Adsorption of Chiral [5]-Aza[5]helicenes on DNA Can Modify Its Hydrophilicity and Affect Its Chiral Architecture: A Molecular Dynamics Study

Abstract

Helicenes are interesting chiral molecules without asymmetric carbon atoms but with intrinsic chirality. Functionalized 5-Aza[5]helicenes can form non-covalent complexes with anticancer drugs and therefore be potential carriers. The paper highlights the different structural selectivity for DNA binding for two enantiopure compounds and the influence of concentration on their adsorption and self-aggregation process. In this theoretical study based on atomistic molecular dynamics simulations the interaction between (M)- and (P)-5-Aza[5]helicenes with double helix B-DNA is investigated. At first the interaction of single pure enantiomer with DNA is studied, in order to find the preferred site of interaction at the major or minor groove. Afterwards, the interaction of the enantiomers at different concentrations was investigated considering both competitive adsorption on DNA and possible helicenes self-aggregation. Therefore, racemic mixtures were studied. The helicenes studied are able to bind DNA modulating or locally modifying its hydrophilic surface into hydrophobic after adsorption of the first helicene layer partially covering the negative charge of DNA at high concentration. The (P)-enantiomer shows a preferential binding affinity of DNA helical structure even during competitive adsorption in the racemic mixtures. These DNA/helicenes non-covalent complexes exhibit a more hydrophobic exposed surface and after self-aggregation a partially hidden DNA chiral architecture to the biological environment.

Synthesis of Aza[n]helicenes (n = 4–7) via Photocyclodehydrochlorination of 1-Chloro-N-aryl-2-naphthamides

“…Azahelicenes as electron-deficient aromatics possess modified physicochemical properties compared to the parent helicenes. The potential applications of azahelicenes range from fluorescent dyes, photoinitiators, ligands for coordination chemistry, , and asymmetric catalysts − to DNA intercalators. , The nanostructured thin films based on azahelicenes are currently studied by material scientists as unique photo- and electroactive materials . Moreover, azahelicenes, as inherently chiral molecules, can be easily resolved into individual enantiomers, which opens space for research on their chiroptical properties .…”

“…Chloro-N-(2-naphthyl)benzamide (2a). GP1 was followed with 2-chlorobenzamide (1) (100 mg, 0.64 mmol), 2-bromonaphthalene (133 mg, 0.64 mmol), Pd(dba) 2(15 mg, 26 μmol), Xantphos (22 mg, 38 μmol), and Cs 2 CO 3 (293 mg, 0.90 mmol). The crude product was purified by column chromatography (8:1 PE/EA) to provide 2a (112 mg, 62%) as a white powder.…”

Adsorption and Self-Aggregation of Chiral [5]-Aza[6]helicenes on DNA Architecture: A Molecular Dynamics Study

“…For the two different MD simulations considering two different enantiomers, the values of potential energy and van der Waals contributions reported in Figure (central panel in Figure ) displayed different kinetics of the adsorption process, which were faster for the ( M )-6H enantiomer. It should be highlighted that for the same helicenes, i.e., ( M )-5H and ( M )-5H, the kinetics of the adsorption process were very similar, still emphasizing how another aromatic ring in the helicene structure affects the kinetics of the adsorption process on DNA.…”

“…Furthermore, thanks to π−π interactions, helicene molecules self-aggregate on the DNA structure, forming aggregates with an ordered arrangement of aromatic rings in minor or major grooves, as has been conducted in previous work. 30 In the following sections, the theoretical results on the interaction between DNA and (M)-6H and (P)-6H molecules are reported. The aim of this work is to understand how the chiral surface exposed by minor grooves and major grooves can affect the arrangement of adsorbed molecules or layers of helicenes or self-aggregates attached on the outer DNA surface.…”

“…1 Stoichiometry: Importance of Chiral Structure. Initially, using a simulation protocol proposed in a previous study, 30 the interaction between the minor and major grooves of doublestranded DNA and both (M)-5-aza [6]helicene and (M)-5aza [6]helicene enantiomers are studied. The two initial geometries are similar to those reported in Figure S1 of a previous study on [5]helicenes.…”