Glycine-conjugated coumarin–quinazoline hybrids as potent anticancer agents: synthesis, cytotoxicity, SAR and molecular docking studies
BIOORGANIC CHEMISTRY, ss.1-10, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.bioorg.2026.110394
- Dergi Adı: BIOORGANIC CHEMISTRY
- Derginin Tarandığı İndeksler: Academic Search Ultimate (EBSCO), Scopus, Science Citation Index Expanded (SCI-EXPANDED), BIOSIS, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE
- Sayfa Sayıları: ss.1-10
- İstanbul Medipol Üniversitesi Adresli: Evet
Özet
A novel series of twelve coumarin–quinazoline hybrids, comprising six glycine-conjugated (9a–f) and six directly linked analogues (8a–f), was synthesized and characterized by FT-IR, 1H/13C NMR, elemental analysis and LC-MS. Cytotoxicity was assessed against PC-3 prostate, PANC-1 pancreatic, A549 lung and MCF-7 breast cancer cell lines by the MTT assay, with HEK-293 cells used to estimate selectivity and with doxorubicin, cisplatin and gemcitabine as reference drugs. Most hybrids were active in the low micromolar range (3.56–6.96 μM) and gave selectivity indices of up to 3.17, compared with 1.14–1.65 for doxorubicin. Compound 9d was the most active against A549 (IC50 = 3.57 ± 0.05 μM), whereas 9c and 9f were the most active against PANC-1 (IC50 = 3.56 ± 0.05 μM), several derivatives exceeding the reference drugs in individual cell lines. Cell-cycle, Annexin V/PI and LDH-release experiments showed a uniform G0/G1 accumulation with depletion of the S-phase population, indicating apoptotic cell death rather than non-specific membrane damage. Molecular docking against PI3Kα, PI3Kγ and ribonucleotide reductase indicated that the glycine linker provides the conformational flexibility required to reproduce key interactions of the co-crystallized ligands, and the G0/G1 arrest was consistent with PI3K rather than RNR inhibition. To the best of our knowledge, glycine conjugation of a coumarin–quinazoline hybrid has not been reported previously, and the results identify it as a substituent- and cell-line-dependent strategy for improving anticancer potency and selectivity.