are summarized in Table
Calibration models and accompanying statistics.
Model number | Model type | Equation | Statistics |
---|---|---|---|
1 | OLS |
|
|
2 | OLS |
|
|
3 | OLS |
|
|
4 | OLS |
|
|
5 | OLS |
|
|
6 | OLS |
|
|
7 | PCR |
|
RMSEC = 0.375; |
RMSECV= 0.418; |
The calculated gas-phase geometries of all complexes under investigation are in excellent agreement with available X-ray crystal structures [
Selected average bond lengths (Å) and valence angles (°) for available crystallographic data (a) and comparison with DFT energy-minimized structures (b).
Comp. | Bond lengths (Å) | Valence angles (°) | ||||||
---|---|---|---|---|---|---|---|---|
M–C | M–Cl | M–N | M–O | O–M–N | O–M–Cl | N–M–Cl | Cl–M–Cl | |
Ru-1 | ||||||||
a | 2.18 | 2.40 | 2.13 | — | — | — | 86.0 | 87.0 |
b | 2.19 | 2.37 | 2.05 | — | — | — | 84.8 | 88.7 |
Ru-7 | ||||||||
a | 2.18 | 2.41 | 2.10 | 2.10 | 77.9 | 86.7 | 85.3 | — |
b | 2.19 | 2.37 | 2.03 | 2.04 | 78.8 | 88.6 | 81.9 | — |
Ru-9 | ||||||||
a | 2.19 |
2.40 |
2.16 |
2.09 | 76.9 | 83.7 | 85.2 | — |
b | 2.18 | 2.37 | 2.04 | 2.03 | 79.1 | 86.6 | 82.8 | — |
Ru-10 | ||||||||
a | 2.19 | 2.42 | 2.10 | 2.09 | 78.0 | 85.2 | 85.2 | — |
b | 2.18 | 2.37 | 2.04 | 2.03 | 79.1 | 86.6 | 82.8 | — |
Chromatographically determined
Chromatographically determined and computationally estimated
Comp. | Chromatographically determined | Estimated | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Model number | Based on | |||||||||
1 | 2 | 3 | 4 | 5 | 6 | 7 |
|
|
|
|
Ru-1 |
|
|
|
|
|
|
3.72 | −13.85 | −19.81 | 4.36 |
Ru-2 |
|
|
|
|
|
|
3.65 | −13.27 | −19.35 | 4.45 |
Ru-3 |
|
|
|
|
|
|
3.97 | −9.99 | −17.63 | 5.59 |
Ru-4 |
|
|
|
|
|
|
2.91 | −14.48 | −19.60 | 3.75 |
Ru-5 |
|
|
|
|
|
|
2.63 | −14.99 | −19.97 | 3.65 |
Ru-6 |
|
|
|
|
|
|
1.63 | −20.77 | −23.24 | 1.81 |
Ru-7 |
|
|
|
|
|
|
1.14 | −20.51 | −22.57 | 1.50 |
Ru-8 |
|
|
|
|
|
|
1.78 | −19.35 | −21.61 | 1.66 |
Ru-9 |
|
|
|
|
|
|
2.14 | −16.88 | −19.70 | 2.06 |
Ru-10 |
|
|
|
|
|
|
2.59 | −15.64 | −19.15 | 2.57 |
Studied ruthenium(II)-arene complexes exhibit unusually high lipophilicity, in the range of 1–4 log units, compared with reported
The lipophilicity of ten ruthenium(II)-arene complexes with potential anticancer and antiproliferative activity has been determined by means of RPTLC on RP-18 silica as stationary and binary acetonitrile-water solvent systems as mobile phase. Based on retention data corresponding chromatographic descriptors for lipophilicity assessment have been obtained. Most of the experimental findings described above have been confirmed by DFT free energy calculations of complexes in octanol and water as solvents, using solvation model based on density (SMD). As results are promising, it can be considered as reliable tool for prediction of lipophilicity and rational design of coordination compounds with desired properties.
The authors declare that they have no conflict of interests.
This work has been supported by the Ministry of Education, Science and Technological Development of Serbia, Grant no. 172017.