10 research outputs found
Functionalization of ÎČâCaryophyllene Generates Novel Polypharmacology in the Endocannabinoid System
The widespread dietary plant sesquiterpene
hydrocarbon ÎČ-caryophyllene
(<b>1</b>) is a CB<sub>2</sub> 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 structureâactivity
study provided evidence for the existence of a well-defined sesquiterpene
hydrocarbon binding site in CB<sub>2</sub> 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 CB<sub>2</sub> 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,ÎČ 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
Iodine-Promoted Aromatization of <i>p</i>âMenthane-Type Phytocannabinoids
Treatment with iodine cleanly converts
various <i>p</i>-menthane-type phytocannabinoids and their
carboxylated precursors
into cannabinol (CBN, <b>1a</b>). The reaction is superior to
previously reported protocols in terms of simplicity and substrate
range, which includes not only tricyclic tetrahydrocannabinols such
as Î<sup>9</sup>-THC (<b>2a</b>) but also bicyclic phytocannabinoids
such as cannabidiol (CBD, <b>3a</b>). Lower homologues from
the viridin series (<b>2c</b> and <b>3c</b>, respectively)
afforded cannabivarin (CBV), a non-narcotic compound that, when investigated
against a series of ionotropic (thermo-TRPs) biological end-points
of phytocannabinoids, retained the submicromolar TRPA1-activating
and TRPM8-inhibiting properties of CBN, while also potently activating
TRPV2. Treatment with iodine provides an easy access to CBN (<b>1a</b>) from crude extracts and side-cuts of the purification
of Î<sup>9</sup>-THC and CBD from respectively narcotic <i>Cannabis sativa</i> (marijuana) and fiber hemp, substantially
expanding the availability of this compound and, in the case of fiber
hemp, dissecting it from narcotic phytocannabinoids
Poly-Electrophilic Sesquiterpene Lactones from <i>Vernonia amygdalina</i>: New Members and Differences in Their Mechanism of Thiol Trapping and in Bioactivity
In addition to known compounds, the
leaves of <i>Vernonia
amygdalina</i> afforded the new sesquiterpene lactones 14-<i>O</i>-methylvernolide (<b>2</b>), 3âČ-deoxyvernodalol
(<b>6</b>), and vernomygdalin (<b>8</b>). These and related
compounds were evaluated for modulation of a series of thiol trapping-sensitive
transcription factors (NF-ÎșB, STAT3, and Nrf2), involved in
the maintenance of the chronic inflammatory condition typical of human
degenerative diseases. Vernolide (<b>1</b>) emerged as a potent
inhibitor of STAT3 and NF-ÎșB and showed cytostatic activity
toward the prostate cancer cell line DU45, arresting the cell cycle
at the S phase. The exomethylene lactones are characterized by multiple
Michael acceptor sites, as exemplified by vernolide (<b>1</b>) and vernodalol (<b>5</b>). By using the nuclear magnetic
resonance-based cysteamine assay, the most reactive thiophilic site
could be identified in both compounds, and competitive experiments
qualified vernolide (<b>1</b>) as being more thiophilic than
vernodalol (<b>5</b>), in agreement with the results of the
pharmacological assays
The Bibenzyl Canniprene Inhibits the Production of Pro-Inflammatory Eicosanoids and Selectively Accumulates in Some <i>Cannabis sativa</i> Strains
Canniprene (<b>1</b>), an isoprenylated
bibenzyl unique to <i>Cannabis sativa</i>, can be vaporized
and therefore potentially
inhaled from marijuana. Canniprene (<b>1</b>) potently inhibited
the production of inflammatory eicosanoids via the 5-lipoxygenase
pathway (IC<sub>50</sub> 0.4 ÎŒM) and also affected the generation
of prostaglandins via the cyclooxygenase/microsomal prostaglandin
E<sub>2</sub> synthase pathway (IC<sub>50</sub> 10 ÎŒM), while
the related spiranoid bibenzyls cannabispiranol (<b>2</b>) and
cannabispirenone (<b>3</b>) were almost inactive in these bioassays.
The concentration of canniprene (<b>1</b>) was investigated
in the leaves of 160 strains of <i>C. sativa</i>, showing
wide variations, from traces to >0.2%, but no correlation was found
between its accumulation and a specific phytocannabinoid profile
Jatrophanes from <i>Euphorbia squamosa</i> as Potent Inhibitors of <i>Candida albicans</i> Multidrug Transporters
A series of structurally related
jatroÂphane diterpenoids
(<b>1</b>â<b>6</b>), including the new euphoÂsquamosins
AâC (<b>4</b>â<b>6</b>), was purified from
the Iranian spurge <i>Euphorbia squamosa</i> and evaluated
for its capacity to inhibit drug efflux by multiÂdrug transporters
of <i>Candida albicans</i>. Three of these compounds showed
an interesting profile of activity. In particular, deacetylÂserrulatin
B (<b>2</b>) and euphoÂsquamosin 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 fluconÂazole.
These compounds were transported by <i>Ca</i>Cdr1p, as shown
by the observation of an 11â14-fold cross-resistance of yeast
growth, and could also inhibit the secondary MFS-transporter <i>Ca</i>Mdr1p. In contrast, euphoÂsquamosin 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
jatroÂphane diterpenes to be a new class of potent inhibitors
of multiÂdrug 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 ÎČ-turmerones, <b>2</b>â<b>4</b>, respectively) was developed. The
comparative evaluation of these compounds against a series of anti-inflammatory
targets (NF-ÎșB, 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 structureâactivity 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>â<b>c</b>, <b>6</b>â<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
ÎČ-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>â<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 [(â)-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-ÎșB and STAT-3) showed only marginal activity on
NF-ÎșB 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
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-ÎșB, 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
Additional file 1: of Hypoxia mimetic activity of VCE-004.8, a cannabidiol quinone derivative: implications for multiple sclerosis therapy
Figure S1. VCE-004.8 inhibits COX-2 expression and PGE2 release in LPS-stimulated rat primary microglia cells. (A) PGE2 released was analyzed in the supernatants from primary microglia cells treated as in A. Data represent the meanâ±âSD (nâ=â3). *pâ<â0.05 **pâ<â0.01, ***pâ<â0.001 (one-way ANOVA followed Tukeyâs test). (B) Primary microglia cells were pre-treated with increasing concentrations of VCE-004.8, then stimulated with LPS for 24 h and the expression of COX-2 analyzed by immunoblot (nâ=â2). (PPTX 384 kb