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The Alpine wormwood Artemisia vallesiaca All. was considered the most valuable ingredient of vermouth, a celebrated aromatized wine. A. vallesiaca has a very limited geographical distribution, and the booming market of vermouth decimated its natural population, resulting in the eventual replacement of this rare species with more common and less expensive wormwoods like A. absinthium L.. Over the past years, attempts to revive the original recipe(s) of vermouth have fostered the establishment of cultivations of A. vallesiaca in pre-montane settings. In order to assist these projects, the phytochemical profile of cultivated plants and of several native populations of A. vallesiaca from the Swiss Valais were comparatively evaluated, focusing on sesquiterpene lactones and on lipophilic flavonoids, the hallmark constituents of Artemisia species. Remarkably, no significant difference was detected between the samples, despite the different origins. The lipophilic flavonoids of A. vallesiaca were similar to those of related species used in the production of vermouth, but the presence of C-9 oxygenated 11β-methyl germacranolides and eudesmanolides (herbolides) made its sesquiterpene lactone profile peculiar. In addition to known compounds, two novel germacranolides were also characterized (herbolides J and K), and the major sesquiterpene lactone from the plant, the bitter germacranolide herbolide D (4), was detected and quantified by 1H NMR in a bitter liqueur aromatized with A. vallesiaca. Taken together, these observations qualify herbolides as marker to identify A. vallesiaca in aromatized alcohol matrixes.

The renewed interest in dimeric salicylates as broad-spectrum anti-inflammatory and anti-diabetic agents provided a rationale to investigate the dimerization of the substituted salicylate Δ9-tetrahydrocannabinolic acid (THCA-A, 3a) as a strategy to solve its instability to decarboxylation and to generate analogues and/or pro-drugs of this native pre-cannabinoid. Activation of the carboxylic group with the DCC-HOBt-DMAP protocol afforded a high yield of the OBt ester 4, that was next converted into the highly crystalline di-depsidic dimer 5 upon treatment with DMAP. The mono-depsidic dimer 6 was also formed when the reaction was carried out with partially decarboxylated THCA-A samples. The structure of the depsidic dimers was established by spectroscopic methods and by aminolysis of 5 into the pre-cannabinoid amide 7. Both dimers showed excellent shelf stability and did not generate significant amounts of Δ9-THC upon heating. However, only the didepsidic dimer 5 activated PPAR-γ, the major target of pre-cannabinoids, but strong binding to serum proteins abolished this activity, also shielding it from the action of esterases., Graphical abstract THCA-A was dimerized to a highly crystalline bis-depsidic analogue by carboxylate activation as HOBt ester followed by treatment with DMAP. The dimer was stable toward decarboxylation and partially retained the PPAR-γ-activating properties of THCA-A.Image 1

The present work aims to characterize and investigate the anti-inflammatory activity of hop extracts (cv. Cascade) in an in vitro model of gastric inflammation. The biological activities of hydroalcoholic and aqueous extracts from cones were evaluated by comparing IL-8 inhibition induced by TNFα. The hydroalcoholic extract demonstrated a higher inhibitory effect, which was just slightly affected by an in vitro simulated gastric digestion. The identification of active compounds was performed by a bio-guided fractionation which afforded 11 fractions, one of which inhibited IL-8 release in a concentration-dependent fashion in human gastric epithelial AGS cells. Phytochemical analysis revealed xanthohumol A and xanthohumol D as the main active components. The present study provides some experimental evidences that Humulus lupulus L. may exert an anti-inflammatory activity on the gastric district by the inhibition of the IL-8 secretion, partially due to its prenylated chalcones content.

As part of a study on the structure-activity relationships of the anticancer agent tigilanol tiglate (EBC-46, 2), the allylic oxidation of phorbol triacetate (1c) and of the acetonide of its 3αH-dihydroderivative (5) was investigated. The aim was to introduce an oxygen function at C-5 en route to point-like analogues of 2, but functionalization of C-10 was instead observed. This was followed by oxidative fragmentation of ring B to the 9,10-secotigliane derivative 6 and oxidation of the endocyclic Δ6 double bond to the C-6/C-10 oxygen bridged 7-oxotigliane 7. Despite the over-functionalization of ring B, these observations suggest the possibility to modify positions overlooked in the oxidase phase of tigliane biosynthesis and explore novel areas of the phorbol chemical space.

