Synthesis of imidazo-thiadiazole linked indolinone conjugates and evaluated their microtubule network disrupting and apoptosis inducing ability

Abstract A series of imidazo[2,1- b ][1,3,4]thiadiazole linked indolinone conjugates were synthesized and investigated for antiproliferative activity in different human cancer cell lines by changing various substitutions at indolinone and phenyl ring systems. Among them conjugates 7 , 14 and 15 were exhibited potent antiproliferative activity with GI 50 values from 0.13 to 3.8 μΜ and evaluated for cell cycle analysis, tubulin polymerization assay and apoptosis. Treatment with 7 , 14 and 15 were resulted in accumulation of cells in G2/M phase, inhibition of tubulin assembly, disruption of microtubule network. Inhibition of tubulin polymerization was further supported by Western blot analysis. In addition, the conjugates ( 7 , 14 and 15) also showed apoptosis in HeLa cell line, detailed biological studies such as Hoechst 33,258 staining, DNA fragmentation and caspase-3 assays suggested that these compounds induce cell death by apoptosis. Docking studies revealed that these compounds ( 7 , 14 and 15) bind with αAsn101, αThr179, αSer178, βCys241, βLys254 and βLys352 in the colchicine-binding site of the tubulin.