Structure‐Toxicity Relationships of Trans‐Cinnamic Aldehyde and Its Substituted Analogs

Objective Trans‐cinnamic aldehyde (CA) is a compound found in cinnamon and has promising potential as an agent for smoking cessation therapy. Current pharmaceutical options to treat nicotine addiction are only moderately effective and new approaches are needed. In this study, we aim to explore the hepatotoxicity profiles of CA and its structurally‐related analogs as one step in a more‐extensive evaluation of these agents to treat nicotine addiction. Methods Mouse hepatocytes were exposed to varying concentrations of CA or its structurally‐related analogs and toxicity was measured by determining median lethal dose (LC50) values. Stock solutions for all compounds were prepared in DMSO and proper vehicle controls were performed for all experiments. Cells were treated with either CA or one of eight analogs: α‐bromocinnamaldehyde (Br‐CA), α‐chlorocinnamaldehyde (Cl‐CA), 3‐phenylpropionaldehyde (sat‐CA), α‐methylcinnamaldehyde (Me‐CA), 2‐nitrocinnamaldehyde (N‐CA), 2‐trifluoromethylcinnamadehyde (CF3‐CA), 2,6‐difluorocinnamaldehyde (F‐CA), and 2‐methylcinnamaldehyde (2‐Me‐CA). After the LC50 determinations were completed, two different luminescence‐based assays were performed to assess reactive oxygen species production and glutathione (GSH) depletion during exposure to CA and its analogs. A cutoff of p < 0.05 was used to determine significance by means of one‐way analysis of variance (ANOVA) with post‐hoc Least Significant Difference (LSD) tests. Results Significant differences in LC50 values were observed across the tested compounds indicating minor structural changes to the structure of CA can have profound toxicologic effects. CA analogs modified to contain electron‐withdrawing groups, as well as CA itself, were generally more toxic (lower LC50 values) than those that did not contain electron‐withdrawing groups. Furthermore, this toxicity was associated with significantly greater reactive oxygen species production and GSH depletion compared to the other CA analogs at equi‐toxic doses. Conclusion These results indicate analogs that contain electron‐withdrawing groups share a similar or inferior toxicity profile compared to CA significantly impacting the generation of reactive oxygen species and GSH depletion. However, this toxicity profile is unique for other CA analogs that do not contain electron‐withdrawing groups, which appear to propagate toxicity through alternative cell death mechanisms. Information generated from this study will help to inform future pharmacologic studies in animal and human models as these agents are further evaluated as potential aids for smoking cessation therapy. Support or Funding Information This work was supported by the Pacific University Research Incentive Grant Program This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .