Synthesis of 1,4-disubstituted 1,2,3-triazole Derivatives Using Click Chemistry and their Src Kinase Activities
Alexandre Lebeau, Cyril Abrioux, David Bénimèlis
1Nîmes University, EA 7352 CHROME, 30021, Nîmes, France.. France.
Background:
Tyrosine kinases (TK) are enzymes that catalyze the phosphorylation of tyrosine residues on proteins by the transfer of phosphate moiety of ATP. TK are key regulators of various cell functions, such as cellular growth, proliferation, migration, differentiation, and apoptosis. Src mutations and/or overexpression has been correlated with tumor growth, metastasis, and angiogenesis [4,5]. Thus, the design and the discovery of novel Src kinase inhibitors remains critically important.
Methods:
A series of 1,4-disubstituted 1,2,3-triazoles derivatives were designed and prepared as potential inhibitors for Src kinase. In this manuscript, all of the designed compounds were screened via molecular docking using PLANTS as virtual screening software to identify new inhibitors of Src kinase. Subsequently, all of the screened compounds were synthesized via Huisgen's 1,3-dipolar cycloaddition between terminal alkynes (1) and methyl 2-azidoacetate (2) with Cu(I) in excellent yields at room temperature.
Results:
In the present study, we report the design and the synthesis of a series of 1,4-disubstituted 1,2,3-triazoles involving one pot condensation of methyl 2-azidoacetate and different terminal alkynes. All the synthesized triazoles were characterized by IR, 1 H, 13 C, 19 F NMR, and HRMS. They were investigated as inhibitors of Src kinase.
Conclusion:
A series of 1,4-disubstituted 1,2,3-triazole compounds were synthesized through an easy, convenient Cu(I) catalyzed click reaction and evaluated for their Src kinase activity. Compound 3m exhibited significant inhibitory activity against Src Kinase. These results, along with molecular design docking observations, are significant evidence to demonstrate the compound 3m could be optimized as a potential Src kinase inhibitor in further studies.
Insights
Novel 1,4-disubstituted 1,2,3-triazoles were synthesized and evaluated as potential inhibitors of Src kinase. Compound 3m demonstrated significant Src kinase inhibitory activity, suggesting its potential for further development.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Biochemistry
Background:
- Tyrosine kinases (TK) regulate crucial cell functions, including growth and apoptosis.
- Src kinase is implicated in tumor growth, metastasis, and angiogenesis.
- Targeting Src kinase is critical for cancer therapy.
Purpose of the Study:
- To design and synthesize novel 1,4-disubstituted 1,2,3-triazoles as potential Src kinase inhibitors.
- To evaluate the inhibitory activity of synthesized compounds against Src kinase.
- To identify lead compounds for further optimization.
Main Methods:
- Virtual screening using molecular docking (PLANTS) to identify potential Src kinase inhibitors.
- Synthesis of 1,4-disubstituted 1,2,3-triazoles via Cu(I)-catalyzed click reaction (Huisgen's 1,3-dipolar cycloaddition).
- Characterization of synthesized compounds using NMR and HRMS.
Main Results:
- A series of 1,4-disubstituted 1,2,3-triazoles were successfully synthesized in excellent yields.
- All synthesized compounds were evaluated for their Src kinase inhibitory activity.
- Compound 3m exhibited significant inhibitory activity against Src kinase.
Conclusions:
- Cu(I)-catalyzed click chemistry provides an efficient route to 1,4-disubstituted 1,2,3-triazoles.
- Compound 3m is a promising Src kinase inhibitor candidate.
- Further optimization of compound 3m could lead to novel therapeutic agents.
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