Yasemin G. İşgör

Synthesis and Activity of Novel 5‐Substituted Pyrrolo[2,3‐d]pyrimidine Analogues as pp60c‐Src Tyrosine Kinase Inhibitors

Therapy with receptor tyrosine kinase inhibitors provides an improved treatment option in a number of diseases such as cancer, myocardial infection, osteoporosis, stroke, and neurodegeneration. We have designed, synthesized, and evaluated a series of novel 2‐amino‐5‐[(benzyl)imino]methyl‐3,7‐dihydro‐4H‐pyrrolo[2,3‐d]pyrimidine‐4‐one 7a and 2‐amino‐5‐[(substituted‐benzyl)imino]methyl‐3,7‐dihydro‐4H‐pyrrolo[2,3‐d]pyrimidine‐4‐one 7b‐e derivatives as potential tyrosine kinase inhibitors. These compounds were synthesized by condensation reaction using 2‐tritylamino‐4‐oxo‐4,7‐dihydro‐3H‐pyrrolo[2,3‐d]pyrimidine‐5‐carbaldehyde 5 and appropriate benzylamines followed by detritylation. Compounds were evaluated for their inhibitory activity toward tyrosine phosphorylation for the pp60c‐Src tyrosine kinase. Compounds 7a, 7d, and 7e demonstrated potent inhibitory activities against pp60c‐Src tyrosine kinase with IC50 values of 13.9, 34.5, and 78.4 μM, respectively. Dihalogenated compounds 7d and 7e have 3 to 7‐times lower IC50 values than that of the parent compound 7a.

Evaluation of New Indole and Bromoindole Derivatives as pp60c-Src Tyrosine Kinase Inhibitors

A series of N‐benzyl‐indole‐3‐imine‐, amine derivatives and their 5‐bromo congeners were synthesized and their biological activity were evaluated against the pp60c‐Src tyrosine kinase target. To afford the imine derivatives, aldehydes were reacted with substituted benzylamines and the corresponding amine derivatives were obtained by NaBH4 reduction of these imines. Except insoluble N‐benzyl‐indole‐3‐imine derivatives, all the derivatives showed some activity against the kinase target. Screening of these compounds for their biological activity revealed that among N‐benzyl‐indole derivatives, those bearing 5‐bromo substitution have the enhanced potency, where the amine derivatives were more active than imines.

Synthesis and pp60c-Src tyrosine kinase inhibitory activities of novel indole-3-imine and amine derivatives substituted at N1 and C5.

A series of novel 1,3,5‐trisubstituted indole derivatives, namely, N‐benzyl 5‐phenyl indole‐3‐imine, N‐benzyl‐5‐(p‐fluorophenyl)indole‐3‐imine and their corresponding amine congeners, were designed and synthesized as pp60c‐Src tyrosine kinase inhibitors, and their inhibitory activities toward pp60c‐Src tyrosine kinase were evaluated by in‐vitro kinase assay. Pre‐screening at two doses of compounds against kinase target revealed that, except for the N‐benzyl‐5‐phenyl indole imine derivatives 7a–7d, all indole derivatives show the target inhibition at varying levels. Consequently, the compounds, 8c, 8f, 8g, and 8h, were selected for prescreening tests. The dose‐response curves for up to six concentrations (250 to 7.8 μM) of the active compounds were obtained by tyrosine kinase assay and the four‐parameter logistic analysis of these data resulted in the IC50s of 4.69, 74.79, 75.06, and 84.23 μM for compounds 8c, 8f, 8g, and 8h, respectively. Therefore, compound 8c, 1‐(1‐benzyl‐5‐phenyl‐1H‐indole‐3‐yl)‐N‐(4‐fluorobenzyl)methanamine·HCl, was the promising inhibitor for pp60c‐Src, followed by compounds 8g and 8h. Under the same conditions, compound 8f did not provide any reasonable inhibition pattern to be considered as active compound. Therefore, among all four active compounds, compound 8f was not found suitable for further analysis.

Novel aminomethylindole derivatives as inhibitors of pp60c-Src tyrosine kinase: synthesis and biological activity.

