Unravelling the Modulation of the Activity in Drugs Based on

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Unravelling the Modulation of the Activity in Drugs Based on Methylated Phenanthroline when Intercalating between DNA Base Pairs Adrià Gil, Ángel Sánchez-González, and Vicenç Branchadell J. Chem. Inf. Model., Just Accepted Manuscript • DOI: 10.1021/acs.jcim.9b00500 • Publication Date (Web): 16 Aug 2019 Downloaded from pubs.acs.org on August 20, 2019

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Journal of Chemical Information and Modeling

Unravelling the Modulation of the Activity in Drugs Based on Methylated Phenanthroline when Intercalating between DNA Base Pairs Adrià Gil* †,§, Angel Sanchez-Gonzalez §, Vicenç Branchadell ‡. †

CIC Nanogune, Tolosa Hiribidea 76, 20029 Donostia - San Sebastian, Gipuzkoa, Basque

Country, Spain. §

Centro de Química e Bioquímica and BioISI – Biosystems and Integrative Sciences Institute,

DQB, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016, Lisboa, Portugal. ‡

Departament de Química, Universitat Autònoma de Barcelona, Campus UAB, 08193, Bellaterra,

Catalonia, Spain.

ACS Paragon Plus Environment

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ABSTRACT

Phenanthroline derivatives intercalate between base pairs of DNA and produce cytotoxic effects against tumoral cells. Nevertheless, modulation of their efficiency by substitution remains unclear in bibliography. In this work the effects of methylation of phenanthroline, in number and position, when intercalates between Guanine-Cytosine base pairs (GC/CG) were studied with PM6-DH2 and DFT-D methods including dispersion corrections. An analysis of the geometries, electronic structure and energetics in the interaction was carried out for the studied systems. Our results were compared to experimental works to gain insight on the relation structure-interaction for the intercalated system with cytotoxicity. The trends are explained including not only intrinsic contributions to energy: ΔEPauli, ΔEdisp, ΔEorb and ΔEelstat but also the solvation energy, ΔESolv. A subtle balance between the number of stabilizing weak interactions (CH/, CH/n, etc.) and steric hindrance seems to be related to the efficiency of such drugs.


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1. INTRODUCTION

DNA intercalation of metal complexes is currently one of the most studied processes in chemotherapy treatments for cancer.1,2 In particular, the antitumoral activity of 1,10phenanthroline (phen) complexes has been proved recently in our group3 and several reviews about intercalation of flat ligands between DNA base pairs (bps) have been published in the last years.2,4,5 This topic about the interaction of phen with DNA is of current interest after the recent review of Viganor et al.6 in which they highlight the use of phen derivatives as a potential alternative therapeutics in the Era of Antibiotic Resistance. Moreover, quite recent determinations of crystal structures7-10 evidenced that intercalation may occur through the Minor Groove, which is opposite to the classic opinion that intercalation is easier at the Major Groove, because it is supposed that the strain in the structure will be less. Theoretical studies were also published in the last years on the intercalation of phen, 2,2’-bipyridine (bipy) and dppz in DNA structure.11-15 The structural understanding of the interactions of intercalators with DNA results of interest due to the wide range of medical applications16 and insights on how the functional groups in different number and different position modulate the activity of such drugs and stablish differences in the biological activity results crucial for a rational and efficient drug design. This is the case of the cytotoxic assays performed by Brodie et al.17 where methylation of phen in the [Pt(en)(phen)]Cl2 complex in different number and different position led to very different biological activities. Indeed, for the considered methylated intercalating ligands (see Scheme 1), only 5,6-Me2phen and 5-Mephen had remarkable activity against the L1210 mouse leukemia cell line.17 The authors concluded that the activity of the structures measured by IC50 (concentration of the compound required to induce 50% inhibition of cell growth) can be modulated from ~2 to more than 50 μM by changing the position and number of methyl groups of the intercalating ligand. Nevertheless, although the biological


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properties of many intercalators have been studied, the intrinsic relationship between molecular structure and cytotoxicity has yet to be elucidated.

Scheme 1. Intercalation mechanism of phen, and its derivatives, between GC/CG bps via Minor Groove. The lower GC pair is transparent, and upper CG pair is in solid color. In this work we present a computational study of the intercalation of methylated phen taking into account different positions and numbers of methyl groups (see Scheme 1). Geometries, energies, bond properties and weak interactions are discussed in terms of the Energy Decomposition Analysis (EDA), Quantum Theory of Atoms in Molecules (QTAIM) and Non-Covalent Interaction (NCI) index. We also relate our results for the intercalation through the Minor Groove to the experimental evidences on cytotoxicity reported by Brodie et al.17 by using the same methylated intercalating ligands.


