Activity–Selectivity of Flavonoid Derivatives in Endometriotic Cells

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 (-NO2 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.