Design, synthesis, molecular modeling, in vivo studies and anticancer activity evaluation of new phthalazine derivatives as potential DNA intercalators and topoisomerase II inhibitors

Abstract

Herein we report the design and synthesis of a new series of phthalazine derivatives as Topo II inhibitors and DNA intercalators. The synthesized compounds were in vitro evaluated for their cytotoxic activities against HepG-2, MCF-7 and HCT-116 cell lines. Additionally, Topo II inhibitory activity and DNA intercalating affinity were investigated for the most active compounds as a potential mechanism for the anticancer activity. Compounds 15h, 23c, 32a, 32b, and 33 exhibited the highest activities against Topo II with IC₅₀ ranging from 5.44 to 8.90 µM, while compounds 27 and 32a were found to be the most potent DNA binders at IC₅₀ values of 36.02 and 48.30 µM, respectively. Moreover, compound 32a induced apoptosis in HepG-2 cells and arrested the cell cycle at the G2/M phase. Besides, compound 32a showed Topo II poisoning effect at concentrations of 2.5 and 5 μM, and Topo II catalytic inhibitory effect at a concentration of10 μM. In addition, compound 32b showed in vivo a significant tumor growth inhibition effect. Furthermore, molecular docking studies were carried out against DNA-Topo II complex and DNA to investigate the binding patterns of the designed compounds.

Keywords: Anticancer; Apoptosis; DNA-intercalation; Molecular docking; Phthalazine; Topoisomerase II.