Functionalization of β‑Caryophyllene Generates Novel Polypharmacology in the Endocannabinoid System

The widespread dietary plant sesquiterpene hydrocarbon β-caryophyllene (<b>1</b>) is a CB₂ cannabinoid receptor-specific agonist showing anti-inflammatory and analgesic effects in vivo. Structural insights into the pharmacophore of this hydrocarbon, which lacks functional groups other than double bonds, are missing. A structure–activity study provided evidence for the existence of a well-defined sesquiterpene hydrocarbon binding site in CB₂ receptors, highlighting its exquisite sensitivity to modifications of the strained endocyclic double bond of <b>1</b>. While most changes on this element were detrimental for activity, ring-opening cross metathesis of <b>1</b> with ethyl acrylate followed by amide functionalization generated a series of new monocyclic amides (<b>11a</b>, <b>11b</b>, <b>11c</b>) that not only retained the CB₂ receptor functional agonism of <b>1</b> but also reversibly inhibited fatty acid amide hydrolase (FAAH), the major endocannabinoid degrading enzyme, without affecting monoacylglycerol lipase (MAGL) and α,β hydrolases 6 and 12. Intriguingly, further modification of this monocyclic scaffold generated the FAAH- and endocannabinoid substrate-specific cyclooxygenase-2 (COX-2) dual inhibitors <b>11e</b> and <b>11f</b>, which are probes with a novel pharmacological profile. Our study shows that by removing the conformational constraints induced by the medium-sized ring and by introducing functional groups in the sesquiterpene hydrocarbon <b>1</b>, a new scaffold with pronounced polypharmacological features within the endocannabinoid system could be generated. The structural and functional repertoire of cannabimimetics and their yet poorly understood intrinsic promiscuity may be exploited to generate novel probes and ultimately more effective drugs

Amines Bearing Tertiary Substituents by Tandem Enantioselective Carbolithiation–Rearrangement of Vinylureas

In the presence of (−)-sparteine or a (+)-sparteine surrogate, organolithiums add to <i>N</i>-alkenyl<i>-N</i>′-arylureas to give benzylic organolithiums in an enantioselective manner. Under the influence of DMPU, these organolithiums undergo rearrangement with migration of the <i>N</i>′-aryl ring from N to C, leading to the urea derivatives of enantiomerically enriched amines bearing tertiary substituents. Basic hydrolysis returns the functionalized amine, providing a new synthetic route to compounds with quaternary stereogenic centers bearing nitrogen

Antimicrobial Phenolics and Unusual Glycerides from <i>Helichrysum italicum</i> subsp. <i>microphyllum</i>

During a large-scale isolation campaign for the heterodimeric phloroglucinyl pyrone arzanol (<b>1a</b>) from <i>Helichrysum italicum</i> subsp. <i>microphyllum</i>, several new phenolics as well as an unusual class of lipids named santinols (<b>5a</b>–<b>c</b>, <b>6</b>–<b>8</b>) have been characterized. Santinols are angeloylated glycerides characterized by the presence of branched acyl- or keto-acyl chains and represent a hitherto unreported class of plant lipids. The antibacterial activity of arzanol and of a selection of <i>Helichrysum</i> phenolics that includes coumarates, benzofurans, pyrones, and heterodimeric phloroglucinols was evaluated, showing that only the heterodimers showed potent antibacterial action against multidrug-resistant <i>Staphylococcus aureus</i> isolates. These observations validate the topical use of <i>Helichrysum</i> extracts to prevent wound infections, a practice firmly established in the traditional medicine of the Mediterranean area

Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors

Pentacyclic triterpenoid acids (PCTTAs) are pleiotropic agents that target many macromolecular end-points with low to moderate affinity. To explore the biological space associated with PCTTAs, we have investigated the carboxylate-to-hydroxamate transformation, discovering that it de-emphasizes affinity for the transcription factors targeted by the natural compounds (NF-κB, STAT3, Nrf2, TGR5) and selectively induces inhibitory activity on HIF prolyl hydrolases (PHDs). Activity was reversible, isoform-selective, dependent on the hydroxamate location, and negligible when this group was replaced by other chelating elements or O-alkylated. The hydroxamate of betulinic acid (<b>5b</b>) was selected for further studies, and evaluation of its effect on HIF-1α expression under normal and hypoxic conditions qualified it as a promising lead structure for the discovery of new candidates in the realm of neuroprotection