2. Academic Validation
  3. Development of novel synthesized phthalazinone-based PARP-1 inhibitors with apoptosis inducing mechanism in lung cancer

Development of novel synthesized phthalazinone-based PARP-1 inhibitors with apoptosis inducing mechanism in lung cancer

  • Bioorg Chem. 2018 Apr;77:443-456. doi: 10.1016/j.bioorg.2018.01.034.
Hadia Almahli 1,  Elie Hadchity 2,  Maiy Y Jaballah 3,  Racha Daher 2,  Hazem A Ghabbour 4,  Maha M Kabil 5,  Nasser S Al-Shakliah 6,  Wagdy M Eldehna 7
Affiliations

Affiliations

  • 1 University of Oxford, Department of Chemistry, Chemistry Research Laboratory, 12 Mansfield Road, OX1 3TA, Oxford, UK; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, P.O. Box 11829, Badr City, Cairo, Egypt.
  • 2 Anti-Tumor Therapeutic Targeting Laboratory, Faculty of Sciences, Lebanese University, Hadat, Lebanon.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Abbassia, Egypt.
  • 4 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. Electronic address: [email protected].
  • 5 Department of Infection Control, King Saud University Medical City, Riyadh, Saudi Arabia.
  • 6 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
PMID: 29453076 DOI: 10.1016/j.bioorg.2018.01.034
Abstract

Herein we report the synthesis of two series of 4-phenylphthalazin-1-ones 11a-i and 4- benzylphthalazin-1-ones 16a-h as anti-lung adenocarcinoma agents with potential inhibitory activity against PARP-1. All the newly synthesized phthalazinones were evaluated for their anti-proliferative activity against A549 lung carcinoma cell line. Phthalazinones 11c-i and 16b, c showed significant cytotoxic activity against A549 cells at different concentrations (0.1, 1 and 10 μM) for two time intervals (24 h and 48 h). These nine phthalazinones were further examined for their inhibitory activity towards PARP-1. Compound 11c emerged as the most potent PARP-1 inhibitor with IC50 value of 97 nM, compared to that of Olaparib (IC50 = 139 nM). Furthermore, all these nine phthalazinones passed the filters of Lipinski and Veber rules, and predicted to have good pharmacokinetics properties in a theoretical kinetic study. On the other hand, western blotting in A549 cells revealed the enhanced expression of the cleaved PARP-1, alongside, with the reduced expression of pro-caspase-3 and phosphorylated Akt. In addition, ELISA assay confirmed the up-regulation of active Caspase-3 and caspase-9 levels compared to the control, suggesting the activation of the apoptotic machinery in the A549 cells. Finally, molecular docking of 11c into PARP-1 active site (PDB: 5WRZ) was performed to explore the probable binding mode.

Keywords

Apoptosis; Lung adenocarcinoma; Molecular docking; PARP-1 inhibitors; Phthalazinones.

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