Covering up to January 2016Cannabis sativa L. is a prolific, but not exclusive, producer of a diverse group of isoprenylated resorcinyl polyketides collectively known as phytocannabinoids. The modular nature of the pathways that merge into the phytocannabinoid chemotype translates in differences in the nature of the resorcinyl side-chain and the degree of oligomerization of the isoprenyl residue, making the definition of phytocannabinoid elusive from a structural standpoint. A biogenetic definition is therefore proposed, splitting the phytocannabinoid chemotype into an alkyl- and a β-aralklyl version, and discussing the relationships between phytocannabinoids from different sources (higher plants, liverworts, fungi). The startling diversity of cannabis phytocannabinoids might be, at least in part, the result of non-enzymatic transformations induced by heat, light, and atmospheric oxygen on a limited set of major constituents (CBG, CBD, Δ9-THC and CBC and their corresponding acidic versions), whose degradation is detailed to emphasize this possibility. The diversity of metabotropic (cannabinoid receptors), ionotropic (thermos-TRPs), and transcription factors (PPARs) targeted by phytocannabinoids is discussed. The integrated inventory of these compounds and their biological macromolecular end-points highlights the opportunities that phytocannabinoids offer to access desirable drug-like space beyond the one associated to the narcotic target CB1.

Phytochemical investigation of the apolar extract obtained from aerial parts of the Iranian endemic plant Echinophora platyloba DC (Apiaceae) resulted in the characterization of the polyacetylene fraction of this plant. This resulted to be composed of the known echinophorins A and B, embedding the very rare α-pyrone terminal, and of the new echinophorin D (3), including also three conjugated triple bonds. The chemical structures of these compounds were secured by detailed inspection of MS and 1D/2D NMR spectra. The isolated polyacteylenes were evaluated for their modulation of six thermo-TRP channels and they revealed a selective activity on TRPA1, an ion channel involved in the mediation of neuropathic and inflammatory pain. This is the first report on the activity of plant polyacetylenes on transient receptor potential (TRP) channels.

Unlike all other caffeinated plants, guayusa (Ilex guayusa Loes.) and mate (Ilex paraguariensis A. St. Hill) contain high amounts of pentacyclic triterpenoid acids and alcohols. A phytochemical investigation on these plants revealed a similar triterpenoid profile and a content of ursolic acid (0.7-1%) and amyrin esters (up to 0.5%), quite unusual for dietary plants. The major constituent of the amyrin complex from both plants is α-amyrin palmitate (2a), accompanied by lower amounts of its corresponding palmitoleate (2b) and by the corresponding constitutional isomers from the β-series (3a and 3b, respectively). Ursolic acid (1) was identified as the responsible for the activity of mate and guayusa extracts in the activation of TGR5, a nuclear receptor of relevance for the prevention and management of diabetes and metabolic syndrome because of its involvement in the regulation of energy expenditure and insulin sensitivity.

During our search for potential templates of HIV-1 reverse transcriptase (RT) and integrase (IN) dual inhibitors, the methanolic extract obtained from aerial parts of

During our search for potential templates of HIV-1 reverse transcriptase (RT) and integrase (IN) dual inhibitors, the methanolic extract obtained from aerial parts of Limonium morisianum was investigated. Repeated bioassay-guided chromatographic purifications led to the isolation of the following secondary metabolites: myricetin, myricetin 3-O-rutinoside, myricetin-3-O-(6″-O-galloyl)-β-d-galactopyranoside, (-)-epigallocatechin 3-O-gallate, tryptamine, ferulic and phloretic acids. The isolated compounds were tested on both HIV-1 RT-associated RNase H and IN activities. Interestingly, (-)-epigallocatechin-3-O-gallate and myricetin-3-O-(6″-O-galloyl)-β-d-galactopyranoside potently inhibited both enzyme activities with IC50 values ranging from 0.21 to 10.9 μM. Differently, tryptamine and ferulic acid exhibited a significant inhibition only on the IN strand transfer reaction, showing a selectivity for this viral enzyme. Taken together these results strongly support the potential of this plant as a valuable anti HIV-1 drugs source worthy of further investigations.

Treatment with iodine cleanly converts various p-menthane-type phytocannabinoids and their carboxylated precursors into cannabinol (CBN, 1a). The reaction is superior to previously reported protocols in terms of simplicity and substrate range, which includes not only tricyclic tetrahydrocannabinols such as Delta(9)-THC (2a) but also bicyclic phytocannabinoids such as cannabidiol (CBD, 3a). Lower homologues from the viridin series (2c and 3c, 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 (1a) from crude extracts and side-cuts of the purification of Delta(9)-THC and CBD from respectively narcotic Cannabis sativa (marijuana) and fiber hemp, substantially expanding the availability of this compound and, in the case of fiber hemp, dissecting it from narcotic phytocannabinoids.

Cannabinochromene (CBC, 1a) is the archetypal member of a class of more than twenty isoprenylated 5-hydroxy-7-alkyl(aralky)benzo[2H]pyranes first reported from Cannabis sativa L. but also occurring in unrelated plants (Rhododendron species) as well as liverworts and fungi. The chemistry, synthesis, and bioactivity of CBC (1a) is reviewed, highlighting its underexploited pharmacological potential and rich chemistry.

