Innovative Multitarget Organoselenium Hybrids With Apoptotic and Anti-Inflammatory Properties Acting as JAK1/STAT3 Suppressors

Abstract

Herein, we report the design, synthesis, and characterization of novel organoselenium (OSe) hybrids (5–19) via modifications of the lead, N-(4-selaneylphenyl)-2-selaneylacetamide. The OSe-based thiazol 9 showed the highest growth inhibition % (GI%) of 64.72% relative to the positive reference doxorubicin (DOX), with a GI% of 79.5%. Furthermore, the novel OSe derivatives showed low GI% values compared to the normal cell lines employed, demonstrating their selectivity. The OSe tethered N-chloroacetamide 5 and Schiff base 19 showed a cytotoxic effect with an IC₅₀ of (25.07 and 11.61 µM), respectively, against the A549 tumor cell line and IC₅₀ of (34.22 and 20.12 µM), respectively, against the HELA cancer cell line. Enzyme-linked immunosorbent assay to study the JAK1 and the STAT3 inhibitory potentials of OSe compounds 5 and 19 in the A549 cancer cells both showed promising inhibitory activities with IC₅₀ values of 25.07 and 11.61 µM, respectively. Protein expression analysis on the A549 cancer cell line on OSe compounds 5 and 19 showed upregulation of P53, BAX, and Caspases 3, 6, 8, and 9 as apoptotic proteins. However, both candidates expressed downregulation of the antiapoptotic proteins (BCL2, MMP2, and MMP9). Moreover, OSe compounds 5 and 19 described the downregulation of the examined inflammatory proteins: COX2, IL-6, and IL-1β. In addition, OSe compound 19 showed potential cell cycle arrest at the G0, S, and G2-M layers, with an increase in cellular levels. Finally, molecular docking studies of OSe compound 19 showed the most promising inhibitory potential toward the JAK1 and STAT3 target receptors, with binding scores and interactions exceeding that of the cocrystallized inhibitor of JAK1.