Development of 2,9‐Disubstituted Acridines as Topoisomerase IIα Inhibitors with Strong Anticancer Activity – Synthesis, Biological Evaluation and In Silico Study

A series of 2,9-disubstituted acridines (16a-16h) is synthetized and assessed for their biological activities. The acridines feature various 9-anilino or 9-phenylalkyl substituents and are prepared via a linear sequence of six steps using commercially available starting materials. The relationship between the physicochemical properties of the 2,9-disubstituted acridines and their biological activity is studied, and the DNA binding capacities of the synthetized acridines are determined using spectroscopic (Kb 0.5-10.4 × 104 M-1) and thermal denaturation (ΔTm 4.2-9.8 °C) methods. The inhibitory potential of acridines 16a-16h toward human topoisomerase I/IIα is evaluated, and 9-phenylbutyl acridine 16h is found to inhibit human topoisomerase IIα at concentrations as low as 5 μm. Acridines 16a-16h are also subjected to in vitro screening against selected cancer cell lines; the most potent anticancer activity is observed against melanoma A2058 cell lines at IC50 values ranging from 3 to 6 μm.