Activity–Selectivity of Flavonoid Derivatives in Endometriotic Cells

High Resolution Image Download MS PowerPoint Slide Natural polyphenolics, more specifically flavonoids and derivatives, constitute chemically versatile scaffolds with a broad biological potential. In this study, different flavonoid derivatives ( 1 – 37 ) were assessed for cytotoxicity in Ishikawa and 12Z epithelial cell lines, serving as models of eutopic endometrium and endometriosis, respectively, to elucidate structure–activity relationships. Flavonoids bearing multiple hydroxyl and methoxy substituents exhibited high polarity, an elevated topological polar surface area (TPSA), and numerous hydrogen-bond donors and acceptors, consistently demonstrating low cytotoxicity and, in several cases, cytoprotective effects. In contrast, chalcones containing electron-withdrawing substituents (−NO 2 and −Cl) and higher lipophilicity (log P > 3.5) displayed marked and selective toxicity toward 12Z cells. Among these, compounds 24 [( E )-3-(4-(dimethylamino)phenyl)1-(3-hydroxyphenyl)prop-2-en-1-one] and 28 [( E )-3-(benzo[ d ][1,3]dioxol-5-yl)-1-(4-chlorophenyl)prop-2-en-1-one)] emerged as the most promising selective candidates, reducing 12Z cell viability to approximately 50% while maintaining or enhancing Ishikawa cell viability (>100%). Additional derivatives, including 14 [( E )-3-(benzo[ d ][1,3]dioxol-5-yl)-1-phenylprop-2-en-1-one], 17 [( E )-3-(benzo[ d ][1,3]dioxol-5-yl)-1-(4-nitrophenyl)prop-2-en-1-one], 23 [( E )-3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one], and 30 [( E )-1-phenyl-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one], also exhibited statistically significant selectivity. Correlation analysis further revealed a strong association between lipophilicity and 12Z cytotoxicity ( r = −0.73), whereas elevated TPSA and extensive hydrogen bonding correlated with cytoprotective behavior. Collectively, these results highlight chalcones as promising molecular frameworks in which substituent-dependent physicochemical properties are associated with distinct biological outcomes, ranging from selective endometriotic cytotoxicity to endometrial cytoprotective effects.