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Updated: Apr 16, 2026
Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Synthesis, molecular docking and antitumor activity of novel pyrrolizines with potential as EGFR-TK inhibitors
1Pharmaceutical Chemistry Department, College of Pharmacy, Taif University, Taif 21974, Saudi Arabia; Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Abstract:
A new series of pyrrolizine derivatives 4-8c were synthesized, their structures were confirmed by spectral and elemental analyses. Cytotoxic activity of these compounds was evaluated against breast (MCF7), colon (HCT116) and liver (HEPG2) cancer cell lines using sulphorhodamine-B (SRB) assay method. All the tested compounds showed highly potent activity against MCF7 cell line with IC50 range equal 8-194 nM/ml and compound 8c was the best active one (IC50 = 8.6 nM/ml). 8b was the best active compound on both HCT116 and HEPG-2 cancer cell lines; its IC50 is 26.5 and 12.3 nM/ml respectively. Docking studies into ATP binding site of EGFR tyrosine kinase were performed to predict their scores and mode of binding to amino acids, moreover, inhibitory activity of these compounds against EGFR-TKs was evaluated; their inhibitory percent ranged from 40.4 to 97.6, compound 8c and 8b showed inhibitory activity at 97.6% and 88.4% respectively.
Insights
New pyrrolizine derivatives show potent anticancer activity. Compound 8c is highly effective against breast cancer cells, while 8b targets colon and liver cancer cells, indicating potential for new cancer therapies.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Cancer Research
Background:
- Pyrrolizine derivatives are heterocyclic compounds with diverse biological activities.
- Cancer remains a major global health challenge, necessitating the development of novel therapeutic agents.
- Targeting specific cancer cell lines and molecular pathways is crucial for effective treatment.
Purpose of the Study:
- To synthesize and characterize novel pyrrolizine derivatives.
- To evaluate the cytotoxic activity of these compounds against human breast (MCF7), colon (HCT116), and liver (HEPG2) cancer cell lines.
- To investigate the inhibitory potential of these compounds against Epidermal Growth Factor Receptor (EGFR) tyrosine kinases.
Main Methods:
- Synthesis of pyrrolizine derivatives (compounds 4-8c) followed by structural confirmation using spectral and elemental analyses.
- Cytotoxicity assessment using the sulphorhodamine-B (SRB) assay to determine IC50 values.
- Molecular docking studies into the ATP binding site of EGFR tyrosine kinase and evaluation of inhibitory activity against EGFR-TKs.
Main Results:
- All synthesized pyrrolizine derivatives exhibited significant cytotoxic activity against MCF7 cells, with IC50 values ranging from 8-194 nM/ml. Compound 8c demonstrated the highest potency (IC50 = 8.6 nM/ml).
- Compound 8b showed the most potent activity against HCT116 (IC50 = 26.5 nM/ml) and HEPG-2 (IC50 = 12.3 nM/ml) cell lines.
- Docking studies and enzyme inhibition assays revealed that compounds 8c and 8b possess strong inhibitory activity against EGFR-TKs, with inhibition percentages of 97.6% and 88.4%, respectively.
Conclusions:
- The novel pyrrolizine derivatives display promising cytotoxic effects against multiple human cancer cell lines.
- Compounds 8c and 8b show significant potential as EGFR tyrosine kinase inhibitors, warranting further investigation for cancer therapy development.
- The structure-activity relationship suggests that specific pyrrolizine derivatives can be optimized for targeted cancer treatment.
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