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  3. Computational, in vitro and radiation-based in vivo studies on acetamide quinazolinone derivatives as new proposed purine nucleoside phosphorylase inhibitors for breast cancer

Computational, in vitro and radiation-based in vivo studies on acetamide quinazolinone derivatives as new proposed purine nucleoside phosphorylase inhibitors for breast cancer

  • Eur J Med Chem. 2023 Feb 15:248:115087. doi: 10.1016/j.ejmech.2023.115087.
Mostafa G M El-Gazzar 1,  Mostafa M Ghorab 2,  Mohamed A Amin 3,  Mohamed Korany 3,  Mohammed A Khedr 4,  Marwa G El-Gazzar 1,  Tamer M Sakr 5
Affiliations

Affiliations

  • 1 Department of Drug Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, 11787, Egypt.
  • 2 Department of Drug Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, 11787, Egypt. Electronic address: [email protected].
  • 3 Labeled Compounds Department, Hot Labs Center, Egyptian Atomic Energy Authority, Cairo, 13759, Egypt.
  • 4 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, Cairo, 11795, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Kuwait.
  • 5 Radioactive Isotopes and Generator Department, Hot Labs Center, Egyptian Atomic Energy Authority, Cairo, 13759, Egypt.
PMID: 36610250 DOI: 10.1016/j.ejmech.2023.115087
Abstract

The present work describes a quinazolinone-based lead optimization for the development of novel purine nucleoside Phosphorylase (PNP) inhibitors with quinazolinone scaffold. Nineteen compounds were proposed and docked against PNP, the best 14 compounds with highest docking and affinity scores and low RMSD values were synthesized. Synthesis of new quinazolinone derivatives with variable acetamide substituents on two positions on quinazoline ring was performed. The structures assigned to the products were concordant with the microanalytical and spectral data. In vitro cytotoxicity on human breast Cancer cell line (MCF7) was performed and identified compound 6g as the most potent with IC50 (0.99 ± 0.11 μM) which was further tested against five different breast Cancer cell lines in addition to normal breast cell to determine the selectivity. Compound 6g was subjected to molecular dynamic simulation study, radiolabelling and biodistribution study to investigate its stability and selectivity toward breast cancers. The in vitro PNP inhibition results were aligned with the in silico, cytotoxicity, and biodistribution results where 6g showed the most potent PNP inhibitory activity with IC50 (0.159 ± 0.007 μM) when compared to Peldesine (BCX-34) IC50 (0.041 ± 0.002 μM).

Keywords

Biodistribution; Breast cancer; Molecular dynamics; PNP inhibitors; Quinazolinone; Radiosynthesis.

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