Structure Activity-Relationships (SARs) of the five possible isomers of RuCl 2(Azpy) 2 were predicted thanks to DFT method. Azpy stands for 2-phenylazopyridine and the structure of the isomers α-RuCl 2(Azpy) 2, β-RuCl 2(Azpy) 2, γ-RuCl2(Azpy)2, δ-RuCl 2(Azpy) 2 and ε-RuCl 2(Azpy) 2 call respectively α-Cl, β-Cl, γ-Cl, δ-Cl and ε-Cl are defined according to chlorine atoms orientations. Hence, they are divided into two groups. In the first group comprising α-Cl, β-Cl and ε-Cl, both chlorine atoms are in cis position and Azpy ligands are intervertical. Whereas the two others isomers ( γ-Cl and δ-Cl), they form the second group. Here, both chlorine are in trans position and Azpy are planar. The five synthesized isomers were investigated as potential antitumor agents. Then, regarding the DNA, its bases are stacked by pair. Therefore, complexes are assumed to insert and to stack on them through intercalative mode. So the electronic and geometric structures become more important to describe their SARs. Consequently, group 2 regarding γ-Cl and δ-Cl presents the best structure to allow intercalation between DNA base-pairs. Besides, the energy order of the lower unoccupied molecular orbital (LUMO) of the isomers is ELUMO( β-Cl) > ELUMO( α-Cl) > ELUMO( ε-Cl) > ELUMO( γ-Cl) > ELUMO( δ-Cl). The energy gap between LUMO and HOMO was also sorted as Δ(L-H)( β-Cl) > Δ(L-H)( α-Cl) > Δ(L-H)( ε-Cl) > Δ(L-H)( γ-Cl) > Δ(L-H)( δ-Cl). In addition, the total dipole moment was classified as μ( ε-Cl) > μ( β-Cl) > μ( α-Cl) > μ( γ-Cl) > μ( δ-Cl). Finally, net charge of the ligand Azpy was also classified as QL( δ-Cl) > QL( γ-Cl) > QL( ε-Cl) > QL( α-Cl) > QL( β-Cl). All those parameters show that δ-Cl isomer displays the highest activity as antitumor drug when intercalating between the DNA basepairs Cytosine-Guanine/Cytosine-Guanine (CG/CG).
The interest in the bidentate 2-phenylazopyridine ligand (Azpy) is due to its ability to stabilize ruthenium at a low state of oxidation [
Azopyridine ligands as indicated in
The 2-phenylazopyridine is assumed to be the ancestor ligand that is up today the most exploited with ruthenium atom. However, many other types of azo ligand are also being experienced [
According to the synthesis, the complex of ruthenium performed with Azpy ligand is RuCl2(Azpy)2. However, the non symmetry of the ligand Azpy gives actually rise to five isomers complexes named α-Cl, β-Cl, γ-Cl, δ-Cl and ε-Cl [
In reality, they have been synthesized by different team of researchers regarding their fascinating activity. Except β-Cl, all of them present a C2 symmetry. Thus, both azopyridine ligands are equivalent. Besides, regarding the symmetrical complexes, only δ-Cl shows different chloride atoms. Hitherto, the major synthesis consist of merging reactant RuCl3・3H2O with Azpy ligand [
Furthermore, the cytotoxic activity consists of the complex binding to DNA that will induce the death of the cell. However, there exist two processes through which the ruthenium complexes bind to DNA base-pairs similarly to platinum drugs. The first trend indicates that the chloride atoms are actually hydrolyzed. Therefore the ruthenium is allowed to bind covalently to the nucleobase of the DNA [
It was reported that the possibility of the interaction between DNA and ruthenium complexes requires to know the electronic structure of both of them. It is to say that the energies, the components of the frontier molecular orbitals, the atomic charge populations and the geometrical structure of not merely ruthenium complexes but also HOMO-LUMO predictions of the DNA play an important role [
We remind that the stability of the stacked CG/CG was determined by comparing the HOMO energies of all the three isomers since it is admitted that the bonding between the stacked DNA base-pairs and the drug comes from electrons exchange. So, HOMO should belong to DNA and LUMO comes from the drug.