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2. COMPUTATIONAL DETAILS

In this work we consider the so-called ring models18 to study the intercalation process. For the construction of the models, the 2ROU crystal structure from the Protein Data Bank (PDB) was used. We saturated the N2 of guanine after removing the ligand intercalated and bonded between GC/CG, the 1R-trans-anti-benzo[c]phenantrene. We also removed the rest of DNA sequence keeping only the intercalation pocket (bps, phosphates and sugars) and we put hydrogens in all the four oxygens that limited the phosphate backbone. We put manually the intercalator (phen and phen derivatives) between base pairs keeping the equidistance and maximum overlap to reproduce the intercalation through the Minor Groove. Na+ atoms were added to neutralize the negative charge of phosphates. Because of the size and nature of the studied systems, full geometry optimizations were carried out by means of the semi-empirical Hamiltonian PM6-DH219 which includes dispersion corrections and yields satisfactory results in stacked systems where non-covalent interactions play an important role.19,20 Moreover, PM6-DH2 was also successfully tested optimizing the 1BNA structure from PDB and comparing several geometric parameters of the optimized structure with the original PDB structure (see Figure S15 and Table S1 of the Supporting Information). All PM6DH2 optimizations were carried out with MOPAC2016 software21 without any constrain. The electron density was explored with QTAIM22 by using AIMALL software.23 This software was also used to calculate the Non-Convalent Interactions index based on the peaks that appear in


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the reduced density gradient at low density values, which is mapped with the second value of the Hessian.24 The EDA25,26 was performed to calculate the contribution of the different energy terms to the interaction energy between the two fragments: 1) the intercalator and 2) the surrounding structure formed by the DNA bps, sugars, phosphates and ions. In such analysis the interaction energy, ΔEint, is split into different contributions associated to orbital (ΔEorb), Pauli (ΔEPauli) and electrostatic (ΔEelstat) terms, following the Morokuma-type energy decomposition method.25,26 ADF software2729

was used to carry out the EDA in which single-point calculations were performed by using the

B3LYP-D3 functional with the explicit Grimme’s D3 correction to include dispersion forces30-33 and the uncontracted polarized triple-ζ basis set of Slater-type orbitals (TZP). The importance of solvent effects for this kind of systems including phen derivatives and bps was already seen in a previous work34 and solvent effects were taken into account with the continuous solvent model COSMO.35 Finally, because in previous works on the intercalation of phen derivatives36,37 we obtained low values for the Basis Set Superposition Error (BSSE), 8~12% was reported, BSSE was not taken into account in the present study.

3. RESULTS AND DISCUSSION

First, the QTAIM topological analysis of the electron density (ρ) is provided. The electron density at bond critical points (BCPs) describes the strength of the bond between two bonded atoms and the electron-energy density (Ed) describes the stability of the chemical bond, being the values close to zero a characteristic for weak interactions. Table 1 summarizes the total number of π-π, CH-H,


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CH-π, CH-n, Me-H, Me-π and Me-n BCPs for the considered intercalators and as a general trend the presence of methyl groups increases the number of weak interactions. Figure 1 shows the topological analysis of electron density for three selected structures intercalating via Minor Groove (see Supporting Information for the rest of the structures). Only the weak interactions between the intercalator and DNA structure are represented in order to show a clearer picture. For all structures, several BCPs associated to weak π-π interactions were found between the intercalator and bps, represented by the corresponding BCPs. To present a clear image, such interactions are represented in the blue box only for non-methylated structure (Figure 1 A). Several interactions between DNA structure and H atoms from the aromatic rings were also found: CH-nsugar, CH-πbase and CH-Hsugar (some of them depicted in green boxes). These last H•••H interactions for nearby hydrogen atoms were already corroborated for several structures at different level of theory.38-41 The presence of the methyl group in positions 5 and 6 (Figure 1 B) yields 6 Me-π weak interactions (depicted in red boxes and red dotted lines), two of them with the O atoms of the bps present a high value of ρ (0.012 au). The methylation in positions 3, 4, 7 and 8 yields several Me-n interactions with sugars while the Me-π interactions have been reduced and weakened (ρ=0.001, 0.004 and 0.008 au), see Figure 1 C.


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Table 1. Number of BCPs found for weak interactions between intercalators and DNA structure.

