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Novel 3,3'-diindolylmethane derivatives as multi-pathway modulators: targeting estrogen-dependent and independent
Elif Ince-Erguc1, Bita Entezari2,3, Hanif Sirinzade4
1Department of Pharmaceutical Toxicology, Izmir Kâtip Çelebi University, Izmir, Turkey.
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.
Insights
Novel 3,3'-diindolylmethane (DIM) derivatives show promise as multi-target drugs for hormone-dependent breast cancer, effectively inhibiting estrogen pathways and cancer cell growth while sparing normal cells.
Area of Science:
- Medicinal Chemistry
- Oncology
- Endocrinology
Background:
- Breast cancer mortality is high, with estrogen exposure a key risk factor.
- Targeting estrogen pathways is crucial for hormone-dependent breast cancer treatment.
Purpose of the Study:
- Design, synthesize, and evaluate novel 3,3'-diindolylmethane (DIM) derivatives.
- Investigate their potential as multi-target modulators of estrogen-related pathways in breast cancer.
Main Methods:
- Synthesized and characterized DIM derivatives.
- Assessed biological activities including aromatase (CYP19A1) and CYP1B1 inhibition, estrogen receptor activity, cytotoxicity, and cell migration.
- Utilized molecular docking and in silico ADME analyses.
Main Results:
- Derivatives displayed significant antiestrogenic activity and multi-target inhibition.
- Achieved potent aromatase and CYP1B1 inhibition.
- Showed selective cytotoxicity in ER-positive breast cancer cells and inhibited cell migration.
Conclusions:
- DIM derivatives act as selective, multi-target modulators of estrogen pathways.
- These compounds show potential as adjuvant therapy for hormone-dependent breast cancer.
