Abstract
Herein we report the synthesis and structural elucidation of two novel imine-based ligands, 2-(1,10-phenanthrolin-5-yl)imino)methyl)-5-bromophenol (PIB) and N-(1,10-phenanthrolin-5-yl)-1-(thiophen-3-yl)methanimine (PTM) ligands. An in vitro cytotoxicity assay of the synthesized molecules was carried out against breast, cervical, colorectal, and prostate cancer cell lines as well as immortalized human keratinocytes. The observations indicated that both the molecules possesses dose-dependent selective cytotoxicity of cancer cells with no detrimental effect on the normal cell lines. Furthermore, the detailed computational analysis of newly synthetized ligands (PIB and PTM) has been conducted in order to identify their most important parts from the perspective of local reactivity. The IC50 values of PIB treatment on MCF-7, HeLa, HCT-116 and PC-3 were 15.10, 16.25, 17.88, 17.55 and 23.86 micromoles, respectively. Meanwhile, the IC50 values of PTM on MCF-7, HeLa, HCT-116, PC-3 and HaCat were observed to be 14.82, 15.03, 17.88, 17.28 and 21.22 micromoles, respectively. For computational analysis, we have employed the combination of Density Functional Theory (DFT) calculations and MD simulations. DFT calculations provided us with information about structure and reactivity descriptors based on the electron distribution. Surfaces of molecular electrostatic potential (MEP) and averaged local ionization energy (ALIE) indicated the sites within studied molecules that are most reactive. These results indicated the importance of nitrogen atoms and OH group. Additionally, the values of bond dissociation for hydrogen abstraction showed that both molecules, especially the PTM, are stable toward the influence of autoxidation mechanism. On the other side, MD simulations gave us an insight how ligands interact with water molecules. Namely, the radial distribution functions (RDF) indicated that the hydrogen atom of the OH group in the case of the PIB has the most pronounced interactions with water.
Highlights
Nitrogen-containing ligands are constantly gaining attention of chemists due to their stable chelating property [1]
To identify the most important atoms from the perspective of interactions with water molecules, we used the concept of radial distribution functions (RDF), which provide the information about the probability density of finding a water molecule with respect to the distance between atoms
To identify the most important atoms from the perspective of interactions with water molecules, we used the concept of radial distribution functions (RDF), which provide the information about the probability density of finding a water molecule with respect to the distance between atoms of considered molecules
Summary
Nitrogen-containing ligands are constantly gaining attention of chemists due to their stable chelating property [1] These types of molecular entities find wide array of applications [2,3]. It is noteworthy that phenanthroline derivatives are of exceptional scientific interest owing to their biomedical significance, with established tumoricidal and antimicrobial activities [6] Imines, such as Ketamine, azomethine and aldamine, have demonstrated significant anti-proliferative properties so that they have been considered potent clinical candidates for the treatment of cancer [7]. A metal-mediated coordination compound containing 1,10-phenanthroline ligand complexes were reported to show potent DNA binding and anti-cancer activity in human laryngeal carcinoma (Hep-2) cells [10]. It may be deemed imperative to understand the cytotoxic behavior of the phenanthroline derivatives across different types of cancer as well as normal cell lines along with validation of the mechanistic route in an attempt to identify potent phenanthroline derived drug candidates to qualify for in vivo and pre-clinical evaluation
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