Novel 3,9-Disubstituted Acridines with Strong Inhibition Activity against Topoisomerase I: Synthesis, Biological Evaluation and Molecular Docking Study.

A series of novel 3,9-disubstituted acridines were synthesized and their biological potential was investigated. The synthetic plan consists of eight reaction steps, which produce the final products, derivatives -, in a moderate yield. The principles of cheminformatics and computational chemistry were applied in order to study the relationship between the physicochemical properties of the 3,9-disubstituted acridines and their biological activity at a cellular and molecular level. The selected 3,9-disubstituted acridine derivatives were studied in the presence of DNA using spectroscopic (UV-Vis, circular dichroism, and thermal denaturation) and electrophoretic (nuclease activity, relaxation and unwinding assays for topoisomerase I and decatenation assay for topoisomerase IIα) methods. Binding constants (2.81-9.03 × 10 M) were calculated for the derivatives from the results of the absorption titration spectra. The derivatives were found to have caused the inhibition of both topoisomerase I and topoisomerase IIα. Molecular docking simulations suggested a different way in which the acridines - can interact with topoisomerase I versus topoisomerase IIα. A strong correlation between the lipophilicity of the derivatives and their ability to stabilize the intercalation complex was identified for all of the studied agents. Acridines - were also subjected to in vitro screening conducted by the Developmental Therapeutic Program of the National Cancer Institute (NCI) against a panel of 60 cancer cell lines. The strongest biological activity was displayed by aniline acridine (MCF7-GI 18.6 nM) and ,-dimethylaniline acridine (SR-GI 38.0 nM). The relationship between the cytostatic activity of the most active substances (derivatives , , and -) and their values of , Log, Δ°, and δ was also investigated. Due to the fact that a significant correlation was only found in the case of charge density, δ, it is possible to assume that the cytostatic effect might be dependent upon the structural specificity of the acridine derivatives.