Targeting tubulin polymerization and DNA binding of 4-thiazolidinone-umbelliferone hybrids: synthesis and cytotoxicity evaluation

The discovery of a series of combretastatin A-4 inspired novel molecular hybrids of 4-thiazolidinone-umbelliferone as prominent cytotoxic agents is reported. Representative compounds exhibited potent anti-proliferative activities against four human cancer cell lines (A549, MDA-MB-231, THP-1 and HL-60). Amongst the compounds tested, 7q showed the highest potency against A549 cells with an IC50 value of 0.96 +/- 1.09 mu M and a selectivity index of 51.7. The flow cytometric analysis of compound 7q treated A549 cells showed apoptosis induction by the annexin-v/PI dual staining assay and the effect of 7q on different phases of the cell cycle was also analyzed. Target based studies demonstrated inhibition of tubulin polymerization by 7q at an IC50 value of 2.65 +/- 0.47 mu M and its effective binding with CT-DNA. Further, molecular modelling studies revealed that 7q has a prominent binding affinity towards the alpha/beta-tubulin receptor with remarkable protein-ligand interactions and binding energy.

Automated summary

A series of novel cytotoxic agents inspired by combretastatin A-4 were reported, with compound 7q showing the highest potency against A549 cells through induction of apoptosis and inhibition of tubulin polymerization. Molecular modeling studies revealed 7q's prominent binding affinity towards the alpha/beta-tubulin receptor with remarkable protein-ligand interactions.