Imidazole-functionalized cyclotriphosphazene derivatives: Synthesis, biological evaluation and molecular insights into glioblastoma inhibition
Inorganic Chemistry Communications, cilt.194, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 194
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.inoche.2026.117514
- Dergi Adı: Inorganic Chemistry Communications
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Chimica, DIALNET
- Anahtar Kelimeler: ADMET, Anti-cancer, Brain cancer, Cyclotriphosphazene, Imidazole/benzimidazole, Molecular docking
- Kocaeli Üniversitesi Adresli: Evet
Özet
In this study, the anticancer activity of two imidazole-substituted cyclotriphosphazene derivatives, MCp (2-methylimidazole) and BCp (benzimidazole), was systematically evaluated in glioblastoma models (U87 and LN229) through an integrated in vitro–in silico approach. Both compounds induced a significant dose-dependent reduction in cell viability, showing higher selectivity toward glioblastoma cells compared to non-malignant MRC-5 cells, and promoted apoptosis as the primary mode of cell death. In addition, they caused pronounced G0/G1 phase cell cycle arrest and suppressed cell proliferation. Beyond cytotoxic effects, both compounds reduced wound closure in U87 cells, an effect consistent with anti-migratory activity, although a contribution from concurrent antiproliferative effects cannot be excluded. Gene expression analyses supported these findings, revealing upregulation of the pro-apoptotic gene BAX, downregulation of BCL-2, and decreased expression of CCND1, MMP2, and MMP9, along with modulation of epithelial–mesenchymal transition markers through increased CDH1 and decreased VIM expression. Molecular docking studies suggested that BCp exhibited a broader multi-target binding profile, while MCp showed more selective interactions, particularly with MDM2. Both compounds displayed favorable binding affinities toward key proteins involved in apoptosis (MDM2), cell cycle regulation (WEE1), growth signaling (EGFR), and DNA repair (MGMT), supporting a multi-pathway mechanism of action. In addition, in silico ADMET analysis revealed distinct pharmacokinetic and toxicity profiles for MCp and BCp, including predicted BBB permeability. Overall, these findings indicate that imidazole-based cyclotriphosphazene derivatives exert potent anticancer effects in glioblastoma through coordinated regulation of apoptosis, cell cycle progression, and cell migration, highlighting their promise as multi-target therapeutic candidates for further development in brain cancer treatment.