Evaluation of novel aminomethyl indole derivatives as Src kinase inhibitors and antioxidant agents.
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.


CONCLUSIONS
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.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ankara, Ankara, Turkey. olgen@pharmacy.ankara.edu.tr
Süreyya
S
Ölgen
Zühal
Z
Kılıç-Kurt
Fatma
F
Sener
Yasemin G
YG
Işgör
Tülay
T
Coban
D000818:Animals; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008862:Microsomes, Liver / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000975:Antioxidants; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013482:Superoxide Dismutase; D019061:src-Family Kinases