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

Abdel-Ghany A El-Helby; Helmy Sakr; Rezk R Ayyad; Hazem A Mahdy; Mohamed M Khalifa; Amany Belal; Mahmoud Rashed; Abdou El-Sharkawy; Ahmed M Metwaly; Mostafa A Elhendawy; Mohamed M Radwan; Mahmoud A ElSohly; Ibrahim H Eissa

doi:10.1016/j.bioorg.2020.104233

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

Bioorg Chem. 2020 Oct:103:104233. doi: 10.1016/j.bioorg.2020.104233. Epub 2020 Aug 26.

Authors

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
² Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: rezek_ayad@yahoo.com.
³ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: hazem_hady2001@azhar.edu.eg.
⁴ Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
⁵ Department of Anatomy, Faculty of Medicine, Al-Azhar University, Cairo, Egypt; Department of Anatomy, College of Medicine, Jouf University, Saudi Arabia.
⁶ Pharmacognosy Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
⁷ Department of Agriculture Chemistry, Faculty of Agriculture, Damietta University, Damietta, Egypt.
⁸ National Center for Natural Products Research, University of Mississippi, MS 38677, USA; Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
⁹ National Center for Natural Products Research, University of Mississippi, MS 38677, USA; Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA.
¹⁰ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address: Ibrahimeissa@azhar.edu.eg.

PMID: 32882440
DOI: 10.1016/j.bioorg.2020.104233

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects
Cell Line, Tumor
DNA / metabolism
DNA Topoisomerases, Type II / metabolism
Drug Design
Drug Screening Assays, Antitumor
G2 Phase Cell Cycle Checkpoints / drug effects
Humans
Intercalating Agents / chemical synthesis
Intercalating Agents / metabolism
Intercalating Agents / therapeutic use*
Molecular Docking Simulation
Molecular Structure
Neoplasms / drug therapy*
Phthalazines / chemical synthesis
Phthalazines / metabolism
Phthalazines / therapeutic use*
Protein Binding
Rats
Structure-Activity Relationship
Topoisomerase II Inhibitors / chemical synthesis
Topoisomerase II Inhibitors / metabolism
Topoisomerase II Inhibitors / therapeutic use*

Substances

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