| Yazarlar (7) |
Blinera Zognjani
|
|
Arleta Rifati Nixha
|
Doç. Dr. Hatice Esra DURAN
Kafkas Üniversitesi, Türkiye |
|
Mustafa Arslan
|
|
Gizem Yildiztekin
|
|
Abdulilah Ece
|
|
Cueneyt Turkes
|
| Özet |
| Aldose reductase (ALR2; AKR1B1), a NADPH-dependent cytosolic oxidoreductase, plays a central role in the polyol pathway and is implicated in hyperglycemia-induced tissue injury. Beyond its metabolic function, elevated ALR2 expression has been reported in several malignancies, including hepatocellular and pulmonary carcinomas, highlighting its potential as a therapeutic target in metabolic-oncologic interface. In this study, a novel set of eleven N-substituted phthalimide-carboxylic acid derivatives (5a-5k) was synthesized and evaluated for ALR2 inhibition, pharmacokinetic characteristics, and cancer-selective safety. Among the series, compound 5f demonstrated the highest inhibitory potency (K = 7.34 nM), outperforming epalrestat (K = 232.1 nM). Glide docking positioned 5f within the ALR2 active site (GlideScore: -6.71 kcal/mol), stabilized via key contacts with Tyr48, His110, and Cys298, along with π-π stacking at Trp219. MM-GBSA analysis corroborated strong binding affinity (ΔG = -64.86 kcal/mol). DFT-derived quantum descriptors, logP, TPSA, and solvation energies supported its favorable interaction profile. ADME/Tox predictions indicated high GI absorption, no P-gp or CYP liabilities, and acceptable bioavailability. In vitro cytotoxicity assays showed negligible activity of 5f against A549 and Hep3B cancer cell lines (IC₅₀ > 160 μM) and no toxicity toward L929 fibroblasts, reflecting safety for long-term use. Transcriptomic data from CCLE and DepMap confirmed AKR1B1 overexpression in these cancer models. Network analysis linked ALR2 to redox imbalance and inflammation, suggesting its broader role in tumorigenesis. |
| Anahtar Kelimeler |
| Aldose reductase inhibitors | Polyol pathway modulation | N -substituted phthalimides | Structure-activity-energy relationship | Molecular docking and MM-GBSA | Protein-protein interaction | Lead optimization |
| Makale Türü | Özgün Makale |
| Makale Alt Türü | SSCI, AHCI, SCI, SCI-Exp dergilerinde yayınlanan tam makale |
| Dergi Adı | Bioorganic Chemistry |
| Dergi ISSN | 0045-2068 Wos Dergi Scopus Dergi |
| Dergi Tarandığı Indeksler | SCI-Expanded |
| Dergi Grubu | Q1 |
| Makale Dili | Türkçe |
| Basım Tarihi | 08-2025 |
| Cilt No | 163 |
| Doi Numarası | 10.1016/j.bioorg.2025.108788 |
| Makale Linki | https://doi.org/10.1016/j.bioorg.2025.108788 |
| Atıf Sayıları | |
| WoS | 1 |
| Google Scholar | 2 |