The pp60c‐Src is one of the ubiquitously expressed Src family kinases and has important functions in malignant cells, including regulation of cell division, growth factor signaling, and movement. Therefore, investigating new small molecule inhibitors of pp60c‐Src is important to discover and develop novel therapeutics for cancer and metastasis. Moreover, some of the small molecule inhibitors that do not qualify for therapeutic use may become very useful tool to explore the role of Src kinase in normal cells as well as in a variety of disease models. Our continuous efforts to find novel inhibitors of pp60c‐Src aimed for therapeutic and research use, we synthesized newly designed aminomethylindole derivatives as novel small molecule inhibitors and investigated their inhibitory effect on pp60c‐Src tyrosine kinase. Here, we report one potential inhibitor of the pp60c‐Src from five active molecules of all nine compounds, which were synthesized and screened for the biological activity of the molecules against pp60c‐Src target.

The potential medicinal value of plants from Asteraceae family with antioxidant defense enzymes as biological targets.

Abstract Context: Plants and most of the plant-derived compounds have long been known for their potential pharmaceutical effects. They are well known to play an important role in the treatment of several diseases from diabetes to various types of cancers. Today most of the clinically effective pharmaceuticals are developed from plant-derived ancestors in the history of medicine. Objective: The aim of this study was to evaluate the free radical scavenging activity and total phenolic and flavonoid contents of methanol, ethanol, and acetone extracts from flowers and leaves of Onopordum acanthium L., Carduus acanthoides L., Cirsium arvense (L.) Scop., and Centaurea solstitialis L., all from the Asteraceae family, for investigating their potential medicinal values of biological targets that are participating in the antioxidant defense system such as catalase (CAT), glutathione S-transferase (GST), and glutathione peroxidase (GPx). Materials and methods: In this study, free radical scavenging activity and total phenolic and flavonoid contents of the plant samples were assayed by DPPH, Folin–Ciocalteu, and aluminum chloride colorimetric methods. Also, the effects of extracts on CAT, GST, and GPx enzyme activities were investigated. Results and discussion: The highest phenolic and flavonoid contents were detected in the acetone extract of C. acanthoides flowers, with 90.305 mg GAE/L and 185.43 mg Q/L values, respectively. The highest DPPH radical scavenging was observed with the methanol leaf extracts of C. arvense with an IC50 value of 366 ng/mL. The maximum GPx and GST enzyme inhibition activities were observed with acetone extracts from the flower of C. solstitialis with IC50 values of 79 and 232 ng/mL, respectively.

The role of metal coordination complexes in cytosolic cellular defense

The metal coordination complexes are known to induce cytotoxic effects on various cell lines and shown to have great potential for therapeutic interventions. Their main mechanism of action is through the mediation of enzyme activities in signaling pathways essential for cellular functioning. The overall cellular responses are dose-dependent and require high exposure levels and duration to overcome cellular defense against external toxicants. However, their effect through signal transduction components is limited due to the conferred drug resistance associated with glutathione transferase (GST)-mediated mechanisms. The GST family of enzymes is not only related to anticancer drug resistance, but also associated with cancer development where they may also contribute kinase signaling events including non-receptor protein tyrosine kinase (PTK)-related pathways. In the current study, we evaluated the effect of symmetrical and mononuclear complexes of Pd(II), Pt(II), and Ni(II) with organic ligands on cytosolic targets involved in glutathione utilization, antioxidant defense, and kinase signaling by virtue of acellular in vitro analyses.

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 pp60c-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 IC50 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.

N-Substituted Indole-3-imine Derivatives and their Amine Congeners: Antioxidant and Src Kinase Inhibitory Effects

Current evidences demonstrated that the activity of protein kinases can be controlled through oxidative stress induced by reactive oxygen species (ROS) and normalized by antioxidants. Recent studies with ROS, generated by mitochondria, suggested the potential signalling role of these species, where ROS, especially hydrogen peroxide, were proposed as membrane-related signalling components. The protein regulation by cellular redox states has shown that protein tyrosine kinase members, such as Src kinase and some of the members of the Src family kinases (SFKs), are proteins regulated by the cellular oxidation and reduction status. In this context, the oxidant or antioxidant potential of the synthetic Src kinase inhibitors previously synthesized and studied by our research group, such as N-substituted indole-3-imine and -amine derivatives, were investigated employing various acellular in vitro methods including microsomal NADPH-dependent inhibition of lipid peroxidation (LP), interaction of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and scavenging of superoxide anion radicals. Here, we report that some of the synthetic inhibitors designed for Src kinase target have both antioxidant and kinase inhibition properties.