Design and Synthesis of Novel Chalcone Derivatives Targeting Bladder and Liver Cancer: Cytotoxicity Evaluation and Preliminary Mechanistic Studies

The high incidence and mortality rates of bladder and liver cancers, combined with the challenges of early diagnosis, contribute to significant strain on healthcare systems. Standard chemotherapy treatments, which commonly use drug combinations, often cause intense side effects, reducing patient compliance and limiting therapeutic success. Considering the promising activity of a chalcone derivative of 2-methoxy-4-propylphenol against HepG2 cancer cells (hit compound <b>1</b>), discovered recently by our group, we synthesized new chalcone derivatives of this hit compound with three structural patterns to try to increase its activity, selectivity, and spectrum of action against other tumor lineages. Among the 12 new chalcones obtained, the <i>O</i>-methylated derivative <b>3</b> was the most promising one with IC₅₀ values between 3.03 and 5.92 μM against all evaluated cancer cells (HeLa, HepG2, T24, and TOV-21G) and selective indices up to 18.2 considering the healthy MRC-5 cells studied. The cytotoxicity of <b>3</b> against these human cells was lower compared to the hit compound <b>1</b>, and when compared to the control drug doxorubicin, this new chalcone exhibited higher selectivity indices across all of the evaluated cells. In addition to cytotoxicity, the compound inhibited clonogenicity and migration in bladder and liver cancer cells, independent of metabolic capacity, while inducing cytostasis in the liver and early apoptosis in bladder cancer cells.