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Evaluating Bis-Phenacyl Bromide-Based Bis-Heterocyclic Templates as Anticancer Prototypes and Potential PARP1
Refaie M Kassab1, Mohamed Ali2, Sami A Al-Hussain3
1Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613, Egypt.
Chemmedchem
|May 9, 2025
Summary
New bis-heterocyclic compounds show potent anticancer activity by inhibiting Poly(ADP-ribose) polymerase 1 (PARP1). These novel agents demonstrate selective cancer cell killing and promise for future cancer therapy development.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Poly(ADP-ribose) polymerase 1 (PARP1) is crucial for DNA repair and a significant target for cancer treatment.
- Developing novel compounds with selective antineoplastic activity and PARP1 inhibition is a key area of research.
Purpose of the Study:
- To synthesize and evaluate novel bis-heterocyclic derivatives for their anticancer potential against various cell lines.
- To assess the Poly(ADP-ribose) polymerase 1 (PARP1) inhibitory activity of these synthesized compounds.
- To elucidate the mechanism of action underlying the observed cytotoxicity.
Main Methods:
- Synthesis of novel bis-heterocyclic compounds based on a bis-phenacyl bromide scaffold.
- Anticancer activity assessment against eight malignant cell lines and Poly(ADP-ribose) polymerase 1 (PARP1) inhibition assays.
- Mechanistic studies including apoptosis markers (caspase-7, cytochrome C, BAX, p53, BCL-2) and cell cycle analysis.
- Molecular docking simulations to predict binding interactions with PARP1.
Main Results:
- The synthesized derivatives displayed selective cytotoxicity against MCF7 and PC-3 cancer cell lines, with minimal toxicity to others.
- Several derivatives (5a-e, 13, 18, 34, 35, 36) were highly effective against PC-3 cells (IC50 < 10 µM).
- Derivatives 5a, 5d, 5e, 12, 25, 28a, and 34 showed potent activity against MCF7 cells, outperforming doxorubicin.
- Compounds 5a-e, 8a, 13, 34, and 36 exhibited sub-nanomolar IC50 values for PARP1 inhibition, surpassing olaparib.
- Cytotoxicity was linked to induced programmed cell death and sub-G1 cell cycle arrest.
- Molecular docking confirmed favorable interactions between the derivatives and the PARP1 active site.
Conclusions:
- The novel bis-heterocyclic derivatives possess significant antineoplastic potential and potent Poly(ADP-ribose) polymerase 1 (PARP1) inhibitory activity.
- These compounds demonstrate selective cytotoxicity and induce cancer cell death through apoptosis and cell cycle arrest.
- The findings support the development of these derivatives as promising next-generation anticancer agents and PARP1 inhibitors.
