Synthesis of selenium-N-heterocyclic carbene adducts with antiproliferative activity against human lung cancer cells: experimental and computational investigations

Abstract

Abstract Three new mononuclear selenium adducts (MC1–MC3) and their corresponding N-heterocyclic carbene (NHC) salts (ML1–ML3) derived from benzimidazole were synthesized and characterized to evaluate their anticancer potential. The benzimidazolium ligands were synthesized by the N-alkylation of 1-phenethyl-1H-benzimidazole and subsequently converted into selenium compounds using elemental selenium. 1H NMR,13C NMR, FTIR, and elemental analysis confirmed the structure of the prepared compounds. In parallel, the antiproliferative activities of the resulting compounds were assessed against A549, L929, and EA.hy926 cell lines using the MTT assay, with 5-fluorouracil (5-FU) serving as a reference compound. The study found that organoselenium compounds exhibited significant anticancer activity against A549 lung cancer cells, compared with the respective benzimidazolium salts, while demonstrating low toxicity toward normal cells. Among them, MC3 exhibited the highest cytotoxicity (IC50 = 1.75 ± 0.17 μM), even better than 5-FU (IC50 = 3.12 ± 0.18 μM). Furthermore, density functional theory studies indicate that selenium adducts show low highest occupied molecular orbital–lowest unoccupied molecular orbital gaps and more electronic reactivity as compared to ligands. Additionally, molecular docking of selenium compounds against HIF revealed that MC3 displays high binding affinity (−6.4 kcal mol−1), which is consistent with the observed experimental trends. These results highlight the potential of selenium-containing NHC compounds as versatile anticancer agents in medicinal chemistry. Graphical abstractMulti-panel figure with synthesis setup, anticancer bar chart of IC50 values, docking study diagram, and DFT study showing MC3 with Eg_gap = 1.96 eV.The figure features four sections around a central synthesis graphic depicting a stirring setup with a flask. The top left section shows an "Anticancer Study," a bar chart displaying IC50 values (in µM) for compounds ML1, ML2, ML3, MC1, MC2, MC3, and 5-FU. The bottom left presents a "Docking Study," illustrating molecular interactions between a central molecule and amino acids TYR A29, LYS A28, LEU A8, TYR A13, and GLY A12. The top right section is a "DFT Study," highlighting molecular orbitals of MC3 with an energy gap indicated as Eg_gap = 1.96 eV. HIGHLIGHTS Three new selenium-containing NHC compounds were prepared by using a solution method. Newly synthesized compounds were characterized by standard spectroscopic techniques. Antiproliferative activity and selectivity of compounds were evaluated against A549, L929, and EA.hy926 cell lines. Computational investigations were conducted to support the experimental findings.