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Published on: April 3, 2009
Integrated In Silico and In Vitro Study of Copper Nanocatalyzed Carbonyl-Functionalized Triazoles-Inducing S Phase
Joydip Mondal1, Tiasha Dasgupta2, Chitluri Kiran Kumar2
1School of Advanced Sciences, Department of Chemistry, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India.
Abstract:
The demand for novel, selective anticancer agents, driven by drug resistance and systemic toxicity of current treatments, underscores the importance of targeted drug discovery. Present research involved cytotoxic screening of a series of synthesized copper nanocatalyzed carbonyl-functionalized triazoles (3a-p), where 3i and 3j have shown highest selectivity index (SI) scores of 2.30 and 4.44, respectively. Computational validation of the lead compounds demonstrated specific interaction with BCL2-associated X protein (BAX) and BCL2, characterized by strong binding affinities ranging between -6.73 and -7.70 kcal/mol. Corresponding protein-ligand complexes demonstrated robust conformational stability throughout their 100 ns of molecular dynamics simulation. Subsequent in vitro validation using MCF-7 cells firmly corroborated the in silico findings, by revealing significant upregulation of BAX (p < 0.001) and downregulation of BCL2 (p < 0.001). Compound induced cellular stress, elevated the ROS-producing cell population up to 40%. Resulting cellular oxidative stress, rapidly depleted the glutathione reserves up to 50% (p < 0.001), consequently compromising the mitochondrial membrane potential leading to mitochondrial dysfunction. Furthermore, the compound induced S-phase cell cycle arrest (upto 51.5%), played a pivotal role in promoting apoptosis by activating DNA damage response pathways. In conclusion, this study has successfully identified two lead compounds (3i & 3j) that modulate multiple converging oncogenic pathways, providing compelling preclinical candidates for targeted management of breast cancer.
Insights
Two novel triazole compounds (3i and 3j) show promise as targeted breast cancer treatments. They induce cancer cell death by disrupting key proteins and cellular processes, offering a new avenue for drug discovery.
Area of Science:
- Medicinal Chemistry
- Nanotechnology
- Cancer Biology
Background:
- Growing resistance and toxicity of current cancer treatments necessitate novel, selective anticancer agents.
- Targeted drug discovery is crucial for developing effective and safer cancer therapies.
Purpose of the Study:
- To synthesize and evaluate copper nanocatalyzed carbonyl-functionalized triazoles for anticancer activity.
- To identify lead compounds with high selectivity and investigate their molecular mechanisms against breast cancer.
Main Methods:
- Cytotoxic screening of synthesized triazole compounds (3a-p).
- Computational validation including protein-ligand binding affinity and molecular dynamics simulations.
- In vitro studies using MCF-7 cells to assess BCL2-associated X protein (BAX) and BCL2 modulation, cellular stress, and apoptosis induction.
Main Results:
- Compounds 3i and 3j exhibited the highest selectivity index (SI) scores.
- In silico analysis revealed strong binding affinities to BCL2-associated X protein (BAX) and BCL2.
- In vitro studies confirmed BAX upregulation, BCL2 downregulation, increased reactive oxygen species (ROS), glutathione depletion, and S-phase cell cycle arrest, leading to apoptosis.
Conclusions:
- Compounds 3i and 3j effectively modulate multiple oncogenic pathways involved in breast cancer.
- These compounds demonstrate significant potential as preclinical candidates for targeted breast cancer therapy.
- The study highlights the therapeutic promise of functionalized triazoles in cancer treatment.