π-πbase

CH-πbase

CH-Hsug

CH-n Osug

Me-Hsug

Me-n Osug

Me-πbase

Tot. BCPs

Phen

13

2

3

2

-

-

-

20

4-Mephen

14

2

3

2

-

-

3

24

5-Mephen

10

1

2

2

-

-

4

19

4,7-Me2phen

12

1

4

2

1

-

4

24

5,6-Me2phen

10

-

4

2

-

-

6

22

3,4,7,8-Me4phen

14

1

1

2

4

4

6

32


8

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Figure 1. Bonding scheme from QTAIM topological analysis of the electron density for phen, 5,6Me2phen, and 3,4,7,8-Me4phen, intercalated between GC/CG bps via minor groove. Dotted lines represent the bond paths with the corresponding Bond Critical Point (BCP) for weak interactions between the intercalator and the bps of DNA (π-π, CH-H CH-π, CH-n, Me-H, Me-π, and Me-n). The bond distances are presented for the considered interactions in Å along with ρ in au and the Ed also in au for the corresponding BCPs.

Further analysis of the weak interactions between the intercalator and DNA structure is provided by NCI index.24 Figure 2 shows the NCI analysis computed for the Intercalator-DNA structure for phen, 5,6-Me2phen, and 3,4,7,8-Me4phen when intercalating via Minor Groove (see Supporting Information for the remaining systems). Blue and pale green indicate negative values, which implies stabilizing interaction, while yellow and red indicate positive and destabilizing interaction. For the phen intercalation (Figure 2 A), it is noteworthy the agreement between NCI and QTAIM analyses, in the interplanar region between bps and intercalator the BCPs zones correspond with the most stabilized regions (zones depicted in cyan). In addition, the presence of H•••H interaction is also corroborated with negative values for the NCI index (positions 3 and 8). For 5,6-Me2phen (Figure 2B), it is shown that the presence of methyl groups increase the regions of stabilizing interaction between intercalator and bps around Me, two of these Me-π interactions with the O atoms of the bps present a lenticular isosurface depicted in blue with a considerable negative value (see Figure 2B). On the other hand, the 3,4,7,8-Me4phen yields more interactions with the sugarphosphate chains combining positive and negative values, indicating stabilizing and destabilizing areas around the methyl groups in positions 3 and 8, while the methyl group in 4 and 7 present one


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interaction with a nearby base (Figure 2 C). For 4-Mephen and 5-Mephen interactions between Me and N and O atoms of the bps are also present, together with the aforementioned H•••H interactions. On the other hand, for 4,7-Me2phen the two Me groups interact only with the C or N atoms of the bps being more closely to the sugar chains and presenting the corresponding H•••H interactions (see Supporting Information).


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A) 3

9 4

8

B)

6

5

C)

3 8

-0.02

4

7

0

+0.02

Figure 2. NCI index plots with gradient isosurfaces (s=0.5 a.u.) computed for the optimized structures for A) phen, B) 5,6-Me2phen, and C) 3,4,7,8-Me4phen intercalators between GC/CG bps.


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The interaction energy ΔEint between fragments can be decomposed into the following contributions: The electrostatic contribution (ΔEelstat), the charge transfer and polarization terms (ΔEorb), the dispersion contribution as explicit correction term (ΔEdisp), and the destabilizing interactions between occupied orbitals (ΔEPauli). ΔEint = ΔEelstat + ΔEorb + ΔEdisp + ΔEPauli Figure 3 shows the contributions of the EDA for the intercalation through the minor groove for all the intercalators. In general, the implementation of -CH3 groups increases the attractive terms, being the ΔEorb the lower contribution to stabilizing energies. It is noteworthy the importance of ΔEdisp for the attractive interaction (from -52.3 to -62.8 kcal mol-1) but this stabilization needs the smaller contributions of ΔEorb and specially ΔEelstat to balance the repulsive effect of ΔEPauli contribution in agreement with our previous results for phen and methylated and oxygenated derivatives.34,36,37 Such repulsion results significantly important for the 3,4,7,8-Me4phen intercalator, reaching a value of 106 kcal mol-1. From the numbers of the EDA it is concluded that it is more important the position of the methyl group, that yields effective weak interactions, than the number of substitutions. Indeed, the 5,6-Me2phen is the most stabilized ligand (more than 3,4,7,8-Me4phen) and negative values for NCI surfaces appear between Me groups and O and N atoms of the bps. Moreover, blue areas appear for CH-n interactions with the sugars for H in positions 3 and 8 (see Figure 2B). This situation is also presented for 5-Mephen where the methyl shows stabilizing interactions with N and O atoms of the bps (see supporting information, Figure S6). In addition, the repulsive effects for 5-Mephen have the lowest value (77,7 kcal/mol). These results are in agreement with the experimental works of Brodie et al.17 where 5-Mephen and 5,6-


