Synthesis of (Z)-(arylamino)-pyrazolyl/isoxazolyl-2-propenones as tubulin targeting anticancer agents and apoptotic inducers

Abstract

A new class of pyrazole and isoxazole conjugates were synthesized and evaluated for their cytotoxic activity against various human cancer cell lines. These compounds have shown significant cytotoxicity with lower IC₅₀ values. FACS results revealed that A549 cells treated with these compounds arrested cells at the G2/M phase of the cell cycle apart from activating cyclin B1 protein levels. Particularly, compounds 9a and 9b demonstrated a remarkable inhibitory effect on tubulin polymerization and showed a pronounced inhibitory effect on tubulin polymerization with IC₅₀ values of 1.28 μM and 0.28 μM respectively, whereas nocodazole, a positive control, has shown lower antitubulin activity with an IC₅₀ value of 2.64 μM. Furthermore, these compounds induced apoptosis by loss of mitochondrial membrane potential, propidium iodide (PI) staining and the activation of caspase-3. Results of a fluorescence based competitive colchicine binding assay suggest that these conjugates bind successfully at the colchicine binding site of tubulin. These investigations reveal that such conjugates containing pyrazole with a trimethoxy phenyl ring and indole moieties have potential for the development of newer chemotherapeutic agents.