Novel 3,3′-diindolylmethane derivatives as multi-pathway modulators: targeting estrogen-dependent and independent breast cancer carcinogenesis
DARU, Journal of Pharmaceutical Sciences, cilt.34, sa.2, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 34 Sayı: 2
- Basım Tarihi: 2026
- Doi Numarası: 10.1007/s40199-026-00625-x
- Dergi Adı: DARU, Journal of Pharmaceutical Sciences
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CINAHL, EMBASE, MEDLINE, Academic Search Ultimate (EBSCO), Middle East & Africa Database (ProQuest), Natural Science Collection (ProQuest), Biological Science Database (ProQuest), Biomedical Reference Collection: Corporate Edition (EBSCO), Health Research Premium Collection (ProQuest)
- Anahtar Kelimeler: 3,3-Dindolylmethane derivatives, Aromatase, Breast cancer, CYP1B1, Cytotoxicity, Estrogen receptor
- İstanbul Kent Üniversitesi Adresli: Evet
Özet
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.