Electrophilic attack to a double bond, the classic trigger of intramolecular isoprenoid cyclizations, is apparently silent in Cannabis and the diversity of the cannabinome can be ultimately traced to the oxidative cyclization of cannabigerolic acid (CBGA, 1a), a process triggered by the generation of an aromatic electrophilic species. To expand the chemical space of the cannabinoid chemotype, we have investigated an oxidative trigger based on the addition of iodine to the terminal isoprenyl double bond of cannabigerol (CBG, 1b), the decarboxylated and thermally stable version of CBGA (1a). Apart from the predictable product of an iodine-induced cascade cyclization (3), also a pair of unprecedented spiranes named spirocannabigerols (4a,b), derived from the formation of an edge-protonated cyclopropyl cation was also formed, along with a product (5) resulting from the incorporation, in a Friedel-Craft fashion, of the reaction solvent (toluene). Biological evaluation of these compounds on six thermo-transient receptor potential channels (TRPs) showed a remodeling of bioactivity compared to GBC, with emphasis on TRPA1 rather than TRPM8.

Phytochemical investigation of the apolar extract obtained from aerial parts of the Iranian endemic plant Echinophora platyloba DC (Apiaceae) resulted in the characterization of the polyacetylene fraction of this plant. This resulted to be composed of the known echinophorins A and B, embedding the very rare &alpha, pyrone terminal, and of the new echinophorin D (3), including also three conjugated triple bonds. The chemical structures of these compounds were secured by detailed inspection of MS and 1D/2D NMR spectra. The isolated polyacteylenes were evaluated for their modulation of six thermo-TRP channels and they revealed a selective activity on TRPA1, an ion channel involved in the mediation of neuropathic and inflammatory pain. This is the first report on the activity of plant polyacetylenes on transient receptor potential (TRP) channels.

Vitis vinifera cv Falanghina is an ancient grape variety of Southern Italy. A thorough phytochemical analysis of the Falanghina leaves was conducted to investigate its specialised metabolite content. Along with already known molecules, such as caftaric acid, quercetin-3-O-β-D-glucopyranoside, quercetin-3-O-β-D-glucuronide, kaempferol- 3-O-β-D-glucopyranoside and kaempferol-3-O-β-D-glucuronide, a previously undescribed biflavonoid was identified. For this last compound, a moderate bioactivity against metastatic melanoma cells proliferation was discovered. This datum can be of some interest to researchers studying human melanoma. The high content in antioxidant glycosylated flavonoids supports the exploitation of grape vine leaves as an inexpensive source of natural products for the food industry and for both pharmaceutical and nutraceutical companies. Additionally, this study offers important insights into the plant physiology, thus prompting possible technological researches of genetic selection based on the vine adaptation to specific pedo-climatic environments.

Doxorubicin is a highly active antineoplastic agent, but its clinical use is limited because of its cardiotoxicity. Although nutraceuticals endowed with anti-inflammatory properties exert cardioprotective activity, their bioavailability and stability are inconsistent. In an attempt to address this issue, we evaluated whether bioavailable nanoemulsions loaded with nutraceuticals (curcumin and fresh and dry tomato extracts rich in lycopene) protect cardiomyoblasts (H9C2 cells) from doxorubicin-induced toxicity. Nanoemulsions were produced with a high-pressure homogenizer. H9C2 cells were incubated with nanoemulsions loaded with different nutraceuticals alone or in combination with doxorubicin. Cell viability was evaluated with a modified MTT method. The levels of the lipid peroxidation products malondialdehyde (MDA) and 4-hydroxy-2-butanone (4-HNA), and of the cardiotoxic-related interleukins IL-6, IL-8, IL-1&beta, and IL-10, tumor necrosis factor-alpha (TNF-&alpha, ), and nitric oxide were analyzed in cardiomyoblasts. The hydrodynamic size of nanoemulsions was around 100 nm. Cell viability enhancement was 35&ndash, 40% higher in cardiomyoblasts treated with nanoemulsion + doxorubicin than in cardiomyoblasts treated with doxorubicin alone. Nanoemulsions also protected against oxidative stress as witnessed by a reduction of MDA and 4-HNA. Notably, nanoemulsions inhibited the release of IL-6, IL-8, IL-1&beta, TNF-&alpha, and nitric oxide by around 35&ndash, 40% and increased IL-10 production by 25&ndash, 27% versus cells not treated with emulsions. Of the nutraceuticals evaluated, lycopene-rich nanoemulsions had the best cardioprotective profile. In conclusion, nanoemulsions loaded with the nutraceuticals described herein protect against cardiotoxicity, by reducing inflammation and lipid oxidative stress. These results set the stage for studies in preclinical models.

With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets., Covering: up to 2018 With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.

The data show the frequencies by which the amino acid residues lysine, histidine and cysteine of six proteins of the malaria parasite Plasmodium falciparum are post-translationally modified by the lipoperoxydation endproduct 4-hydroxynonenal after challenging the parasitized red blood cell with plakortin. Plakortin is an antimalarial endoperoxide whose molecular anti-parasitic effect is described in Skorokhod et al. (2015) [1]. Plakortin did not elicit hemoglobin leakage from host red blood cells and did not oxidize reduced glutathione.

