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Development of novel synthesized phthalazinone-based PARP-1 inhibitors with apoptosis inducing mechanism in lung cancer.
Bioorg Chem. 2018 04; 77:443-456.BC

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Almahli H
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.
Hadchity E
Anti-Tumor Therapeutic Targeting Laboratory, Faculty of Sciences, Lebanese University, Hadat, Lebanon.
Jaballah MY
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Abbassia, Egypt.
Daher R
Anti-Tumor Therapeutic Targeting Laboratory, Faculty of Sciences, Lebanese University, Hadat, Lebanon.
Ghabbour HA
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: haghabbour@ksu.edu.sa.
Kabil MM
Department of Infection Control, King Saud University Medical City, Riyadh, Saudi Arabia.
Al-Shakliah NS
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Eldehna WM
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.

MeSH

Antineoplastic AgentsApoptosisCell ProliferationCells, CulturedDose-Response Relationship, DrugDrug Screening Assays, AntitumorHumansLung NeoplasmsMolecular Docking SimulationMolecular StructurePhthalazinesPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsStructure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29453076

Citation

Almahli, Hadia, et al. "Development of Novel Synthesized Phthalazinone-based PARP-1 Inhibitors With Apoptosis Inducing Mechanism in Lung Cancer." Bioorganic Chemistry, vol. 77, 2018, pp. 443-456.
Almahli H, Hadchity E, Jaballah MY, et al. Development of novel synthesized phthalazinone-based PARP-1 inhibitors with apoptosis inducing mechanism in lung cancer. Bioorg Chem. 2018;77:443-456.
Almahli, H., Hadchity, E., Jaballah, M. Y., Daher, R., Ghabbour, H. A., Kabil, M. M., Al-Shakliah, N. S., & Eldehna, W. M. (2018). Development of novel synthesized phthalazinone-based PARP-1 inhibitors with apoptosis inducing mechanism in lung cancer. Bioorganic Chemistry, 77, 443-456. https://doi.org/10.1016/j.bioorg.2018.01.034
Almahli H, et al. Development of Novel Synthesized Phthalazinone-based PARP-1 Inhibitors With Apoptosis Inducing Mechanism in Lung Cancer. Bioorg Chem. 2018;77:443-456. PubMed PMID: 29453076.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Development of novel synthesized phthalazinone-based PARP-1 inhibitors with apoptosis inducing mechanism in lung cancer. AU - Almahli,Hadia, AU - Hadchity,Elie, AU - Jaballah,Maiy Y, AU - Daher,Racha, AU - Ghabbour,Hazem A, AU - Kabil,Maha M, AU - Al-Shakliah,Nasser S, AU - Eldehna,Wagdy M, Y1 - 2018/02/07/ PY - 2017/12/20/received PY - 2018/01/19/revised PY - 2018/01/27/accepted PY - 2018/2/18/pubmed PY - 2019/1/15/medline PY - 2018/2/18/entrez KW - Apoptosis KW - Lung adenocarcinoma KW - Molecular docking KW - PARP-1 inhibitors KW - Phthalazinones SP - 443 EP - 456 JF - Bioorganic chemistry JO - Bioorg Chem VL - 77 N2 - 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. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/29453076/Development_of_novel_synthesized_phthalazinone_based_PARP_1_inhibitors_with_apoptosis_inducing_mechanism_in_lung_cancer_ DB - PRIME DP - Unbound Medicine ER -