Topo II inhibition and DNA intercalation by new phthalazine-based derivatives as potent anticancer agents: design, synthesis, anti-proliferative, docking, and in vivo studies

This research presents the design and synthesis of a novel series of phthalazine derivatives as Topo II inhibitors, DNA intercalators, and cytotoxic agents. In vitro testing of the new compounds against HepG-2, MCF-7, and HCT-116 cell lines confirmed their potent cytotoxic activity with low IC50 values. Topo II inhibition and DNA intercalating activities were evaluated for the most cytotoxic members. IC50 values determination demonstrated Topo II inhibitory activities and DNA intercalating affinities of the tested compounds at a micromolar level. Amongst, compound 9d was the most potent member. It inhibited Topo II enzyme at IC50 value of 7.02 +/- 0.54 mu M with DNA intercalating IC50 of 26.19 +/- 1.14 mu M. Compound 9d was then subjected to an in vivo antitumor examination. It inhibited tumour proliferation reducing solid tumour volume and mass. Additionally, it restored liver enzymes, proteins, and CBC parameters near-normal, indicating a remarkable amelioration in their functions along with histopathological examinations.

Automated summary

This research presents the design and synthesis of a novel series of phthalazine derivatives that act as Topo II inhibitors, DNA intercalators, and cytotoxic agents. In vitro testing confirmed their potent cytotoxic activity against HepG-2, MCF-7, and HCT-116 cell lines. Further evaluation showed their Topo II inhibitory and DNA intercalating activities at a micromolar level. Compound 9d exhibited the most potent activity and was able to inhibit tumor proliferation and restore liver function and blood parameters in vivo.