Benzylidene thiazolidinediones: Synthesis, in vitro investigations of antiproliferative mechanisms and in vivo efficacy determination in combination with Imatinib

[Display omitted] •A series of benzylidene TZD derivatives with potent antiproliferative activity against K562 cells.•Compounds 3t and 3x could block the cell cycle in the sub G0/G1 phase.•Compounds 3t and 3x could inhibit the expression of cell proliferation markers, PCNA and Cyclin D1.•Compound 3x upregulated apoptosis markers, cleaved PARP1 and activated caspase 3.•Compounds 3t and 3x exhibited promising in vitro and in vivo antitumor activity in combination with Imatinib in the K562 xenografts. Thiazolidinedione (TZD) has been an interesting scaffold due to its proven antidiabetic activity and encouraging findings in anticancer drug discovery. We synthesised benzylidene thiazolidinedione derivatives which exhibited excellent antiproliferative effects in chronic myeloid leukemic cells K562 and the most active compounds 3t and 3x had GI50 value of 0.9 and 0.23 µM respectively. Both the compound was found to arrest the growth of K562 cells in G0/G1 phase in a time and dose dependent manner. Further, western blot analysis revealed that 3t and 3x could also inhibit the expression of cell proliferation markers, PCNA and Cyclin D1 and compound 3x up-regulated apoptosis markers, cleaved PARP1 and activated caspase 3, which could be a possible mechanism for the excellent antiproliferative effects exhibited by these compounds. In vitro combination studies of 3t and 3x with Imatinib found to potentiate the antitumor effects of Imatinib. Further in vivo efficacy in K562 xenografts, of 3t and 3x alone and in combination with Imatinib was found to be promising and far better than control group and combination treatment was found to be more effective as compared to only Imatinib treated or test compound treated animals. Thus, our findings suggest that these compounds are promising antitumor agents and could help to enhance the anticancer effects of Imatinib and other tyrosine kinase inhibitors, when used in combination.