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Me2phen present cytotoxic activity. On the other hand, Brodie et al. reported no cytotoxicity for 4-Mephen and 4,7-Me2phen. For these substitutions, the authors suggested from viscosity experiments that the mode of binding is concentration dependent and the intercalation appears only at high concentrations. At lower concentrations another mode of interaction appears which could be groove binding because the authors stated that the increase in viscosity is almost negligible for these two ligands and it is known from the bibliography that the groove binder Hoechst 33258 also does not alter the relative viscosity because it does not cause any increase in the axial length of the DNA.42,43 The high value of ΔEPauli for 3,4,7,8-Me4phen can be explained attending to the geometrical results for the whole structure, where the implementation of the four -CH3 groups (two of them close to the chain formed by the sugars and phosphates) yields a Roll distortion44,45 of the DNA structure (Figure 4). This roll motion is specially produced by the methylation in positions 3 and 8. To verify it we also studied the systems 3,5,6,8-Me4phen and 3,8-Me2phen and we see that not only the roll motion is produced for these two additional systems but also the behavior in the EDA, QTAIM and NCI analysis is similar to that of the 3,4,7,8-Me4phen ligand (see Supporting Information). At this point we also analyzed the behavior of the 4,5,6,7-Me4phen ligand to verify that the position of the substitution is more important than the number of substitutions and for this 4,5,6,7-Me4phen ligand without substitution in positions 3 and 8 we did not obtained any roll motion. Moreover, the EDA, QTAIM and NCI analyses for this last ligand (see Supporting Information) are more similar to those of the disubstituted 5,6-Me2phen ligand than to those of the tetrasubstituted 3,4,7,8-Me4phen ligand, which is in agreement with our statement that more than the number of substitutions it is the position of the substitution who rules the stabilization of the intercalation.


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ΔEint = ΔEelstat + ΔEorb + ΔEdisp + ΔEPauli -21.1

-30.6

-18.7

-52.3

+80.6

-24.2

-33.5

-19.2

-55.6

+84.2

-28.2

-34.5

-17.0

-54.4

+77.7

-24.3

-32.8

-20.9

-57.2

+86.6

-33.9

-38.8

-17.5

-60.7

+83.1

-22.5

-41.0

-24.8

-62.8

+106.1

phen 4-Mephen 5-Mephen 4,7-Me2phen 5,6-Me2phen

3,4,7,8-Me4phen

Figure 3. Cumulative bar diagram for the energy (kcal mol-1) contributions in the EDA computed at B3LYP-D3/TZP theoretical level.

α

α

α

3,7

5,9

A) phen

aaa

B) 5,6-Me2phen

33,3

C) 3,4,7,8-Me4phen

Figure 4. Side view for the selected intercalated systems. A) phen, B) 5,6-Me2phen, and C) 3,4,7,8-Me4phen intercalators between GC/CG bps.


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To gain insight about the effect of the solvent in the process, the contribution of the desolvation penalty is added to the total interaction energy in Table 2. We observe that the 5-Mephen and 5,6Me2phen remain the most stabilized structures after the intercalation between the bps with -28.2 and -33.9 kcal mol-1, respectively.

Table 2. Contributions of the solvation energies for the (GC/X/CG) systems intercalated through the Minor Groove at B3LYP-D3/TZP level. Energies in kcal mol-1.

phen

4- Mephen

5- Mephen

4,7- Me2phen

5,6-Me2phen

3,4,7,8-Me4phen

Esolv(Total System)

-123.6

-121.0

-120.2

-121.9

-119.7

-123.4

Esolv(Intercalator)

-15.6

-16.8

-15.6

-17.6

-16.1

-18.2

Esolv(Pocket)

-116.6

-115.3

-115.8

-115.5

-115.8

-121.0

8.6

11.1

11.2

11.2

12.2

15.8

-12.5

-13.1

-17.0

-13.1

-21.7

-6.7

ΔESolva) ΔEint + ΔESolv a)

ESolv = ESolv(Total System) – ESolv(Intercalator) – ESolv(Pocket)

Thus, the experimental results found in bibliography about cytotoxicity against cancer cell growth can be explained with the results of the EDA along with the desolvation penalty and those obtained from the analysis of the electron density. In this experimental work Brodie et al.17 found that 5,6Me2phen was the most effective system followed by 5-Mephen and we have shown the importance of solvent effects, the steric contribution and the presence of effective number of CH-H, CH-n CHπ interactions from aromatic structure and methyl groups to explain the experimental results.


