Effects of oxygenation on the intercalation of 1,10-phenanthroline-5,6/4,7-dione between DNA base pairs: a computational study

Abstract

The effects of oxygen in positions 4,7 and 5,6 of phenanthroline when this ligand intercalates between guanine-cytosine and adenine-thymine DNA base pairs (GC/CG and AT/TA) have been studied at the M06-2X/6-31+G(d,p) level of calculation. We focused on the changes in the structure, stabilization and energy contributions in the analysis of the interaction. The obtained trends in stabilization are explained by a model including repulsive Pauli (ΔE) contributions, and attractive dispersion (ΔE), orbital (ΔE) and electrostatic (ΔE) contributions to energy. When no solvation is considered, the intrinsic ΔE contribution results are crucial for the stabilization of the system. However, the inclusion of the solvation energy ΔE can reverse the final stability trend of the systems becoming, thus, the driving force of the process. Therefore, the solvent will have a relevant influence in the potential cytotoxicity of the intercalation drugs.

Elucidating the intercalation of methylated 1,10-phenanthroline with DNA: the important weight of the CH/H interactions and the selectivity of CH/π and CH/n interactions

“…1,3,4 Some theoretical studies have been carried out considering at ligands like 1,10-phenanthroline (phen) derivatives, 2,2 0 -bipyridine (bipy) and dipyridophenazine (dppz) by several authors [5][6][7][8][9] and also in our group. [10][11][12][13][14] On the other hand, the cytotoxic activity of metal complexes containing phen has been also proven experimentally by our collaborators. 15 In addition, the interest of phen derivatives for medical applications has been increased with its potential applications as alternative treatments against antibiotic resistant bacteria.…”

“…[42][43][44][45] The solvent effects have been included with the COSMO solvent approach 46 because the relevance of solvation in these biological systems has been reported previously. 12 The Basis Set Superposition Error (BSSE) was not considered due to the fact that in previous works, 10,11 where the intercalation of phen derivatives between DNA bps was already studied, the error was only 8-12%.…”

New Insights on the Interaction of Phenanthroline Based Ligands and Metal Complexes and Polyoxometalates with Duplex DNA and G-Quadruplexes

“…Refs. [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 46 , 47 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 ] Thus, our main goal has been to understand, at a fundamental level, the interaction of phen derivatives with dDNA and how the substitution by means of different functional groups can modulate their interaction, efficiency as intercalators, and their cytotoxicity. Small molecules, including phen derivatives and dDNA, can interact in different modes [ 15 ] (see Figure 1 ): Cross-link interactions occur when the molecule reacts with DNA by forming covalent bonds between two nucleotides [ 111 , 112 ] and the small molecule is placed mainly in the major groove.…”

“…Refs. [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 46 , 67 , 113 ] In the case of phen derivatives, substitution by different functional groups may increase or decrease the strength of the intercalation between bps. X-H··Y, CH/π, CH/n, H···H bonds or other weak interactions, not only with the bps but also with the sugar and phosphate backbone, may stabilize intercalation of phen derivatives (as we recently demonstrated).…”

“…Refs. [ 38 , 39 , 40 , 41 , 42 , 46 , 47 , 114 ] Moreover, the use of QTAIM and NCI analyses provides a very detailed view of the weak interactions between atoms that rule the cytotoxic effects of the small molecules when interacting with DNA.…”