Design, synthesis and tubulin polymerization inhibition activity of newly synthesized hydrazone-linked to combretastatin analogues as potential anticancer agents

A new series of hydrazone derivatives were synthesized by varying the active part (hydrazide group) of cis-vinyl amide derivatives, characterized by 1H NMR, 13C NMR spectral data and screened for their cytotoxic activity against MCF-7 breast cancer cell line. Results indicated that compounds 3 g, 3k and 4 were potent cytotoxic agents (IC50 = 4.02-5.36 & mu;M) relative to CA-4 as a reference compound. The most active hydrazinyl compounds were further evaluated for the & beta;-tubulin inhibition activity. Cellular cycle analysis of the inhibitory effect of N(furan-2-ylmethylene)hydrazinyl 4 on each phase of the cell cycle of breast adenocarcinoma MCF-7 cells was investigated using flow cytometric analysis. Test compound elicited cellular cycle arrest at G2/M phase. Annexin V dual staining analysis results revealed that treatment of MCF-7 cells with N-(furan-2-ylmethylene)hydrazinyl 4 increase the percentage of apoptosis compared to negative untreated control. Besides, N-(furan-2-ylmethylene) hydrazinyl 4 induced apoptosis via decreased the level of mitochondrial membrane potential relative to untreated control cells as revealed by flow cytometry analysis. Moreover, molecular modeling investigations were conducted to clarify the manner in which the most potent compound binds within the tubulin's colchicinebinding pocket, thereby elucidating the reasons behind its exceptional cytotoxicity and its superior ability to inhibit tubulin when compared to CA-4.

Automated summary

A new series of hydrazone derivatives were synthesized and screened for their cytotoxic activity against MCF-7 breast cancer cell line. Some compounds exhibited potent cytotoxicity and inhibition of β-tubulin. Flow cytometric analysis revealed that one compound induced cell cycle arrest at G2/M phase and increased apoptosis compared to untreated control. Molecular modeling investigations were conducted to explain the compound's exceptional cytotoxicity and superior ability to inhibit tubulin when compared to CA-4.