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The system with more CH-H, CH-n and CH-π interactions is 3,4,7,8-Me4phen, but this structure present the highest solvation energy penalty (see Table 2) and the highest steric repulsion (mainly produced by the Me groups located in positions 3 and 8, close to the chain formed by sugars and phosphates). For this structure, attending to NCI analysis, Figure 2C, we can see the zones of repulsive interactions (red) combined with zones of attractive interaction (blue) between Me groups (in 3 and 8 positions) and the sugar chains. In consequence this intercalation is the less favorable and this structure presents the lowest cytotoxic effects reported in the work of Brodie et al.17 On the other hand, 5,6-Me2phen, which presents the most favorable intercalation, with a considerable number of CH-n and CH-π interactions shows the best balance between repulsive and attractive contributions, see Figure 3. Moreover, even considering the desolvation penalty it remains as the most stable system. In addition, considering the results from the analysis of the topology of  for this structure, stable interactions for each -CH3 group with the nearby O and N atoms of the bps appear in the NCI isosurfaces and in the case of the interaction with the O atom a considerable negative value represented by a blue lenticular isosurface (Figure 2B) is shown. Also from the analysis of BCPs, this interaction with the O atom has a significantly high value for ρ (Figure 1B). Moreover, in positions 3 and 8, the H atom of the aromatic ring interacts with the sugars with significantly negative values for NCI isosurface (Figure 1B and Figure 2B) these stabilizing interactions without a bulky groups close to sugar chains, together with the π-π and the Me-π interactions make the 5,6-Me2phen the most stable intercalator. The same happens for 5Mephen (see Supporting Information). In consequence, the methylation in 5 and 6 positions yields the most cytotoxic structures in agreement with the experimental results reported by Brodie et al.17 On the other hand, for the 4-Mephen and 4,7-Me2phen Brodie et al. already pointed that the


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intercalation requires high concentrations due to the preference of another mode of interaction, which could be groove binding, for these two compounds.

4. CONCLUSIONS

In conclusion, the number of -CH3 groups in phen structure favors the cytotoxicity but the position has to be selected in order to minimize the steric repulsion, being the zones close to the chains the most unfavorable positions, while the methylation in 5 and 6 position yields favorable weak interactions with nearby O and N atoms, without counterproductive steric effects for the intercalation. The solvent effects have an important role in the process of stabilization of the intercalator between bps. Therefore, our computational results are in agreement with the hypothesis of Brodie et al. who said that the position of the substituent methyl groups and/or the number of methyl groups may determine the differences in biological activity. Our present work provides comprehension and rationalization to understand the chemical reasons that confirms such hypothesis.

ASSOCIATED CONTENT Supporting Information contains the QTAIM topologies and NCI analyses for all the studied systems phen, 4-Mephen, 5-Mephen, 4,7-Me2phen, 5,6-Me2phen, 3,4,7,8-Me4phen, 3,5,6,8Me4phen, 4,5,6,7-Me4phen and 3,8-Me2phen when intercalating through the Minor Groove, the definition of Roll distortion along with figures showing it for the studied systems, the EDAs for


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3,5,6,8-Me4phen, 4,5,6,7-Me4phen and 3,8-Me2phen systems, a table comparing characteristic geometrical parameters of the original 1BNA PDB structure and the PM6-DH2 optimized 1BNA structure, a figure with the superposition of both structures including the RMSD and the cartesian coordinates of all the optimized studied structures.

AUTHOR INFORMATION Corresponding Author Adrià Gil* Email: [email protected]; [email protected] Notes The authors declare no competing financial interests.

ACKNOWLEDGMENTS This research was financially supported by the Fundação para a Ciência e a Tecnologia (FCT) by means of the project PTDC/QUI-QFI/29236/2017 and by the Spanish Ministry of Economy, Industry and Competitiveness under the Maria de Maeztu Units of Excellence Programme – MDM-2016-0618. A. G. is thankful to Diputación de Gipuzkoa for current funding in the frame of Gipuzkoa Fellows Program. A. G. is also grateful to Prof. Maria José Calhorda for fruitful discussions in this work and for the years he spent in Prof. Calhorda’s lab.

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