Activity of novel quinoxaline-derived chalcones on in vitro glioma cell proliferation

Gliomas are the most common and devastating tumors of the central nervous system (CNS). Many pieces of evidence point out the relevance of natural compounds for cancer therapy and prevention, including chalcones. In the present study, eight synthetic quinoxaline-derived chalcones, structurally based on the selective PI3Kγ inhibitor AS605240, were evaluated for anti-proliferative activity and viability inhibition using glioma cell lines from human and rat origin (U-138 MG and C6, respectively), at different time-periods of incubation and concentrations. The results revealed that four chalcones (compounds 1, 6, 7 and 8), which present methoxy groups at A-ring, displayed higher efficacies and potencies, being able to inhibit either cell proliferation or viability, in a time- and concentration-dependent manner, with an efficacy that was greater than that seen for the positive control compound AS605240. Flow cytometry analysis demonstrated that incubation of C6 cells with compound 6 led to G1 phase arrest, likely indicating an interference with apoptosis. Furthermore, compound 6 was able to visibly inhibit AKT activation, allied to the stimulation of ERK MAP-kinase. The chalcones tested herein, especially those displaying a methoxy substituent, might well represent promising molecules for the adjuvant treatment of glioma progression.

Graphical abstractChalcones derived from quinoxaline-6-carbaldehyde, structurally based on the selective PI3Kγ inhibitor AS605240, were assayed in glioma cell lines from human and rat origin (U-138 MG and C6, respectively), and compound 6 presented the best activity (2.64 μM for U-138 MG cells and 1.35 μM for C6 cells).Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Synthetic chalcones, based on the PI3Kγ inhibitor AS605240 were evaluated. ► The anti-proliferative activity was assessed on two glioma cell lines. ► Four of the tested chalcones displayed higher efficacies and potencies. ► Chalcone 6 led to G1 phase arrest, AKT inhibition and ERK 1/2 activation.