Helichrysum umbraculigerum Less. has been reported to be a prolific producer of phytocannabinoids from the alkyl-, aralkyl-, normal-, and abnormal types. Investigation of an acetone extract from the aerial parts of the plant afforded two novel amorfrutin-type phytocannabinoids ( 3b , 4 ) and the new geranylated phloroglucinol 5a . The presence of cannabigerol (CBG, 1a ) and its acidic precursor (pre-CBG, CBGA, 1b ), previously reported from this plant, could not be confirmed, but the phenethyl analogue of CBG (Heli-CBG, 2a) and the methyl ester of its carboxylated version ( 2b ) were isolated. Heli-CBG ( 2a ) was assayed against a series of metabotropic (CB 1 and CB 2 )- and ionotropic (thermo-TRPs) targets of phytocannabinoids, comparing its profile with the one of cannabigerol (CBG). A decreased affinity for cannabinoid receptor was observed, along with substantial retention of the thermo-TRP profile. The biogenetic relationships between the isoprenylated phenolics from H. umbraculigerum are discussed, highlighting the relevance of this species for biogenetic investigations on phytocannabinoids

Helichrysum umbraculigerum Less. has been reported to be a prolific producer of phytocannabinoids from the alkyl-, aralkyl-, normal-, and abnormal types. Investigation of an acetone extract from the aerial parts of the plant afforded two novel amorfrutin-type phytocannabinoids (3b, 4) and the new geranylated phloroglucinol 5a. The presence of cannabigerol (CBG, 1a) and its acidic precursor (pre-CBG, CBGA, 1b), previously reported from this plant, could not be confirmed, but the phenethyl analogue of CBG (Heli-CBG, 2a) and the methyl ester of its carboxylated version (2b) were isolated. Heli-CBG (2a) was assayed against a series of metabotropic (CB1 and CB2)- and ionotropic (thermo-TRPs) targets of phytocannabinoids, comparing its profile with the one of cannabigerol (CBG). A decreased affinity for cannabinoid receptor was observed, along with substantial retention of the thermo-TRP profile. The biogenetic relationships between the isoprenylated phenolics from H. umbraculigerum are discussed, highlighting the relevance of this species for biogenetic investigations on phytocannabinoids

Bardoxolone methyl (1) is the archetypal member of triterpenoid cyanoacrylates, an emerging class of bioactive compounds capable of transient covalent binding to thiols. The mechanistic basis for this unusual “pulsed reactivity” profile and the mode of its biological translation are unknown. To provide clues on these issues, a series of 1-dehydrooleanolates bearing an electron-withdrawing group at C-2 (7a-m) were prepared from oleanolic acid (3a), +and comparatively investigated in terms of reactivity with thiols and bioactivity against a series of electrophile-sensitive transcription factors (Nrf2, NF-B, STAT3). The emerging picture suggests that the triterpenoid scaffold sharply decreases the reactivity of the enone system by steric encoumbrance, and that only strongly electrophilic and sterically undemanding substituents like a cyanide or a carboxylate group can re-establish Michael reactivity, albeit in a transient way for the cyanide group. In general, a substantial dissection between the thiol trapping ability and the modulation of biological end-points sensitive to thiol alkylation was observed, highlighting the role of shape complementarity for the activity of triterpenoid thia-Michael acceptors.

In the present work we performed a combined experimental and computational study on the interaction of the natural antimalarial endoperoxide plakortin and its synthetic analogue 4a with heme. Obtained results indicate that the studied compounds produce reactive carbon radical species after being reductively activated by heme. In particular, similarly to artemisinin, the formation of radicals prone to inter-molecular reactions should represent the key event responsible for Plasmodium death. To our knowledge this is the first experimental investigation on the reductive activation of simple antimalarial endoperoxides (1,2-dioxanes) by heme and results were compared to the ones previously obtained from the reaction with FeCl2. The obtained experimental data and the calculated molecular interaction models represent crucial tools for the rational optimization of our promising class of low-cost synthetic antimalarial endoperoxides.

Melanoma is the most common form of skin cancer. Given its high mortality, the interest in the search of preventive measures, such as dietary factors, is growing significantly. In this study we tested, in vitro and in vivo, the potential anti-cancer effect of the acetyl deacylasadisulfide (ADA), a vinyl disulfide compound, isolated and purified from asafoetida a foul-smelling oleo gum-resin of dietary and medicinal relevance. ADA markedly suppressed proliferation of human melanoma cell lines by inducing apoptosis. Moreover, treatment of melanoma cells with ADA reduced nuclear translocation and activation of NF-κB, decreased the expression of the anti-apoptotic proteins c-FLIP, XIAP and Bcl-2 and inhibited the phosphorylation and activation of both AKT and ERK proteins, two of the most frequently deregulated pathways in melanoma. Finally, the results obtained in vitro were substantiated by the findings that ADA significantly and dose-dependently reduced lung metastatic foci formation in C57BL/6 mice. In conclusion, our findings suggest that ADA significantly inhibits melanoma progression in vivo and could represent an important lead compound for the development of new anti-metastatic agents.

