Abstract
The anticancer study of nitrogen-chelating ligands can be of tremendous help in choosing ligands for the anticancer metal complexes design especially with ruthenium(II). The inhibitory anticancer activities of some nitrogen-chelating ligands containing bis-pyrazole, bipyridine, and phenanthroline were studied using experimental screening against cancer cell and theoretical docking methods. In vitro anticancer activities showed compound 11 as the most promising inhibitor, and the computational docking further indicates its strong inhibitory activities towards some cancer-related receptors. Among the twenty-one modelled ligands, pyrazole-based compounds 7, 11, and 15 are the most promising inhibitors against the selected receptors followed by 18 and 21 which are derivatives of pyridine and phenanthroline, respectively. The presence of the carboxylic unit in the top five ligands that displayed stronger inhibitory activities against the selected receptors is an indication that the formation of noncovalent interactions such as hydrogen bonding and a strong electron-withdrawing group in these compounds are very important for their receptor interactions. The thermodynamic properties, the polarizabilities, and the LUMO energy of the compounds are in the same patterns as the observed inhibitory activities.
Highlights
E selected receptors used for the docking studies are carbonic anhydrase II (CA-II), cathepsins B (Cat B) [24], two different DNAs (DNA-1 [25] and DNA-2), DNA gyrase (Gyrase) [26], histone deacetylase7 (HDAC7) [27], histone protein in the nucleosome core particle (HIS) [28], BRAF kinase (Kinase) [29], recombinant human albumin [30], ribonucleotide reductase (RNR) [31], topoisomerase II (Top II) [32], thioredoxin reductase (TrxR) [33], and thymidylate synthase (TS) [34]. ese receptors play significant roles in cancer growth and are a unique target in cancer therapy
4.1. e Binding Site Predictions of the Compound from the Docking Methods. e results obtained from the different docking methods and packages: Molegro-QC, Molegro, Vina, AutoDock-QC, and AutoDock, are shown in Figure 2. e features of the interactions of the ligands with the receptors using different docking methods are similar
In most of the receptors, the same binding sites were located by docking methods, and very similar conformational orientations of the ligands in the binding sites were predicted with some found to overlap each other (Figure 2)
Summary
Nitrogen-chelating ligands such as bis-pyrazole (pz), bipyridine (bpyr), and phenanthroline (phn) derivatives are being used in the design of several metal complexes for ranges of applications from biological to nanostructured materials, especially the development of anticancer complexes of ruthenium [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19]. Other studies have shown that these nitrogen-chelating compounds play significant roles in the experimentally observed anticancer activities [20] that might be ascribed to the electronic interactions between the metal centre and the π-electrons in rings [21,22,23]. Despite the use of these nitrogen-chelating ligands in the design of anticancer metal complexes, there has been very few or no attention on the anticancer activities of these ligands individually. To this end, we have selected some derivatives of common nitrogen-chelating ligands as shown in Figure 1 to study their individual anticancer activities with particular focus on their interactions with cancer-related receptors using various docking methods. RHA plays a significant role in the pharmacokinetic availability, bioavailability, and toxicology
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