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

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.
Abdel-Ghany A El-Helby 1,  Helmy Sakr 1,  Rezk R Ayyad 2,  Hazem A Mahdy 3,  Mohamed M Khalifa 1,  Amany Belal 4,  Mahmoud Rashed 1,  Abdou El-Sharkawy 5,  Ahmed M Metwaly 6,  Mostafa A Elhendawy 7,  Mohamed M Radwan 8,  Mahmoud A ElSohly 9,  Ibrahim H Eissa 10
Affiliations

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.

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