Lycium barbarum (Solanaceae), long known to the traditional Chinese medicine because of its many health-promoting effects, has of late spread widely across the Western hemisphere, mainly on account of the nutritional richness in vitamins, minerals and antioxidant metabolites of its fruits. Data on bioactive metabolites from fruits and leaves, which are commonly consumed in soups and salads, are scarce and sometimes even contradictory. By means of NMR, the present study identified the specialised products contained in an Italian cultivar of L. barbarum. Kaempeferol, caffeic acid, 3,4,5-trihydroxycinnamic acid and 5-hydroxyferulic acid were found in fresh fruits; rutin and chlorogenic acid were detected in leaves and flowers; also, a previously undescribed N,N-dicaffeoylspermidine derivative was identified in flowers, while N-feruloyltyramine derivatives, for which interesting anti-inflammatory properties have been reported, turned out to be the major bioactive molecules in stems. The plethora of the detected bioactive molecules amplifies the nutraceutical value of berries and leaves and prompts the exploitation of L. barbarum flowers and pruned stems as sources of beneficial compounds.

Onopordum illyricum L. is a medicinal plant used in the Mediterranean area as antipyretic for the treatment of respiratory and urinary inflammations and to treat skin ulcers. Repeated chromatographic purification of O. illyricum aerial parts led to the isolation of six known sesquiterpenes, which were evaluated for the inhibition of the pro-inflammatory transcription factors NF-κB and STAT3 and for the activation of the transcription factor Nrf2, which regulates the cellular antioxidant response. Structure–activity relationships were interpreted by the NMR-based cysteamine assay. The sesquiterpene lactone vernomelitensin significantly inhibited NF-κB and STAT3, showing also a significant Nrf2 activation. Accordingly, the cysteamine assay selected vernomelitensin as the most reactive of the isolated sesquiterpenes, identifying the α,β-unsaturated aldehyde moiety as responsible for the higher (re)activity.

Cannabinoids are a complex group of molecules that comprise phytocannabinoids, endocannabinoids, and synthetic cannabinoids. Cannabinoids were initially identified by their ability to bind and activate the classical cannabinoid receptors CB1 and CB2. However, cannabinoids are pleiotropic in nature, and also activate other type of receptors, such as transient receptor potential cation channels, ligand-gated ion channels, deorphanized G protein coupled receptors, and peroxisome proliferator activated receptors such as PPARγ. Thus, cannabinoids may exert their biological activities through CB1/CB2-dependent and independent mechanisms, or a combination of both, which is especially relevant in the case of botanical drugs containing mixtures of phytocannabinoids. PPARγ exerts a wide variety of physiological functions, and its pharmacological manipulation has been exploited for the treatment of diabetes. In addition, PPARγ is recognized as a major target for the development of novel therapies aimed at managing chronic inflammatory and neurodegenerative diseases. Here, we review the published literature on cannabinoids and PPARγ, and discuss their potential therapeutic implications.

Ziziphus jujuba Mill., jujube, leaf infusions are popular bedtime beverages as they improve sleep by soothing the nerves. With the aim of providing further insights into the polyphenol content of jujube leaf infusion and their antioxidant activities, a 2,2-diphenyl-1-picrylhydrazyl (DPPH)-guided purification of the aqueous extract of Z. jujuba Mill. leaves was conducted. Three major antioxidant polyphenols (i.e. quercitrin, catechin and gallocatechin) of the leaves were identified. In addition, a significant antibiofilm bioactivity against Streptococcus mutans, a causative agent of human dental caries, was detected for the aqueous leaf extract and its bio-guided separation resulted in the identification of the lupane triterpenoid alphitolic acid as the main antibiofilm metabolite. The results herein presented further promote the consumption of jujube leaf infusion as a healthy antioxidant bedtime beverage, and associate it to an unreported anti-caries activity.

The peer-reviewed marine pharmacology literature from 2012 to 2013 was systematically reviewed, consistent with the 1998–2011 reviews of this series. Marine pharmacology research from 2012 to 2013, conducted by scientists from 42 countries in addition to the United States, reported findings on the preclinical pharmacology of 257 marine compounds. The preclinical pharmacology of compounds isolated from marine organisms revealed antibacterial, antifungal, antiprotozoal, antituberculosis, antiviral and anthelmitic pharmacological activities for 113 marine natural products. In addition, 75 marine compounds were reported to have antidiabetic and anti-inflammatory activities and affect the immune and nervous system. Finally, 69 marine compounds were shown to display miscellaneous mechanisms of action which could contribute to novel pharmacological classes. Thus, in 2012–2013, the preclinical marine natural product pharmacology pipeline provided novel pharmacology and lead compounds to the clinical marine pharmaceutical pipeline, and contributed significantly to potentially novel therapeutic approaches to several global disease categories.

