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

Mohamed M Khalifa; Ahmed A Al-Karmalawy; Eslam B Elkaeed; Mohamed S Nafie; Mohamed A Tantawy; Ibrahim H Eissa; Hazem A Mahdy

doi:10.1080/14756366.2021.2007905

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

J Enzyme Inhib Med Chem. 2022 Dec;37(1):299-314. doi: 10.1080/14756366.2021.2007905.

Authors

Mohamed M Khalifa¹, Ahmed A Al-Karmalawy², Eslam B Elkaeed³, Mohamed S Nafie⁴, Mohamed A Tantawy^{5

6}, Ibrahim H Eissa¹, Hazem A Mahdy¹

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
² Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, Egypt.
³ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
⁴ Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, Egypt.
⁵ Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Egypt.
⁶ Stem Cells Lab, Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Cairo, Egypt.

Abstract

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 µM with DNA intercalating IC₅₀ 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.

Keywords: DNA; Topo II; antitumer; intercalators; phthalazine.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
DNA / chemistry*
DNA Topoisomerases, Type II / metabolism*
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Mice
Molecular Docking Simulation*
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Phthalazines / chemical synthesis
Phthalazines / chemistry
Phthalazines / pharmacology*
Structure-Activity Relationship
Topoisomerase II Inhibitors / chemical synthesis
Topoisomerase II Inhibitors / chemistry
Topoisomerase II Inhibitors / pharmacology*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Phthalazines
Topoisomerase II Inhibitors
DNA
phthalazine
DNA Topoisomerases, Type II

Grants and funding

The authors extend their appreciation to the Research center at AlMaarefa University for funding this work under TUMA project number “TUMA-2021-4”.