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Phthalimide-tethered isatins as novel poly(ADP-ribose) polymerase inhibitors: Design, synthesis, biological
Mahmoud A El Hassab1, Amer Ali Abd El-Hafeez2, Hadia Almahli3
1Department of Medicinal Chemistry, Faculty of Pharmacy, King Salman International University (KSIU), Ras Sudr, South Sinai, Egypt.
Abstract:
Humanity is currently facing various diseases with significant mortality rates, particularly those associated with malignancies. Numerous enzymes and proteins have been identified as highly promising targets for the treatment of cancer. The poly(ADP-ribose) polymerases (PARPs) family comprises 17 members which are essential in DNA damage repair, allowing the survival of cancer cells. Unlike other PARP family members, PARP-1 and, to a lesser extent, PARP-2 show more than 90% activity in response to DNA damage. PARP-1 levels were shown to be elevated in various tumor cells, including breast, lung, ovarian, and prostate cancer and melanomas. Accordingly, novel series of phthalimide-tethered isatins (6a-n, 10a-e, and 11a-e) were synthesized as potential PARP-1 inhibitors endowed with anticancer activity. All the synthesized molecules were assessed against PARP-1, where compounds 6f and 10d showed nanomolar activities with IC50 = 15.56 ± 2.85 and 13.65 ± 1.42 nM, respectively. Also, the assessment of the antiproliferative effects of the synthesized isatins was conducted on four cancer cell lines: leukemia (K-562), liver (HepG2), and breast (MCF-7 and HCC1937) cancers. Superiorly, compounds 6f and 10d demonstrated submicromolar IC50 values against breast cancer MCF-7 (IC50 = 0.92 ± 0.18 and 0.67 ± 0.12 µM, respectively) and HCC1937 (IC50 = 0.88 ± 0.52 and 0.53 ± 0.11 µM, respectively) cell lines. In addition, compounds 6f and 10d induced arrest in the G2/M phase of the cell cycle as compared to untreated cells. Finally, in silico studies, including docking and molecular dynamic simulations, were performed to justify the biological results.
Insights
Researchers developed novel phthalimide-tethered isatins as potential inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) to combat cancer. Compounds 6f and 10d demonstrated potent PARP-1 inhibition and significant antiproliferative effects against breast cancer cells.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Biochemistry
Background:
- Cancer remains a leading cause of mortality, with enzymes like poly(ADP-ribose) polymerases (PARPs) crucial for cancer cell survival.
- PARP-1, highly active in DNA damage repair and elevated in various cancers, presents a promising therapeutic target.
- Inhibiting PARP-1 could disrupt DNA repair mechanisms, leading to cancer cell death.
Purpose of the Study:
- To synthesize and evaluate novel phthalimide-tethered isatins as potential inhibitors of PARP-1.
- To assess the antiproliferative activity of these compounds against various cancer cell lines.
- To investigate the mechanism of action, including cell cycle arrest and in silico validation.
Main Methods:
- Synthesis of a series of phthalimide-tethered isatins (compounds 6a-n, 10a-e, 11a-e).
- Enzymatic assays to determine PARP-1 inhibitory activity (IC50 values).
- Antiproliferative assays against leukemia, liver, and breast cancer cell lines (MCF-7, HCC1937).
- Cell cycle analysis (G2/M phase arrest) and in silico studies (docking, molecular dynamics).
Main Results:
- Compounds 6f and 10d exhibited potent PARP-1 inhibition with IC50 values in the nanomolar range.
- These compounds demonstrated significant antiproliferative effects against breast cancer cell lines MCF-7 and HCC1937, with submicromolar IC50 values.
- Compounds 6f and 10d induced G2/M phase cell cycle arrest, suggesting a mechanism for their anticancer activity.
- In silico studies supported the observed biological activities.
Conclusions:
- Novel phthalimide-tethered isatins, particularly compounds 6f and 10d, are effective PARP-1 inhibitors.
- These compounds show promising anticancer potential, especially against breast cancer, by inducing cell cycle arrest.
- Further investigation and development of these isatin derivatives could lead to new cancer therapeutics.
