Evaluation of novel aminomethyl indole derivatives as Src kinase inhibitors and antioxidant agents
Süreyya Ölgen1, Zühal Kılıç-Kurt, Fatma Sener
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ankara, Ankara, Turkey. olgen@pharmacy.ankara.edu.tr
Background:
Oxidative stress has been implicated in aging and in a variety of diseases affecting the nervous, respiratory, cardiovascular and gastrointestinal system in humans. Reactive oxygen species (ROS) have been associated with mechanisms to activate kinases, such as protein tyrosine kinases, which may initiate malignant transformation. Significant evidences of the activation of protein kinases by oxidative stress brought increased attention to the role of antioxidants in these mechanisms. Therefore, recent efforts have focused on revealing the relationship between protein kinase inhibition and the levels of ROS production.
Methods:
Antioxidant properties of aminomethyl indole derivatives were investigated by employing various in vitro systems, microsomal NADPH-dependent inhibition of lipid peroxidation (LP), interaction of 2,2-diphenyl-1-picrylhydrazyl and scavenging of superoxide anion radical by virtue of superoxide dismutase inhibitory activity. In vitro tyrosine kinase assays of the aminomethyl indole derivatives were evaluated by changes in the enzymatic activity of pp60(c-Src) tyrosine kinase through alterations in the phosphorylation level of immobilized kinase substrate.
Results:
Analysis of the antioxidant effects of indole 1a-c, bromo indole 2a-c and phenyl indole 3a-c derivatives revealed almost equal inhibition against LP for 5-bromo indole 2a-c and phenyl indole 3a-c derivatives and slight inhibition against superoxide dismutase only for 1a and 1c. Nonsubstituted compounds at position 5 showed half-inhibition of LP. Compound 1a has tyrosine kinase inhibition with an IC(50) of 102.6 ± 1.16 μM.
Conclusion:
The substitution feature at position 5 of the indole ring certainly plays an important role in both tyrosine kinase inhibition and antioxidant capacity. While certain lipophilicity of this substitution is important for antioxidant activity, it may, on the other hand, have a negative impact on the inhibition of Src kinase.
Insights
This study shows that indole derivatives with specific substitutions at position 5 exhibit antioxidant properties and inhibit tyrosine kinases. These findings highlight the role of chemical structure in modulating these biological activities.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Pharmacology
Background:
- Oxidative stress is linked to aging and various human diseases.
- Reactive oxygen species (ROS) can activate kinases, potentially initiating malignant transformation.
- Antioxidants are investigated for their role in mitigating oxidative stress-related mechanisms.
Purpose of the Study:
- To investigate the antioxidant properties of aminomethyl indole derivatives.
- To evaluate the tyrosine kinase inhibitory potential of these compounds.
- To explore the relationship between chemical structure, antioxidant capacity, and kinase inhibition.
Main Methods:
- In vitro antioxidant assays including lipid peroxidation inhibition and superoxide anion radical scavenging.
- In vitro tyrosine kinase assays using pp60(c-Src) tyrosine kinase.
- Evaluation of indole derivatives with varying substitutions at position 5.
Main Results:
- Indole derivatives showed varying inhibition of lipid peroxidation and superoxide dismutase activity.
- Compounds with substitutions at position 5 demonstrated significant lipid peroxidation inhibition.
- Compound 1a exhibited tyrosine kinase inhibition with an IC(50) of 102.6 ± 1.16 μM.
Conclusions:
- Substitution at position 5 of the indole ring is crucial for both antioxidant capacity and tyrosine kinase inhibition.
- Lipophilicity of the substitution enhances antioxidant activity but may reduce Src kinase inhibition.
- The findings provide insights into the structure-activity relationships of indole derivatives for potential therapeutic applications.
