Novel coumarin-6-sulfonamides as apoptotic anti-proliferative agents: synthesis, in vitro biological evaluation, and QSAR studies

Herein, we report the synthesis of different novel sets of coumarin-6-sulfonamide derivatives bearing different functionalities (4a, b, 8a–d, 11a–d, 13a, b, and 15a–c), and in vitro evaluation of their growth inhibitory activity towards the proliferation of three cancer cell lines; HepG2 (hepatocellular carcinoma), MCF-7 (breast cancer), and Caco-2 (colon cancer). HepG2 cells were the most sensitive cells to the influence of the target coumarins. Compounds 13a and 15a emerged as the most active members against HepG2 cells (IC(50) = 3.48 ± 0.28 and 5.03 ± 0.39 µM, respectively). Compounds 13a and 15a were able to induce apoptosis in HepG2 cells, as assured by the upregulation of the Bax and downregulation of the Bcl-2, besides boosting caspase-3 levels. Besides, compound 13a induced a significant increase in the percentage of cells at Pre-G1 by 6.4-folds, with concurrent significant arrest in the G2-M phase by 5.4-folds compared to control. Also, 13a displayed significant increase in the percentage of annexin V-FITC positive apoptotic cells from 1.75–13.76%. Moreover, QSAR models were established to explore the structural requirements controlling the anti-proliferative activities.