Synthesis and biological evaluation of imidazolium conjugated with dimethylcardamonin (DMC) as a novel potential agent against MDA-MB-231 triple-negative breast cancer cells

A new imidazolium ionic liquid (IL) halide conjugated with dimethylcardamonin (DMC, 1 ), namely [Bbim]Br-DMC ( 3 ), was synthesised to improve the biological activity of the natural chalcone. DMC was isolated from seeds of Syzygium nervosum A. Cunn. ex DC. which was an effective anti-breast cancer agent. The compound 1 and 3 showed anticancer activity in MDA-MB-231 cells with IC 50 values of 14.54 ± 0.99 μM and 7.40 ± 0.15 μM, respectively. MTT assay showed that compound 3 had cytotoxic effect at least two-fold greater than compound 1 but was low toxic to normal cells of Hs 578Bst. After 48 h, compound 3 at concentration of IC 50 value inhibited the proliferation and induced morphological changes of MDA-MB-231 cells in a time-dependent manner. The cell cycle profile also showed that compound 3 exerted anti-proliferation activity with the cell cycle arrest at G0/G1 phase and compound 3 also induced apoptosis and reduced mitochondrial membrane potential in MDA-MB-231 cells in a dose-dependent manner. In gene expression assay, compound 3 up-regulated pro-apoptotic genes such as Bax and p53 and suppressed anti-apoptotic Bcl-2 whereas there was no effect on DNA repair gene such as PARP1 . The Bax / Bcl-2 ratio was significantly increased after treated with compound 3 . In the molecular docking study, the interactions between compound 3 and B-DNA structure in the minor groove region via hydrogen bonds was reported. In conclusion, [Bbim]Br-DMC or compound 3 is a potential candidate to induce apoptosis and inhibits proliferation via cell cycle arrest and decreases mitochondrial membrane of triple-negative breast cancer MDA-MB-231 cells. • [Bbim]Br-DMC (compound 3 ) showed greater antiproliferative activity in MDA-MB-231 and MCF-7 breast cancer cell lines. • Compound 3 significantly induced DNA damage, apoptosis, prolonged in G0/G1 phase, and decreased MMP expression level. • Compound 3 promotes intrinsic apoptosis pathway by upregulated Bax and p53 , and downregulated Bcl-2 , and Bax/Bcl-2 ratio. • Compound 3 indicated potential antiproliferative activity by the interaction with DNA, and bring to DNA damage.