Synthesis and Cannabinoid Receptor Activity of Ketoalkenes from Echinacea pallida and Nonnatural Analogues

Abstract

Despite its popularity and widespread use, the efficacy of Echinacea products remains unclear and controversial. Among the various compounds isolated from Echinacea, ketoalkenes and ketoalkenynes exclusively found in the pale purple coneflower (E. pallida) are major components of the extracts. In contrast to E. purpurea alkamides, these compounds have not been synthesized and studied for immunostimulatory effects. We present a practical and useful synthetic approach to the ketoalkenes using palladium-catalyzed cross-coupling reactions and the pharmaceutical results at the human cannabinoid receptors. The synthetic route developed provides overall good yields for the ketoalkenes and is applicable to other natural products with similar 1,4-diene motifs. No significant activity was observed at either receptor, indicating that the ketoalkenes from E. pallida are not responsible for immunomodulatory effects mediated via the cannabinergic system. However, newly synthesized non-natural analogues showed micro-molar potency at both cannabinoid receptors.

Enrichment of Echinacea angustifolia with Bauer Alkylamide 11 and Bauer Ketone 23 Increased Anti-inflammatory Potential through Interference with COX-2 Enzyme Activity

“…An interesting finding from our studies is that Bauer ketone 23 (0.83 µM) alone did not significantly modulate TNF-α protein levels. Egger et al determined that ketones, analyzed at 3% (v/v) in DMSO do not appear to mediate their immunomodulatory effects through the cannabinoid receptors (3) and therefore it is likely that Bauer ketone 23 acts through a different mechanism to inhibit the noted TNF-α gene expression identified in our qRT-PCR studies after a 24 h treatment. Although, these findings do not rule out the possibility that Bauer ketone 23 may interfere indirectly with the endocannabinoid system in a manner that could lead to the inhibition of TNF-α expression.…”

“…Several studies have been conducted to elucidate the cellular mechanism of action for the immune modulatory properties of Echinacea (3–6). These studies have mainly focused on one particular class of compounds of Echinacea , alkylamides, and their ability to interact with cannabinoid receptors.…”

Chemical Constituents, Quantitative Analysis and Antioxidant Activities ofEchinacea purpurea(L.) Moench andEchinacea pallida(Nutt.) Nutt.

“…), cannabinoid receptor (Egger et al . ), acetylcholinesterase, antioxidant (Orhan et al . ), and anti‐inflammatory (Zhai et al .…”

Lithiated anions derived from (alkenyl)pentamethyl phosphoric triamides: Useful synthons for the stereoselective synthesis of 9-oxo- and 10-hydroxy-2(E)-decenoic acids, important components of queen substance and royal jelly of honeybee Apis mellifera

“…Aldehyde 4 is a useful building block in the synthesis of natural compounds e.g. ketoalkenes and ketoalkenynes from Echinacea pallida [24].…”