Naphthalimide derivatives as thalidomide analogs; design, synthesis, and molecular docking of novel anticancer immunomodulatory agents

Abstract

A new series of naphthalimide derivatives were designed and synthesized to afford novel potent antitumor immunomodulatory thalidomide analogs. The synthesized compounds were assayed for their cytotoxic activities against a panel of three cancer cell lines (HepG-2, HCT-116, and MCF-7). Compound 5c demonstrated the most potent activity, particularly against HepG-2 (2.74 ± 0.1 μM) and MCF-7 (3.93 ± 0.2 μM) cells, suggesting its high efficacy. Compounds 5a, 5b, and 7d also showed significant cytotoxicity, with IC₅₀ values below 20 μM for most cell lines. Compound 5a was further evaluated for its immunomodulatory activities through estimation of different immunomodulators in HepG-2 cells. It showed a considerable reduction in human tumor necrosis factor alpha (TNF-α) and a potential inhibition of human vascular endothelial growth factor (VEGF). In addition, 5a caused a significant increase of human caspase-8 (CASP8) and interferon-gamma (IFN-γ) levels. Also, two apoptotic markers have been estimated upon treatment of HepG-2 cells with compound 5a. The results confirmed the ability of the compound to induce apoptosis. Moreover, the effect of 5a on the cell cycle was measured.