In this paper, we study theoretically the structure-activity relationships SARs of the five α-, β-, γ-, δ- and ε-RuCl2(Azpy)2 isomers named respectively α-Cl, β-Cl, γ-Cl, δ-Cl and ε-Cl. This will be the occasion to figure out which of all the complexes shall actually have the highest cytotoxic activity. We remember that only the first three complexes have been experimentally studied [
All the calculations were performed with DFT method using Becke’s three-parameter hybrid B3LYP [
According to the frontier orbital molecular definition, the high activity of the complex is proportional to the low value of the energy gap DE(L-H). Otherwise, the molecule is admitted to be active if the HOMO-LUMO gap is small. Therefore, through
Atoms | RuCl2(Azpy)2 | ||||||||
---|---|---|---|---|---|---|---|---|---|
α-Cl | β-Cl | γ-Cl | δ-Cl | ε-Cl | |||||
Theory | Experiment | Theory | Experiment | Theory | Experiment | Theory | Experiment | Theory | |
N1=N2 | 1.32 | 1.28 | 1.32 1.32 | 1.29 1.3 | 1.32 | 1.31 | 1.31 | 1.28 | 1.32 |
Ru-N2 | 2.03 | 1.98 | 2.02 2.05 | 1.96 2.0 | 2.03 | 1.99 | 2.06 | 2.02 | 2.05 |
Ru-Npy | 2.06 | 2.05 | 2.05 2.07 | 2.02 2.06 | 2.10 | 2.11 | 2.10 | 2.06 | 2.06 |
Ru-Cl1 | 2.48 | 2.40 | 2.48 | 2.40 | 2.48 | 2.38 | 2.51 | 2.38 | 2.49 |
Ru-Cl2 | 2.48 | 2.40 | 2.48 | 2.41 | 2.48 | 2.38 | 2.49 | 2.38 | 2.49 |
Cl1-Ru-Cl2 | 90.60 | 89.50 | 90.18 | 91.10 | 170.71 | 170.50 | 180.00 | 180.00 | 94.10 |
Npy-Ru-Npy | 178.37 | 174.50 | 99.21 | 101.90 | 102.86 | 103.80 | 167.53 | 180.00 | 93.58 |
N2-Ru-N2 | 101.49 | 93.50 | 104.58 | 103.00 | 104.99 | 104.10 | 178.58 | 180.00 | 169.48 |
Isomers | LANL2DZ | |||
---|---|---|---|---|
HOMO | LUMO | DE(L-H) | G˚ | |
α-RuCl2(Azpy)2 | −0.205 | −0.122 | 0.082 | −1301.072 |
β-RuCl2(Azpy)2 | −0.203 | −0.118 | 0.0845 | −1301.067 |
g-RuCl2(Azpy)2 | −0.198 | −0.124 | 0.074 | −1301.059 |
d-RuCl2(Azpy)2 | −0.192 | −0.126 | 0.066 | −1301.061 |
ε-RuCl2(Azpy)2 | −0.198 | −0.123 | 0.075 | −1300.062 |
δ-Cl. Moreover,
The hydrophobic value Log P that expresses the solubility of compound either in organic solvent or in water can be determined by the computed dipole moment. In fact, the dipole moment indicates the water-solubility strength of a molecule. In consequence, the high value implies the poor solubility in organic solvent and a strong solubility in water. Actually, the efficient drugs are fat-soluble since many antimetastatic drugs perform their activity in organic solvent [
The population of atomic net charge has been determined on behalf of the natural atomic population (NPA). It shows the affinity for atom or molecule to gain electron. Regarding
μ | ||||
---|---|---|---|---|
x | y | z | Total | |
α-RuCl2(Azpy)2 | 0 | 0 | −7.2606 | 7.2606 |
β-RuCl2(Azpy)2 | −1.7373 | 0.9617 | 8.6087 | 8.8347 |
g-RuCl2(Azpy)2 | 0 | 0 | 1.6738 | 1.6738 |
d-RuCl2(Azpy)2 | 0 | 0 | −1.3303 | 1.3303 |
ε-RuCl2(Azpy)2 | 0 | 0 | −10.0245 | 10.0245 |
RuCl2(Azpy)2 | Total natural charge | ||
---|---|---|---|
Ru | Ligand Azpy | Cl | |
α-Cl | 0.59 | 0.43 | −1.02 |
β-Cl | 0.58 | 0.42 | −1.00 |
g-Cl | 0.55 | 0.48 | −1.03 |
d-Cl | 0.55 | 0.52 | −1.07 |
ε-Cl | 0.58 | 0.48 | −1.06 |
eV), we notice that the DNA energy is higher. In consequence, ligands are reported to play a key role in affecting their binding affinity to DNA. i.e. the lower LUMO energy of the complex must bind easily to the DNA [
SARs consists of finding out a relation between electronic properties of ruthenium complexes and their cytotoxicity activities. As assumed before, Velders et al. [
In
1) The increase in the rate of chloride hydrolysis due the p-acceptor effect of the azopyridine ligands increasing the effective charge on the metal ion so that the hydrolysis rates are in the range of cisplatin;
2) The increased hydrophobic or intercalative interactions with DNA, which may facilitate covalent binding;
3) And the geometric effects exerted by the ligands, which may facilitate (or inhibit) protein binding to the nucleic acid.
