53172-10-4

Derivatives of 6-shogaol are described herein. Also described herein are methods of preparing the derivatives, as well as methods of using the derivatives to activate Nrf2 and to treat diseases associated with inflammation and/or oxidative stress.

The invention provides a paradol preparation method which comprises the steps: firstly mixing the raw materials of vanillin, 2-nonanone and N,N-dimethyl formamide, then adding glacial acetic acid water solution, stirring, cooling to room temperature, filtering, washing and drying to obtain ketene intermediate; then adding metal sodium, anhydrous sodium acetate and tetrahydrofuran into a reaction bottle, adding the ketene intermediate dissolved into ethyl alcohol into the reaction bottle under protection of nitrogen, decoloring through activated carbon after reaction finishes, filtering and recovering solvent to obtain faint yellow grease, namely paradol. The preparation method disclosed by the invention can avoid generating a lot of hydroxyl byproducts in a hydrogenation reduction process, improves yield, simplifies after-treatment operation, avoids additional catalyst, and greatly shortens operation period; equipment utilization rate is high, total cost is lower and economical benefit is higher.

Oxidative stress is a central component of many chronic diseases. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 p45-related factor 2 (Nrf2) system is a major regulatory pathway of cytoprotective genes against oxidative and electrophilic stress. Activation of the Nrf2 pathway plays crucial roles in the chemopreventive effects of various inducers. In this study, we developed a novel class of potent Nrf2 activators derived from ginger compound, [6]-shogaol (6S), using the Tg[glutathione S-transferase pi 1 (gstp1):green fluorescent protein (GFP)] transgenic zebrafish model. Investigation of structure-activity relationships of 6S derivatives indicates that the combination of an α,β-unsaturated carbonyl entity and a catechol moiety in one compound enhances the Tg(gstp1:GFP) fluorescence signal in zebrafish embryos. Chemical reaction and in vivo metabolism studies of the four most potent 6S derivatives showed that both α,β-unsaturated carbonyl entity and catechol moiety act as major active groups for conjugation with the sulfhydryl groups of the cysteine residues. In addition, we further demonstrated that 6S derivatives increased the expression of Nrf2 downstream target, heme oxygenase-1, in both a dose- and time-dependent manner. These results suggest that α,β-unsaturated carbonyl entity and catechol moiety of 6S derivatives may react with the cysteine residues of Keap1, disrupting the Keap1-Nrf2 complex, thereby liberating and activating Nrf2. Our findings of natural product-derived Nrf2 activators lead to design options of potent Nrf2 activators for further optimization.