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Synthesis and Activity Study of Gefitinib Derivatives Inducing Mitochondrial Apoptosis in Hela Cells
Yue Li1, Xixi Hou2, Shujian Liu3
1Zhoukou Center Hospital, Zhoukou, Henan, China.
Abstract:
Cervical cancer is the fourth most common cancer among women globally. Its development is closely linked to accelerated cell cycle progression and the inhibition of apoptosis in cervical cancer tissues. Gefitinib has demonstrated efficacy in inhibiting cervical cancer cells, and the 1,2,3-triazole structure is widely recognized for its role in inducing mitochondrial apoptosis in tumor cells. In this study, we employed click chemistry to modify the structure of gefitinib, leading to the synthesis of 16 derivatives containing the 1,2,3-triazole moiety. These compounds were evaluated for their in vitro activity against Hela cells. Among them, compound 3p exhibited the most promising anticancer activity, with an IC50 value of 4.09 ± 0.54 μM. Compound 3p significantly inhibited Hela cell colony formation in a dose-dependent manner, accompanied by noticeable morphological changes. Further investigations revealed that 3p induced apoptosis and caused G2/M phase cell cycle arrest in Hela cells. Western blot analysis showed that 3p increased the Bax/Bcl-2 ratio and elevated the levels of cleaved caspase-3 and PARP1, indicating that apoptosis was mediated through the mitochondrial pathway. Additionally, 3p inhibited indoleamine 2,3-dioxygenase 1 (IDO1) enzymatic activity, and molecular docking studies revealed a strong interaction between 3p and the IDO1 active site, suggesting that IDO1 may be a potential target. In conclusion, compound 3p shows promise as a potential therapeutic agent for cervical cancer.
Insights
Researchers developed novel gefitinib derivatives with a 1,2,3-triazole structure to combat cervical cancer. Compound 3p demonstrated significant in vitro anticancer activity by inducing apoptosis and cell cycle arrest, showing potential as a therapeutic agent.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Cervical cancer is a leading global cancer in women, often driven by uncontrolled cell division and resistance to apoptosis.
- Gefitinib shows promise against cervical cancer cells, while 1,2,3-triazole compounds are known to induce mitochondrial apoptosis.
Purpose of the Study:
- To synthesize and evaluate novel gefitinib derivatives containing the 1,2,3-triazole moiety for in vitro anticancer activity against cervical cancer.
- To identify specific compounds that effectively inhibit Hela cell proliferation and induce apoptosis.
Main Methods:
- Synthesis of 16 gefitinib derivatives using click chemistry.
- In vitro evaluation of anticancer activity against Hela cells, including IC50 determination.
- Assessment of effects on cell cycle, apoptosis (Bax/Bcl-2 ratio, cleaved caspase-3, PARP1), and indoleamine 2,3-dioxygenase 1 (IDO1) activity.
- Molecular docking studies to investigate interactions with IDO1.
Main Results:
- Compound 3p exhibited potent in vitro anticancer activity with an IC50 of 4.09 ± 0.54 μM against Hela cells.
- Compound 3p dose-dependently inhibited colony formation, induced morphological changes, G2/M phase cell cycle arrest, and apoptosis via the mitochondrial pathway.
- 3p demonstrated inhibition of IDO1 enzymatic activity, with molecular docking confirming strong binding to the IDO1 active site.
Conclusions:
- Compound 3p, a novel gefitinib derivative, shows significant potential as a therapeutic agent for cervical cancer.
- The observed anticancer effects are attributed to the induction of apoptosis and cell cycle arrest, potentially involving IDO1 inhibition.
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