Glycine-conjugated coumarin-quinazoline hybrids as potent anticancer agents: synthesis, cytotoxicity, SAR and...

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.