Discovery of Novel 3-Cyanopyridines as Survivin Modulators and Apoptosis Inducers
Rehab Sabour1, Marwa F Harras1, Omkulthom Mohamed Al Kamaly2
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt.
Abstract:
The overexpression of survivin is usually accompanied by an increased resistance of cancer cells to chemotherapeutic agents in addition to cancer aggressiveness. Consequently, survivin is considered as an attractive target to develop new promising anticancer candidates. A series of novel 3-cyanopyridine derivatives was synthesized and assessed for their cytotoxic activity against three human cancer cell lines: prostate carcinoma (PC-3), breast cancer (MDA-MB-231) and hepatocellular carcinoma (HepG2). In addition, their activities were evaluated in comparison with a standard anticancer drug 5-FU. Compounds 5c and 5e both exhibited promising cytotoxicity against all the tested cell lines; especially, 5e showed better cytotoxic effect than the reference drug 5-FU. In order to evaluate the safety of these compounds, they were tested on the normal cell line WI-38, revealing their toxic selectivity toward cancer cells over normal ones. Further studies were performed in order to understand their mechanism of action; we examined the ability of our promising compounds 5c and 5e to induce cell cycle arrest. Both resulted in a notable induction of cell cycle arrest at the G2/M phase, along with an increase in the DNA content in the pre-G1 phase, giving us an indication of the incidence of apoptosis. 5c and 5e were further subjected to additional study using Annexin V-FITC assay in order to evaluate their ability to induce apoptosis. The results showed a marked increase in the early and late apoptotic cells, as well as an increase in the percentage of necrosis. Furthermore, Western blotting assay was accomplished using different concentrations of 5c and 5e. The results revealed a striking reduction in survivin expression through proteasome-dependent survivin degradation in addition to a decrease in the expression of some other inhibitor of apoptosis proteins (IAP) family proteins: Livin, XIAP, and C-IAP1 in a concentration-dependent manner. A docking study of 5c and 5e compounds in the dimerization site of survivin was also performed, showing agreement with the in vitro anti-survivin activity.
Insights
Novel 3-cyanopyridine derivatives show potent anticancer activity by targeting survivin. Compounds 5c and 5e effectively induce apoptosis and cell cycle arrest in cancer cells, with good safety profiles.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Survivin overexpression correlates with cancer aggressiveness and chemoresistance.
- Survivin is a validated therapeutic target for novel anticancer drug development.
Purpose of the Study:
- Synthesize and evaluate novel 3-cyanopyridine derivatives for anticancer activity.
- Investigate the mechanism of action and safety profile of promising compounds.
Main Methods:
- Cytotoxicity assays against human cancer cell lines (PC-3, MDA-MB-231, HepG2) and normal cells (WI-38).
- Cell cycle analysis, Annexin V-FITC assay for apoptosis, and Western blotting for protein expression.
- Molecular docking studies against survivin.
Main Results:
- Compounds 5c and 5e demonstrated significant cytotoxicity, with 5e outperforming 5-FU.
- Selective toxicity towards cancer cells over normal cells was observed.
- Compounds induced G2/M cell cycle arrest, apoptosis, and necrosis.
- Downregulation of survivin, Livin, XIAP, and C-IAP1 expression was confirmed via proteasome-dependent degradation.
- Docking studies supported in vitro anti-survivin activity.
Conclusions:
- Novel 3-cyanopyridine derivatives, particularly 5c and 5e, are potent anticancer agents.
- These compounds exert their effects by inducing apoptosis and cell cycle arrest, mediated by survivin downregulation.
- Their selective toxicity and promising efficacy warrant further investigation as lead compounds for cancer therapy.
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