Inhibition of protein kinases by anticancer DNA intercalator, 4-butylaminopyrimido[4′,5′:4,5]thieno(2,3-b)quinoline

Targeting protein kinases (PKs) has been a promising strategy in treating cancer, as PKs are key regulators of cell survival and proliferation. Here in this study, we studied the ability of pyrimido[4′,5′:4,5]thieno(2,3-b)quinolines (PTQ) to inhibit different PKs by performing computational docking and in vitro screening. Docking studies revealed that 4-butylaminopyrimido[4′,5′:4,5]thieno(2,3-b)quinoline (BPTQ) has a higher order of interaction with the kinase receptors than other PTQ derivatives. In vitro screening confirms that BPTQ inhibits VEGFR1 and CHK2, with the IC50 values of 0.54 and 1.70 µmol/L, respectively. Further, cytotoxicity of BPTQ was measured by trypan blue assay. Treatment with BPTQ decreased the proliferation of HL-60 cells with an IC50 value of 12 µmol/L and induces apoptosis, as explicated by the fall in the mitochondrial membrane potential, annexin V labeling and increased expression of caspase-3. Taken together, these data suggest that BPTQ possess ability to inhibit PKs and to induce cell death in human promyelocytic leukemia cells.

Graphical abstractIn this study, the ability of pyrimido[4′,5′:4,5]thieno(2,3-b)quinoline derivatives to interact with different protein kinases was analyzed by molecular docking. 4-Butylaminopyrimido[4′,5′:4,5]thieno(2,3-b)quinoline (BPTQ) showed a higher order of interaction compared to other derivatives, and effectively inhibited the VEGFR1 and CHK2. BPTQ also induced apoptosis in cancer cells.Download high-res image (292KB)Download full-size image