Design, Synthesis and Antiproliferative Activities of Oxidative Stress Inducers Based on 2-styryl-3,5-dihydro-4H-imidazol-4-one Scaffold

Abstract

The 2-styryl-3,5-dihydro-4H-imidazol-4-one might be considered as a system with isosteric properties similar to trans-Cinnamaldehyde (styrylaldehyde), a safe natural compounds that exhibited interesting activities against various cancers. We synthesized a series of compounds that differ structurally in having different alkyl, aryl and heterocyclic substituents at the N3 position of the 2-styryl-4-imidaolone pharmacophore. The compounds were assayed for their cytotoxicity against both cancer and normal cell lines. In addition, their cellular mechanism of action as ROS inducers were investigated. Many of the synthesized compounds showed higher activities on colon, breast and hepatic cancer cell lines than the parent trans-cinnamaldehyde. Compounds 3a and 3e showed selective antiproliferative activity against cancer cell lines at low micromolar to sub-micromolar IC₅₀ value. Compounds were extremely less toxic on normal cell lines BHK and WI-38. Similar to trans-Cinnamaldehyde, the colon cancer cell cycle analysis indicated cell cycle changes consistent with increased oxidative stress leading to apoptosis. Compound 3e caused elevation of all cell oxidative indicators of reactive oxygen species such as a decrease in reduced glutathione, increased malondialdehyde and suppression of catalase and superoxide dismutase activities. Dihydroethidium staining, nuclear fragmentation and increased caspase-3 further confirmed extensive apoptotic induction due to ROS accumulation upon treatment of HCT116 cells with compounds 3a and 3e. Changes in MCF7 cells were less revealing for ROS induction and increased oxidative stress. Conclusion: The compounds represent an example of efficient rescaffolding of a natural compound to a highly potent drug-like analogues.