# Activity–Selectivity of Flavonoid Derivatives in Endometriotic Cells

## TL;DR

This study explores how different flavonoid derivatives affect endometriotic and healthy endometrial cells, identifying promising compounds with selective toxicity.

## Contribution

The paper identifies specific chalcone derivatives with selective toxicity toward endometriotic cells based on their physicochemical properties.

## Key findings

- Flavonoids with multiple hydroxyl and methoxy groups showed low cytotoxicity and cytoprotective effects.
- Chalcones with electron-withdrawing substituents and higher lipophilicity exhibited selective toxicity toward endometriotic 12Z cells.
- Compounds 24 and 28 significantly reduced 12Z cell viability while enhancing Ishikawa cell viability.

## Abstract

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.