Novel Diselenide Bis-Schiff bases tagged with diphenyl ethers: Promising candidates for selective treatment of hypopharyngeal and breast adenocarcinoma

Organoselenium (OSe) compounds have received much attention due to their potential to inhibit tumor growth while also protecting cells from oxidative damage, making them promising cancer prevention agents. However, diphenyl diselenide (Ph₂Se₂) has many drawbacks, such as increased lipophilicity with low oral bioavailability, toxicity issues due to poor selectivity, and limited physicochemical criteria. In this study, we developed two novel sets of diphenyl ether 5a-g and diphenyl ether hybridized with diselenide 6a-g and evaluated their anticancer activity and underlying cytotoxic mechanisms. Utilizing the growth inhibition percentage (GI%) assay, the anticancer activity of the newly synthesized candidates was evaluated against fifteen cancer cell lines. Furthermore, their potential safety and selectivity were tested against human skin fibroblast (HSF) cells. The analysis of structure-activity relationships (SAR) revealed that the human hypopharyngeal cancer cell line (FaDu) and human breast cancer cell line (MDA-MB-468) were the most sensitive to their growth inhibition effect. IC₅₀ values were measured against the most sensitive ones (FaDu, MDA-MB-468, HCT-116, HELA, and A549 cells), where compounds 5b, 5c, and 6a manifested the highest mean IC₅₀ values of 5.71, 4.49, and 6.22 μg/mL, respectively. Furthermore, the superior anticancer candidates 5b, 5c, and 6a were tested for apoptotic activity against a panel of apoptotic and anti-apoptotic markers. Moreover, compounds 5b, 5c, and 6a were estimated against inflammatory markers such as COX ІІ, IL-6, and IL-1β. Besides, the lead compounds (5b, 5c, and 6a) were docked against Caspase-6 and BCL-2 target receptors to investigate their apoptotic potential. Overall, candidates 5b, 5c, and 6a showed an attractive cytotoxic potential as anticancer agents with high selectivity towards hypopharyngeal and breast cancers with apoptotic and anti-inflammatory effects. Indeed, they provided a promising rationale for optimization studies and further mechanistic investigations to estimate their therapeutic potential.