A series of structurally related jatrophane diterpenoids (1−6), including the new euphosquamosins A−C (4−6), was purified from the Iranian spurge Euphorbia squamosa and evaluated for its capacity to inhibit drug efflux by multidrug transporters of Candida albicans. Three of these compounds showed an interesting profile of activity. In particular, deacetylserrulatin B (2) and euphosquamosin C (6) strongly inhibited the drug-efflux activity of the primary ABC-transporter CaCdr1p, an effect that translated, in a yeast strain overexpressing this transporter, into an increased sensitivity to fluconazole. These compounds were transported by CaCdr1p, as shown by the observation of an 11−14-fold cross-resistance of yeast growth, and could also inhibit the secondary MFS-transporter CaMdr1p. In contrast, euphosquamosin A (4) was selective for CaCdr1p, 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.

A series of previously unreported compounds including seven new apotirucallane protolimonoids, xylogranatumines A–G ( 1 – 7 ), were isolated together with three known analogues ( 8 – 10 ) from the twigs and leaves of the Chinese mangrove, Xylocarpus granatum . The structures of these new compounds were elucidated by extensive spectroscopic analysis including 1D and 2D NMR and high-resolution electrospray ionization mass spectrometry (HRESIMS) and by comparison with those of related known compounds in the literature. Xylogranatumine F ( 6 ) exhibited cytotoxic activity against A549 tumor cell in vitro.

We recently proposed 3-methoxy-4-methoxycarbonyl-1,2-dioxanes 3 as promising scaffolds enabling access to potential antimalarial drugs. We present here an optimized two-step synthesis of 3 characterized by high yields, simple work-up procedures and high diastereoselectivity allowing us to readily prepare 3 on multigram scale. The versatility of the 1,2-dioxane scaffold was demonstrated by our generation of a new family of 1,2-dioxane-4-carboxamides 8a–h and the realization of their in vitro activities against chloroquine-sensitive (D10) and chloroquine-resistant (W2) P. falciparum strains. In particular, one of these amides (8e), displayed antimalarial activity on par with the natural product lead plakortin and was 5-fold more active than its methyl ester analogue 3. Structure–activity relationship (SAR) analysis supported by DFT calculations revealed that, for this family of compounds, alkyl substituents at C6 dictate, in large part, the degree of antimalarial activity. This finding contrasts those previously observed for the ester series.

This research was aimed at investigating the essential oil production, chemical composition and biological activity of a crop of pink flowered oregano (Origanum vulgare L. subsp. vulgare L.) under different spatial distribution of the plants (single and binate rows). This plant factor was shown to affect its growth, soil covering, fresh biomass, essential oil amount and composition. In particular, the essential oil percentage was higher for the binate row treatment at the full bloom. The chemical composition of the oils obtained by hydrodistillation was fully characterized by GC and GC-MS. The oil from plants grown in single rows was rich in sabinene, while plants grown in double rows were richer in ocimenes. The essential oils showed antimicrobial action, mainly against Gram-positive pathogens and particularly Bacillus cereus and B. subtilis.

The chemical composition and biological activity of the essential oils obtained from the leaves of two different cultivars of Florence fennel cropped under three different fertilization treatments (Control not fertilized; Mineral Fertilization; Compost from Municipal Solid Wastes) have been analyzed. All the oils were characterized by high anethole concentration and some showed also a good percentage of limonene. Thus, the leaves of Florence fennel, which are agricultural wastes, could be used for the recovery of anethole to be used for its flavoring and biomedical properties. The antimicrobial activity expressed by assays on the examined oils indicates an appreciable effect, generally higher on Gram-positive bacteria. The various samples of Florence fennel analyzed did not show any results with FRAP test. The DPPH test showed a weak capacity of the samples to catch the free radicals from the solution, attributable to their content in anethole.

A detailed investigation of the South China Sea soft coral Sarcophyton trocheliophorum Marenzeller yielded, along with six known terpenes (6-11), the new sarcophytonolides N-R (1-5), whose structures have been elucidated by detailed spectroscopic analysis. Sarcophytonolides N-R are mono- or bicyclic cembranoids characterized by the presence of three/four double bonds and oxidized methyl groups. Some of the isolated compounds showed significant inhibitory activity against human protein tyrosine phosphatase 1B (PTP1B) enzyme, a key target for the treatment of type-II diabetes and obesity, and some preliminary structure-activity relationships have been drawn. This is the first report on the anti-PTP1B activity of cembrane diterpenoids.