Herewith, ruthenium complex was admitted to undergo a chloride hydrolysis before binding covalently to DNA base. Also, the bonding was performed between ruthenium and the DNA base purine and guanine derivatives [
Regarding the geometrical structure of the complexes, their structure-activity relationship can be enhanced if both Azpy ligands are in the same plan. Hence, only γ-Cl and δ-Cl match with that structure [
Considering the frontier molecular orbital, the reaction is the most efficient between two molecules when the HOMO of the first molecule (electron donor) is close to the LUMO of the second one (electron acceptor). If the HOMO is carried by the DNA base-pairs and the LUMO by ruthenium complex then the most reactive complex must have the lowest LUMO energy. In consequence, knowing the HOMO energy of DNA fixed to −1.27 eV according to Kurita and Kobayashi, the LUMO energy of isomers provided by Azpy ligands was classified as following ELUMO(β-Cl) > ELUMO(α-Cl) > ELUMO(ε-Cl) > ELUMO(γ-Cl) > ELUMO(δ-Cl). Here again, δ-Cl is assumed to display the most available ligands to easily accept electrons from HOMO of DNA base-pairs.
Regarding the hydrophobic parameter expressed by log P, it expresses the absorption of the pharmaceutical drug. It is actually a main parameter regarding the studies of the quantitative structure-activity relationship QSAR of biological molecules [
MCF-7 | EVSA-T | WIDR | IGROV | M19 | A498 | H266 | |
---|---|---|---|---|---|---|---|
α-RuCl2(Azpy)2 | 0.6 | 0.1 | 1.9 | 0.8 | 0.2 | 1.2 | 1.5 |
β-RuCl2(Azpy)2 | 4.1 | 1.9 | 11.2 | 7.3 | 2.5 | 8.8 | 10 |
g-RuCl2(Azpy)2 | 5.9 | 5.4 | 16.6 | 11.8 | 4.5 | 15.3 | 14.8 |
5-FU | 5.8 | 3.7 | 1.7 | 2.3 | 3.4 | 1.1 | 2.6 |
CPT | 2.3 | 1.4 | 3.2 | 0.6 | 1.9 | 7.5 | 10.9 |
classification of computed dipole moment of isomers as μ(ε-Cl) > μ(β-Cl) > μ(α-Cl) > μ(γ-Cl) > μ(δ-Cl) shows up that δ-Cl shall display the highest cytotoxicity.
Finally, the atomic net charge of complexes must have an effect on their ability to bind by intercalation between DNA base-pairs. As DNA base-pairs possess the HOMO molecular orbitals, they carry naturally negative charge. Therefore, they bonding to ligands requires that the ligands carry high positive charge. Thus,
The cytotoxicity of five isomers α-RuCl2(Azpy)2, β-RuCl2(Azpy)2, γ-RuCl2(Azpy)2, δ-RuCl2(Azpy)2 and ε-RuCl2 (Azpy)2 were theoretically investigated by DFT-B3LYP method using the pseudo-potential LANL2DZ basis set. Their Structure activity-relationships (SARs) were performed by analyzing their electronic and geometric structure and relating them to their cytotoxic activities. Besides, three modes regarding their bonding to DNA base- pairs are discussed nowadays. The most accepted mode that regards the insertion and the stacking of complexes between the double helical DNA base-pairs consists of intercalation of ligands. Therefore, it requires that the complex displays ligands in the same plan. Its LUMO energy must be low to allow the bonding to the electron donor DNA base-pairs. Also, the complex must possess a low dipole moment that characterizes its absorption in organic solution. Moreover, as the bonding is performed between DNA and electron acceptor ligands Azpy, the ligand must consequently display the high positive charge. Considering the aforementioned properties, we can assume that the most cytotoxic isomers by intercalative mode between DNA base-pairs is δ-RuCl2(Az-py)2.
KafoumbaBamba,Ouattara WawohinlinPatrice,N’Guessan KouakouNobel,NahosséZiao, (2016) SARs Investigation of α-, β-,γ-, δ-,ε-RuCl2(Azpy)2 Complexes as Antitumor Drugs. Computational Chemistry,04,1-10. doi: 10.4236/cc.2016.41001