Jatrophanes from <i>Euphorbia squamosa</i> as Potent Inhibitors of <i>Candida albicans</i> Multidrug Transporters

A series of structurally related jatro­phane diterpenoids (<b>1</b>–<b>6</b>), including the new eupho­squamosins A–C (<b>4</b>–<b>6</b>), was purified from the Iranian spurge <i>Euphorbia squamosa</i> and evaluated for its capacity to inhibit drug efflux by multi­drug transporters of <i>Candida albicans</i>. Three of these compounds showed an interesting profile of activity. In particular, deacetyl­serrulatin B (<b>2</b>) and eupho­squamosin C (<b>6</b>) strongly inhibited the drug-efflux activity of the primary ABC-transporter <i>Ca</i>Cdr1p, an effect that translated, in a yeast strain overexpressing this transporter, into an increased sensitivity to flucon­azole. These compounds were transported by <i>Ca</i>Cdr1p, as shown by the observation of an 11–14-fold cross-resistance of yeast growth, and could also inhibit the secondary MFS-transporter <i>Ca</i>Mdr1p. In contrast, eupho­squamosin A (<b>4</b>) was selective for <i>Ca</i>Cdr1p, possibly as a result of a different binding mode. Taken together, these observations suggest jatro­phane diterpenes to be a new class of potent inhibitors of multi­drug transporters critical for drug resistance in pathogenic yeasts

Turmeric Sesquiterpenoids: Expeditious Resolution, Comparative Bioactivity, and a New Bicyclic Turmeronoid

An expeditious strategy to resolve turmerone, the lipophilic anti-inflammatory principle of turmeric (<i>Curcuma longa</i>), into its individual bisabolane constituents (<i>ar</i>-, α-, and β-turmerones, <b>2</b>–<b>4</b>, respectively) was developed. The comparative evaluation of these compounds against a series of anti-inflammatory targets (NF-κB, STAT3, Nrf2, HIF-1α) evidenced surprising differences, providing a possible explanation for the contrasting data on the activity of turmeric oil. Differences were also evidenced in the profile of more polar bisabolanes between the Indian and the Javanese samples used to obtain turmerone, and a novel hydroxylated bicyclobisabolane ketol (bicycloturmeronol, <b>8</b>) was obtained from a Javanese sample of turmeric. Taken together, these data support the view that bisabolane sesquiterpenes represent an important taxonomic marker for turmeric and an interesting class of anti-inflammatory agents, whose strict structure–activity relationships are worth a systematic evaluation

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

STAT-3 Inhibitory Bisabolanes from <i>Carthamus glaucus</i>

Apart from a large amount (ca. 2.0%) of α-bisabolol β-d-fucopyranoside (<b>2a</b>), the aerial parts of the Mediterranean weed <i>Carthamus glaucus</i> afforded an unusual triglyceride (<i>E</i>-2-crotonyl-1,3-distearolylglycerol, <b>7</b>), two lipophilic flavonoids (<b>6a</b>,<b>b</b>), and a series of bisabolane fucopyranosides variously acylated on the sugar moiety (<b>2b</b>–<b>e</b>) or oxidized on the terpenoid core (<b>3</b>, <b>4a</b>,<b>b</b>, <b>5a</b>,<b>b</b>). The fucopyranoside <b>2a</b> is more soluble in polar media and more versatile in terms of formulation than its aglycone [(−)-α-bisabolol, <b>1</b>], an anti-inflammatory cosmetic ingredient in current short supply in its natural form. A comparative investigation of the activity of α-bisabolol (<b>1a</b>), the fucopyranoside <b>2a</b>, and its senecioate <b>2b</b> on transcription factors involved in inflammation and cancer pathways (NF-κB and STAT-3) showed only marginal activity on NF-κB inhibition for all compounds, while STAT-3 was inhibited potently by the fucoside <b>2a</b> and, to a lesser extent, also by α-bisabolol. These observations qualify <b>2a</b> as an easily available compound, both as an apoptotic lead structure and as a potential alternative to natural α-bisabolol (<b>1</b>) for pharmaceutical and/or cosmetic development

PPAR Modulating Polyketides from a Chinese <i>Plakortis simplex</i> and Clues on the Origin of Their Chemodiversity

Fifteen polyketides, including the first hydroxylated plakortone (<b>12</b>) and plakdiepoxide (<b>15</b>), the first polyketide to embed a vicinal diepoxide, have been isolated from the Chinese sponge <i>Plakortis simplex</i>. The structures of the new metabolites were elucidated by analysis of spectroscopic data, Mosher’s derivatization, and DFT computational calculations. The reactivity of the major endoperoxide of this sponge was investigated, suggesting that furan, furanylidene, and plakilactone derivatives, well-known classes of natural products, could actually be chemical degradation products. Plakdiepoxide is a potent and selective modulator of peroxisome proliferator-activated receptor (PPAR)-γ, while the diunsaturated C₁₂ fatty acid monotriajaponide (<b>13</b>) activates both PPAR-α and PPAR-γ, a dual activity of potential great importance for the treatment of metabolic disorders