Immunomodulation and anticancer evaluation of quinazoline-based thalidomide analogs: Design, synthesis, docking, and dynamic simulation

• DOI: 10.1016/j.molstruc.2024.139082
• Publication Date: 2024-06-21T00:55:59Z
• Authors: Abdallah E. Abdallah; Ibrahim H. Eissa; Ahmed B.M. Mehany; Helmy Sakr; Tamer M Sakr; K.H. Metwaly; Ismail Celik; Khaled El-Adl; Mohamed Ayman El-...
• Keywords: Quinazoline; Docking (animal)

A new series of thalidomide analogs were synthesized and evaluated against HepG-2, HCT-116, PC3, and MCF-7. With IC50 values ranging from 2.41 to 14.78 μM, compounds 4c, 5 g, and 7 demonstrated substantial potencies against all examined cell lines in comparison to thalidomide (IC50 = 32.12 - 76.91 μM)). The most active compounds were further evaluated for their in vitro immunomodulatory activities via IL6, TNF-α and human caspase-3 in MCF-7 cells using thalidomide as a positive control. Compounds 5 g and 4c showed significant reductions in IL6 (80.65 %) and TNF-α (76.14 %), compared to thalidomide (45.11 % and 41.39, respectively). Furthermore, compound 4c exhibited a significant elevation in caspase-3 level (409.33 pg/mL) compared to thalidomide (349.55 pg/mL). In addition, the most active compounds were examined for their COX-I, COX-II, VEGFR inhibitory activities. Compound 5 g was the most active member against COX-I (0.80 μM), compound 4c was the most active member against COX-II (0.80 μM), and compound 4c was the most active member against VEGFR (253 nM). Furthermore, the flowcytometry analyses revealed that compound 4c can arrest the cell line at Pre-G1 phase and induce a significant apoptotic effect (75.75 %) compared to control cells (2.62 %) and thalidomide (65.34 %). Our derivatives were subjected to molecular modeling to assess their binding to Cereblon and also dynamic simulations.