A Template-Based Approach for Guiding and Refining the Development of Cinnamon-Based Phenylpropanoids as Drugs.

BACKGROUND: Structure-activity relationships describe the relationship between chemical structure and biologic activity and are capable of informing deliberate structural modifications to a molecule in order enhance drug properties. METHODS: Here, we present a subtle, yet unique twist on structure-activity relationships in which a collective biologic activity was measured among five cinnamon constituents with a shared phenylpropanoid template (cinnamic acid, cinnamaldehyde, chlorogenic acid, caffeic acid, and ferulic acid). This template-based approach utilized publicly available transcriptomic data through the Gene Expression Omnibus (GEO) to identify a fundamental biologic effect; in essence, a phenylpropanoid template effect. RESULTS: The recurrent identification of cytokine-cytokine receptor interaction and neuroactive ligand receptor pathways in each individual treatment condition strongly supports the fact that changes in gene expression within these pathways is a hallmark of the phenylpropanoid template. With a template effect identified, future structural modifications can be performed in order to overcome pharmacokinetic barriers to clinical use (i.e., traditional structure-activity relationship experiments). Moreover, these modifications can be implemented with a high degree of confidence knowing that a consistent and robust template effect is likely to persist. CONCLUSION: We believe this template-based approach offers researchers an attractive and cost-effective means for evaluating multicomponent natural products during drug development.

Polyphenols reported to shift APAP-induced changes in MAPK signaling and toxicity outcomes.

Due to its widespread availability, acetaminophen (APAP) is the leading cause for drug-induced liver injury in many countries including United States and United Kingdom. When used as recommended, APAP is relatively safe. However, in overdose cases, increased metabolism of APAP to N-acetyl-para-benzoquinoneimine (NAPQI), a reactive metabolite, leads to glutathione (GSH) depletion, oxidative stress, and cellular injury. Throughout this process, a variety of factors play important roles in propagating toxicity, including c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family. Because of its involvement in multiple cellular processes, biomarkers associated with MAPK signaling have generated interest as a mechanistic target for protecting against APAP-induced liver injury and hepatocellular injury, in general. This review summarizes mechanistic details by which natural products, specifically those containing polyphenolic moieties, are capable of attenuating APAP-induced toxicity, at least in part through an ability to modulate MAPKs. These compounds include carnosic acid, chlorogenic acid, davallialactone, extracts from Hibiscus sabdariffa, quercetin-based compounds, and resveratrol. Despite variations in the experimental designs across these studies, common pathways and biomarkers were implicated in cytoprotection when polyphenolic compounds were given with APAP, such as enhanced antioxidant gene expression and reversal of APAP-induced changes in oxidative stress markers and MAPK signaling. Overall, an emphasis should be placed on method standardization for future studies if we are to gain a more in-depth understanding of how polyphenolic moieties contribute to cytoprotection during an APAP overdose event.