Synthesis and Pharmacological Evaluation of Different Piperine Analogs for Therapeutic Potential to Prevent ER Stress

Abstract

Background: Endoplasmic reticulum (ER) is the chief organelle involved in protein folding and maturation. Emerging studies implicate the role of ER stress in the development of chronic kidney disease (CKD). Thus, there is an urgent need for compounds, which have the ability to ameliorate ER stress and prevent CKD. Piperine and its analogs have been reported to exhibit multiple pharmacological activities; however, their efficacy against ER stress in kidney cells has not been studied yet. Hence, the goal of this study was to synthesize different piperine analogs and screen them for pharmacological activity to relieve ER stress using an in vitro model of tunicamycin-induced ER stress using rat renal cells (NRK-52E). Methods: Five piperine analogs were prepared and their chemical structures were elucidated by pertinent spectroscopic techniques. An in vitro model of ER stress was developed using tunicamycin, and the compounds of interest were screened for their effect on cell viability (by MTT assay), and the ER chaperone GRP78 and the pro-apoptotic ER stress marker CHOP (via western blotting). Results: Five piperine analogs were synthesized and their structures were confirmed. Our findings indicate that exposure to tunicamycin (0.5 µg/mL) for 2 hours induces the expression of GRP78 and CHOP, and causes a significant reduction in renal cell viability. Pre-treatment of cells with piperine and its cyclohexylamino analog decreased the tunicamycin-induced upregulation of GRP78 and CHOP. Conclusion: Our findings demonstrate that piperine and its analogs differentially regulate ER stress, and thus represent potential therapeutic agents to treat ER stress-related renal disorders.