Abstract

In recent years, new promising acridine derivatives have appeared, belonging to the unsymmetrical bisacridines (UAs) family with high anticancer activity. Both their physicochemical properties and their mechanism of action at the molecular level have not been thoroughly analyzed so far. Four derivatives were selected for the study, termed as: C-2028, C-2041, C-2045 and C-2053. The first aim of this work was to determine the protonation forms in which the studied compounds exist at different pH. The second aim was the analysis of aggregation process at different conditions. Methods such as UV-Vis and NMR spectroscopy were used for this purpose. The obtained spectral data were subjected to a thorough chemometric analysis, using techniques such as principal components analysis, multiple regression and numerical optimization. Previous studies have shown that a potential molecular target for unsymmetrical bisacridines may be the promoter sequence of the C-Myc proto-oncogene, known as Pu22. Next goal of the presented work was to determine the interactions of the studied compounds with the above mentioned sequence using advanced NMR spectroscopy and molecular dynamics methods. These studies were narrowed down to the two most promising derivatives: C-2045 and C-2053. In order to determine the exact molecular structure of the obtained complexes, a series of one- and two-dimensional NMR spectra of both investigated compounds and their monomeric derivatives (C-1311 and C-1748) were recorded, which allowed to build the initial structures of the studied complexes. In the next step, they were subjected to an equilibrium MD simulation. In the final stage of the research, the nature and strength of the interactions between the studied compounds and the selected G-quadruplex were estimated using the umbrella sampling method, which allowed the determination of the free energy profiles of the obtained complexes. The results obtained allowed to determine the way in which the unsymmetrical bisacridines interact with the C-Myc promoter sequence - their potential molecular target. In addition, their basic physicochemical properties have been determined, which will allow further research on the compounds described above. In this work, a simple and reliable method for the determination of physicochemical constants has been developed and presented, which yields well credible results, even in the case of compounds with a complex structure having many sites capable of protonation.

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