Chemical analysis of the organic extract of Theonella swinhoei yielded two new tridecadepsipeptides of the theonellapeptolide family, namely sulfinyltheonellapeptolide, characterized by a methylsulfinylacetyl group at the N-terminus, and theonellapeptolide If, the first member of this class of compounds to show four valine residues. The structures of the compounds, isolated along with the known theonellapeptolide Id, were determined by extensive 2D NMR and MS/MS analyses followed by application of Marfey’s method. The isolated peptides exhibited moderate antiproliferative activity against HepG2 cells, a hepatic carcinoma cell line.

Plakortides R–U, four new polyketide endoperoxides, have been isolated from the marine sponge Plakinastrella mamillaris. Their structures were elucidated on the basis of extensive NMR spectroscopic (1H and 13C, COSY, HSQC, HMBC, and ROESY) and MS analyses and by chemical methods. In addition, a new method for the unambiguous stereochemical elucidation of 3,6-disubstituted 1,2-dioxines, frequently isolated from Plakinidae sponges, is reported. Pharmacological analysis demonstrated that plakortide U is endowed with in vitro antiplasmodial activity against a chloroquine-resistant strain.

A detailed chemical investigation of the Chinese soft coral Cladiella krempfi has yielded four new eunicellin-based diterpenoids along with five known compounds. The stereostructures of the new metabolites have been elucidated by extensive spectroscopic analysis, mainly based on 2D NMR spectroscopy, and by chemical transformations. A remarkable variation in the diterpene composition in dependence of the exact site of collection was observed. Some of the isolated diterpenoids were shown to exhibit antiproliferative activity against C6 glioma cells, multi-drug resistant tumor cell line.

We recently proposed 3-methoxy-4-methoxycarbonyl-1,2-dioxanes 3 as promising scaffolds enabling access to potential antimalarial drugs. We present here an optimized two-step synthesis of 3 characterized by high yields, simple work-up procedures and high diastereoselectivity allowing us to readily prepare 3 on multigram scale. The versatility of the 1,2- dioxane scaffold was demonstrated by our generation of a new family of 1,2-dioxane-4-carboxamides 8a–h and the realization of their in vitro activities against chloroquine-sensitive (D10) and chloroquine-resistant (W2) P. falciparum strains. In particular, one of these amides (8e), displayed antimalarial activity on par with the natural product lead plakortin and was 5-fold more active than its methyl ester analogue 3. Structure–activity relationship (SAR) analysis supported by DFT calculations revealed that, for this family of compounds, alkyl substituents at C6 dictate, in large part, the degree of antimalarial activity. This finding contrasts those previously observed for the ester series.

An expeditious strategy to resolve turmerone, the lipophilic anti-inflammatory principle of turmeric (Curcuma longa), into its individual bisabolane constituents (ar-, α-, and β-turmerones, 2-4, 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, 8) 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.

Background NeemAzal ® (NA) is a quantified extract from seed kernels of neem, Azadirachta indica A.Juss. (Meliaceae), with a wide spectrum of biological properties, classically ascribed to its limonoid content. NA contains several azadirachtins (A to L), azadirachtin A (AzaA) being its main constituent. AzaA has been shown to inhibit microgamete formation of the rodent malaria parasite Plasmodium berghei , and NA was found to completely inhibit the transmission of Plasmodium berghei to Anopheles stephensi mosquitoes when administered to gametocytemic mice at a corresponding AzaA dose of 50 mg/kg before exposure to mosquitoes. Purpose The present study was aimed at i) assessing the pharmacodynamics and duration of action of NA and AzaA against P. berghei exflagellation in systemic circulation in mice and ii) elucidating the transmission blocking activity (TBA) of the main NA constituents. Study design The NA and AzaA pharmacodynamics on exflagellation were assessed through ex vivo exflagellation assays, while TBA of NA constituents was evaluated through in vitro ookinete development assay. Methods Pharmacodynamics experiments: Peripheral blood from P. berghei infected BALB/c mice with circulating mature gametocytes, were treated i.p. with 50 mg/kg and 100 mg/kg pure AzaA and with NeemAzal ® (Trifolio-M GmbH) at the corresponding AzaA concentrations. The effect magnitude and duration of action of compounds was estimated by counting exflagellation centers, formed by microgametocytes in process of releasing flagellated gametes, at various time points after treatment in ex vivo exflagellation tests. Ookinete Development Assay: The direct effects of NeemAzal ® and AzaA on ookinete development were measured by fluorescence microscopy after incubation of gametocytemic blood with various concentrations of test substances in microplates for 24 h. Results The exflagellation tests revealed an half-life of NA anti-plasmodial compounds of up to 7 h at a NA dose corresponding to 100 mg/kg equivalent dose of AzaA. The ookinete development assay showed an increased activity of NA against early sporogonic stages compared to that of AzaA. The IC 50 value determined for NA was 6.8 µg/ml (CI 95 : 5.95–7.86), about half of the AzaA IC 50 (12.4 µg/ml; CI 95 : 11.0–14.04). Conclusion The stronger activity of NA, when compared to AzaA, could not be explained by an additive or synergistic effect by other azadirachtins (B, D and I) present in NA. In fact, the addition of these compounds at 50 µM concentration to AzaA did not evidence any decrease of the IC 50 against early sporogonic stages to that obtained with AzaA alone. It is likely that other non-limonoid compounds present in NA may contribute to AzaA activity and enhanced pharmacodynamics against exflagellation both in vitro and in vivo .

