Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences · 2026
Novel 3,3'-diindolylmethane derivatives as multi-pathway modulators: targeting estrogen-dependent and independent breast cancer carcinogenesis.
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Ince-Erguc Elif, Entezari Bita, Sirinzade Hanif, Suzen Sibel, Akdemir Atilla, Erdogan Oguz, Gurer-Orhan Hande
Аннотация
PURPOSE: Breast cancer remains a leading cause of cancer-related mortality among women, with prolonged exposure to endogenous estrogens recognized as a major risk factor. This study aimed to design, synthesize, and pharmacologically evaluate novel 3,3'-diindolylmethane (DIM) derivatives as multi-target modulators of estrogen-related pathways in breast cancer.
METHODS: A series of DIM derivatives was synthesized and structurally characterized. Their biological activities were assessed through aromatase (CYP19A1) and CYP1B1 inhibition assays, E-screen assay for estrogen receptor activity, cytotoxicity assays in breast cancer (MCF-7 BUS, MDA-MB-231) and normal breast epithelial (MCF-10 A) cells, and scratch assay for cell migration. Molecular docking and in silico ADME analyses were conducted to support experimental findings.
RESULTS: The derivatives demonstrated significant antiestrogenic activity by targeting multiple components of estrogen signaling. One compound exhibited potent aromatase inhibition (IC₅₀ = 0.79 µM), while two derivatives showed strong CYP1B1 inhibition (IC₅₀ = 0.37 µM and 0.71 µM). Selective cytotoxicity was observed in estrogen receptor-positive cells, with reduced effects on normal cells. Additionally, selected compounds significantly inhibited cell migration. Molecular modeling revealed favorable binding interactions within target enzymes, and ADME analysis indicated acceptable drug-like properties.
CONCLUSION: These findings suggest that DIM derivatives act as selective, multi-target modulators of estrogen-related pathways and may serve as promising adjuvant candidates for hormone-dependent breast cancer therapy.
METHODS: A series of DIM derivatives was synthesized and structurally characterized. Their biological activities were assessed through aromatase (CYP19A1) and CYP1B1 inhibition assays, E-screen assay for estrogen receptor activity, cytotoxicity assays in breast cancer (MCF-7 BUS, MDA-MB-231) and normal breast epithelial (MCF-10 A) cells, and scratch assay for cell migration. Molecular docking and in silico ADME analyses were conducted to support experimental findings.
RESULTS: The derivatives demonstrated significant antiestrogenic activity by targeting multiple components of estrogen signaling. One compound exhibited potent aromatase inhibition (IC₅₀ = 0.79 µM), while two derivatives showed strong CYP1B1 inhibition (IC₅₀ = 0.37 µM and 0.71 µM). Selective cytotoxicity was observed in estrogen receptor-positive cells, with reduced effects on normal cells. Additionally, selected compounds significantly inhibited cell migration. Molecular modeling revealed favorable binding interactions within target enzymes, and ADME analysis indicated acceptable drug-like properties.
CONCLUSION: These findings suggest that DIM derivatives act as selective, multi-target modulators of estrogen-related pathways and may serve as promising adjuvant candidates for hormone-dependent breast cancer therapy.