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.