Humulus lupulus (hop plant) has long been used in traditional medicine as a sedative and antimicrobial agent. More recently, attention has been devoted to the phytoestrogenic activity of the plant extracts as well as to the anti-inflammatory and chemopreventive properties of the prenylated chalcones present. In this study, an Italian sample of H. lupulus cv. "Cascade" has been investigated and three new compounds [4-hydroxycolupulone (6), humudifucol (7) and cascadone (8)] have been purified and identified by means of NMR spectroscopy along with four known metabolites. Notably, humudifucol (7) is the first prenylated dimeric phlorotannin discovered in nature. Because structurally related phloroglucinols from natural sources were found previously to inhibit microsomal prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO), the isolated compounds were evaluated for their bioactivity against these pro-inflammatory target proteins. The prenylated chalcone xanthohumol inhibited both enzymes at low μM concentrations.

TRP (Transient Receptor Potential) channels and CB (cannabinoid) receptors are deputed to the regulation of sensory, homeostatic, and inflammatory events in human organism. Therefore, their modulation promises to have relevant applications in important therapeutic areas as inflammation, pain, and cancer. This review summarizes the contribution of marine research in this relatively young field, highlighting the potential of the chemodiversity carried by marine natural products in the discovery of new ligands.

Fifteen polyketides, including the first hydroxylated plakortone (12) and plakdiepoxide (15), the first polyketide to embed a vicinal diepoxide, have been isolated from the Chinese sponge Plakortis simplex. 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 (13) activates both PPAR-α and PPAR-γ, a dual activity of potential great importance for the treatment of metabolic disorders.

An expeditious isolation method for the cembrane diterpene alcohols incensol (la) and serratol (2) has been developed from respectively African and Indian frankincense. The two native alcohols and a series of semisynthetic derivatives of incensol were evaluated for transient receptor potential vanilloid 3 (TRPV3) activation and the inhibition of NF-kappa B, the putative molecular targets underlying the psychotropic and anti-inflammatory activities of incensol acetate (IA, 1b). Serratol (2) was the most potent TRPV3 activator, outperforming by 2 orders of magnitude the reference agonist thymol and by 1 order of magnitude incensol acetate (1b). Acylation, epimerization, and oxidation did not significantly improve the affinity of incensol for TRPV3, while NF-kappa B inhibition, marginal for both natural alcohols, could be improved by esterification of incensol (1a) with lipophilic acids. Interestingly, incensol (1a) but not IA (1b) was a potent inhibitor of STAT3, raising the possibility that hydrolysis to incensol (1a) might be involved in the in vivo biological activity of IA (1b). Serratol was not amenable to chemical modification, but some marine cembranoids related to the frankincense diterpenoids showed a certain degree of TRPV3-activating properties, qualifying the aliphatic macrocyclic cembrane skeleton as a selective chemotype to explore the pharmacology of TRPV3, a thermo-TRP otherwise resistant to modulation by small molecules.

Azadirachta indica, known as neem tree and traditionally called “nature's drug store” makes part of several African pharmacopeias and is widely used for the preparation of homemade remedies and commercial preparations against various illnesses, including malaria. Employing a bio-guided fractionation approach, molecules obtained from A. indica ripe and green fruit kernels were tested for activity against early sporogonic stages of Plasmodium berghei, the parasite stages that develop in the mosquito mid gut after an infective blood meal. The limonoid deacetylnimbin (3) was identified as one the most active compounds of the extract, with a considerably higher activity compared to that of the close analogue nimbin (2). Pure deacetylnimbin (3) appeared to interfere with transmissible Plasmodium stages at a similar potency as azadirachtin A. Considering its higher thermal and chemical stability, deacetylnimbin could represent a suitable alternative to azadirachtin A for the preparation of transmission blocking antimalarials.

During a large-scale isolation campaign for the heterodimeric phloroglucinyl pyrone arzanol (1a) from Helichrysum italicum subsp. microphyllum, several new phenolics as well as an unusual class of lipids named santinols (5a-c, 6-8) 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 Helichrysum phenolics that includes coumarates, benzofurans, pyrones, and heterodimeric phloroglucinols was evaluated, showing that only the heterodimers showed potent antibacterial action against multidrug-resistant Staphylococcus aureus isolates. These observations validate the topical use of Helichrysum extracts to prevent wound infections, a practice firmly established in the traditional medicine of the Mediterranean area.

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