Molecular recognition between DNA and a copper-based anticancer complex

Abstract

The aim of this work is to describe the specific recognition site between DNA and an anticancer copper complex by means of computational methods. Molecular dynamics were used to find the preferred site of binding between selected DNA chains and [Cu(2,2'-bipyridine)(acetylacetonate)(H(2)O)](+) (Cas). Full DFT optimizations of selected geometries extracted from simulations, followed by a topological analysis of electron density allowed us to define the specific interactions inside the recognition site. Cas links deoxyribose-phosphate by a coordination bond between metal and the phosphate group. There are several C-H···π, O···π(C) and O···π(N) interactions between the sugar group and the aromatic ligand of Cas. The results indicate that the adduct Cas-deoxyribose-phosphate may be an initial step toward the hydrolysis of DNA chains. Overall, this study provides insights into the initial step of the action mechanism of copper complexes as apoptosis-inducing agents and provides guidelines for the design of this kind of drugs.

Synthesis, structural characterization and cytotoxic activity of ternary copper(II)–dipeptide–phenanthroline complexes. A step towards the development of new copper compounds for the treatment of cancer

“…Their Kb values are lower than that of the classical intercalator ethidium bromide (1.4 × 10 6 ) [35], and similar or higher than that of the Cu-phen complex ([Cu 2 (phen) 2 Cl 4 ], Kb of 4.75 × 10 4 M −1 [36]) and are in agreement with an interaction trough groove binding and partial intercalation, which may occur trough partial intercalation of phen moiety and of the phenyl ring of the Phe-containing dipeptides. A similar case of partial intercalation has been proposed recently for a related complex with bipy ([Cu(2,2′-bipyridine)(acetylacetonate)(H 2 O)] + ) by computational studies [37].…”

Pharmacological Importance of Simple Phenolic Compounds on Inflammation, Cell Proliferation and Apoptosis with a Special Reference to β-D-Salicin and Hydroxybenzoic Acid

“…Research indicated DNA-binding drugs exert their effects in an ion-dependent manner as the binding of metal ion complexes occur at specific sites on the DNA. For example, Mg2+ or Zn 2 + complexes preferentially bind to specific sites in DNA (20) .…”

Isomeric Effect on the Pharmacokinetic Behavior of Anticancer CuII Mixed Chelate Complexes: Experimental and Theoretical Approach

“…The DFT level of theory has previously been proven to adequately reproduce experimental structures. [19,20,40] For each complex a wavefunction file was obtained after a single point energy calculation at the same theoretical level. From these files, local and integrated properties were calculated by using the atomic definition of the Quantum Theory of Atoms in Molecules [41] in the AIM-ALL program.…”

“…The bond lengths, angles, and dihedral angles were calculated by using the parmcal program available in the AmberTools suit of programs and previously described. [19] To assess the interactions of the two copper compounds with a bilayer membrane, MD simulations were run with the compounds at two different starting positions (see Figure S1a,b in the Supporting Information). Each compound was manually positioned at either the surface of the membrane or inserted into the geometric center of mass (COM) of the entire membrane system.…”

“…Evidence has been provided for the molecular mechanism implicated in the inhibition of tumor cell proliferation that involves the generation of reactive oxygen species, a decrease in intracellular glutathione, and the direct interaction with nucleic acids triggering independently or cooperatively apoptotic cell death pathways. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] A quantitative structure-activity relationship (QSAR) study developed with compounds of general formulae [Cu(N-N)(acetylacetonato)]NO 3 and [Cu(N-N)(glycinato)]NO 3 showed that the presence of a third aromatic ring in the molecular structure as well as a higher energy employed to produce the Cu II /Cu I transformation increase their cell growth inhibition capacity in the evaluated human tumor cell lines, which indicates that an increase of the size of the aromatic system and of the redox potential are the two main descriptors of biological activity. [8] On the basis of this study, our research group selected 10 molecules with some of the highest antiproliferative activities and different distribution coefficients (log D) for further study (Table 1).…”