Title : Novel Azine Linked Hybrids of 2-indolinone and Thiazolodinone Scaffolds as CDK2 inhibitors with potential anticancer activity
Abstract:
In recent years, cell cycle and checkpoint pathways regulation are offering new therapeutic approaches against cancer. 2-Indolinone, is a well exploited scaffold in the anticancer domain. Accordingly, the current work describes merged structural hybrids and ligand based design and synthesis of novel derivatives of (Z)-3-substituted-2-(((E/Z)-5-substituted-2-oxo-1-substituted-indolin-3-ylidene)hydrazin-ylidene)thiazolidin-4-ones. These hybrids were tested in vitro for their cytotoxicity against three human epithelial cell lines, liver (HepG2), breast (MCF-7), and colon (HT-29) in addition to the diploid human normal cells (WI-38) compared to doxorubicin as a reference drug. Variable cytotoxic effects (IC50 2.59 – 100 micromole) were obtained by these molecules on the three cancer cell lines with pronounced selectivity compared to the normal one WI-38. The most active compounds, with IC50 2.59 – 9.17 micromole, were tested on the expression of four genes ; p53, cdk2, caspase3, and topoisomerase II (topoII) in HepG2 cells as cell cycle key genes for revealing the possible molecular mechanism(s) of their antiproliferative efficacy.
As a general pattern the tested compounds elevated the expression of p53 and caspase3 by 4-5-folds, and downregulated the expression of cdk2 and topoII by 47 - 56%, compared to untreated cells. It is worthy to note that these compounds exert their antiproliferative activity on more than one molecular target.
Apoptotic effect of the most active compound was further investigated using annexin V-FITC/PI dual staining assay and showed that cells treated with this molecule have nearly 18 folds greater effect than that of the control cells. Furthermore, inhibitory activity of the top active five compounds on CDK2 enzyme were tested and revealed that these molecules have comparable inhibitory activity to the reference drug sunitinib.
