Development of hydrazide hydrazone-tethered combretastatin-oxindole derivatives as antimitotic agents

Abstract

A series of new combretastatin-oxindole derivatives via hydrazide hydrazone linker was synthesized by condensation using (E)-bis(phenyl) acrylohydrazides and substituted isatins as synthetic precursors. To determine the potential of these new derivatives, in vitro cytotoxic activity was evaluated using different cancer cell lines, particularly of lung, colorectal, breast and skin origin. A viability study also performed for the most potent compound 9o on HaCaT cells showed its non-toxic nature toward non-malignant cell line. Cell viability assay revealed that derivative 9o with trimethoxy substitution on ring A and N-benzyl substitution on isatin ring exhibited potent anti-cancer activity against lung cancer (A549) cell line with IC50 value 1.26±1.03 µM. Further, staining studies were performed using DAPI, AO/EB to determine induction of changes in nuclear morphology, DNA damage and apoptosis which was also affirmed by annexin V-FITC/PI assay, suggesting involvement of apoptotic mechanism in inhibition of cell growth. Additionally, inducing effect of compound 9o on ROS production indicates ROS-mediated cell death of unwanted cells as well as regulation of apoptosis. The antimitotic attribute was affirmed from cell cycle arrest at G2/M phase and tubulin polymerization inhibition property of compound 9o (IC50 0.17 µM). It is worth mentioning that the pattern of all results was alike standard colchicine. Furthermore, molecular modeling studies were also conducted to determine the binding interaction and ADMET profile of 9o on 3E22 protein.