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

• Published in: Journal of enzyme inhibition and medicinal chemistry 2022-12, Vol.37 (1), p.299-314
• Main Authors: Khalifa, Mohamed M., Al-Karmalawy, Ahmed A., Elkaeed, Eslam B., Nafie, Mohamed S., Tantawy, Mohamed A., Eissa, Ibrahim H., Mahdy, Hazem A.
• Format: Article
• Language: English
• Subjects: Acids; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumer; Antitumor agents; Binding sites; Cancer; Cell Proliferation - drug effects; Chemistry; Cytotoxic agents; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA topoisomerase (ATP-hydrolysing); DNA Topoisomerases, Type II - metabolism; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Enzymes; Humans; intercalators; Mice; Molecular Docking Simulation; Molecular Structure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Pharmaceutical sciences; Pharmacy; phthalazine; Phthalazines - chemical synthesis; Phthalazines - chemistry; Phthalazines - pharmacology; Potash; Potassium; Research Paper; Solid tumors; Structure-Activity Relationship; Topo II; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; Tumor Cells, Cultured
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2021.2007905

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 IC 50 values. Topo II inhibition and DNA intercalating activities were evaluated for the most cytotoxic members. IC 50 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 IC 50 value of 7.02 ± 0.54 µM with DNA intercalating IC 50 of 26.19 ± 1.14 µM. 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.