Exploring the Chemical Space Around Protoflavonoids: Synthesis and Antitumor Activity of Protochalcones

Natural and synthetic protoflavonoids exhibit a wide range of anticancer activities, including strong antiproliferative, proapoptotic, and DNA damage response‐inhibitory activities; however, the surrounding chemical space has remained largely unexplored. In this study, we report the synthesis and biological evaluation of a focused compound library containing the p ‐hydroxydienone pharmacophore of protoflavonoids. Eleven derivatives were synthesized and characterized from chalcone precursors, and their antiproliferative activity was evaluated in four human adherent gynecological cancer cell lines (MCF‐7, MDA‐MB‐231, HeLa, and SiHa). The investigated compounds exhibited mild to strong activity, with several showing notable selectivity for triple‐negative MDA‐MB‐231 cells. Our findings suggest that the unexplored chemical space around protoflavonoids might encompass compounds with valuable bioactivity and warrant further research.