Discovery and biological evaluation of the novel naturally occurring diterpene pepluanone as antiinflammatory agent.

From the whole plant of Euphorbia peplus L., a new diterpene based on a rare pepluane skeleton, named pepluanone (1), was isolated together with a known pepluane diterpene (2). The stereostructure of pepluanone was determined on the basis of an extensive NMR study, MS data, and chemical reaction. The ability of these compounds to act as antiinflammatory agents has been evaluated for the first time by in vivo tests on carrageenin-induced rat paw edema, an experimental model of acute inflammation. Comparison of the bioactivity of pepluanone and compound 2 in terms of chemical structure, evidenced the high efficiency of pepluanone and the absence of appreciable activity for compound 2, thus giving a first insight into the structure-activity relationship. Further in vitro experiments performed on pepluanone let us hypothesize that its activity could be explained in reducing the production of nitric oxide, prostaglandin E(2), and TNF-alpha by inhibiting the expression of inducible nitric oxide synthase, cyclooxygenase-2, and TNF-alpha mRNA through the down-regulation of NF-kappaB binding activity.

Antispasmodic saponins from bulbs of red onion, Allium cepa L. var. Tropea.

A phytochemical analysis of the polar extract from the red bulbs of Allium cepa L. var. Tropea, typical of Calabria, a southern region of Italy, was performed extensively for the first time, leading to the isolation of four new furostanol saponins, named tropeoside A1/A2 (1a/1b) and tropeoside B1/B2 (3a/3b), along with the respective 22-O-methyl derivatives (2a/2b and 4a/4b), almost certainly extraction artifacts. High concentrations of ascalonicoside A1/A2 (5a/5b) and ascalonicoside B (6), previously isolated from Allium ascalonicum Hort., were also found. This is the first report of furostanol saponins in this A. cepa variety. The chemical structures of the new compounds were established through a combination of extensive nuclear magnetic resonance, mass spectrometry and chemical analyses. High concentrations of quercetin, quercetin 4(I)-glucoside, taxifolin, taxifolin 7-glucoside, and phenylalanine were also isolated. The new saponins were found to possess antispasmodic activity in the guinea pig isolated ileum; such an effect might contribute to explaining the traditional use of onion in the treatment of disturbances of the gastrointestinal tract.

[Evaluation of therapeutical appropriateness in psychiatric treatment of schizophrenia, by integrating computer data records with clinical audit results]. / Valutazione dell'appropriatezza prescrittiva in psichiatria: un progetto di clinical audit nella ASL di Caserta.

AIM: The aim is to evaluate prescriptive patterns of atypical antipsychotic drugs for the treatment of schizophrenia in the LHU Caserta in 2011-2013, and to indicate potentially inappropriate therapy; to plan or schedule corrective/preventive activities to support the continuous improvement of health services. METHODS: Retrospective cohort study, based on integration of health records and clinical audit. The study was performed in the following steps: data retrieval and analysis; comparison of data with international literature; editing of the Diagnostic-Therapeutic Path. The analysis was performed by using the administrative database of drug prescriptions and treatment plans in the SANIARP portal, a web platform available to specialist facilities and private and public pharmacies of LHU Caserta. The subject of our analysis was to gain information about the diagnosis and treatment of users of atypical antipsychotics in the LHU of Caserta in the years 2011-2013. RESULTS: We identified 2,768 patients with at least one prescription of atypical antipsychotics and diagnosis coded in the study period. Schizophrenia is the most frequent diagnosis (31.1%) and the most common drug in use is olanzapine (29.1%). About 70% of schizophrenics were on monotherapy with no change in drug, 23.6% were under polytherapy and 7.9% made a switch. DISCUSSION AND CONCLUSION: Our findings were a starting point for editing Diagnostic and Therapeutic Paths aimed at raising the awareness of the scientific community about the appropriateness of diagnosis and treatment in schizophrenia. Pharmacological treatment of schizophrenia should be focused on improving the overall quality of life aimed at remission and possible recovery, although difficult.

Jatrophane diterpenes as modulators of multidrug resistance. Advances of structure-activity relationships and discovery of the potent lead pepluanin A.

From the whole plant of Euphorbia peplus L., five new diterpenes based on a jatrophane skeleton (pepluanins A-E, 1-5) were isolated, together with two known analogues (6 and 7), which served to divulge in detail the structure-activity relationships within this class of P-glycoprotein inhibitors. The results revealed the importance of substitutions on the medium-sized ring (carbons 8, 9, 14, and 15). In particular, the activity is collapsed by the presence of a free hydroxyl at C-8, while it increases with a carbonyl at C-14, an acetoxyl at C-9, and a free hydroxyl at C-15. The most potent compound of the series, pepluanin A, showed a very high activity for a jatrophane diterpene, outperforming cyclosporin A by a factor of at least 2 in the inhibition of Pgp-mediated daunomycin transport.

Jatrophane diterpenes as P-glycoprotein inhibitors. First insights of structure-activity relationships and discovery of a new, powerful lead.

The Mediterranean spurge Euphorbia dendroides L. afforded a series of 10 closely related jatrophane polyesters, nine of which are new, which served as a base for the establishment of structure-activity relationships within this class of P-glycoprotein inhibitors. The results, while pointing to the general role of lipophilicity for activity, also highlighted the relevance of the substitution pattern at the positions 2, 3, and 5, suggesting the involvement of this fragment in binding. The most powerful compound of the series, euphodendroidin D (4), outperformed cyclosporin by a factor of 2 to inhibit Pgp-mediated daunomycin transport.

Saponins and flavonoids of Allium triquetrum.

A phytochemical investigation of the flowers and bulbs of Allium triquetrum has been undertaken, leading to the isolation of five new furostanol saponins, triquetrosides A1/A2 (1a/1b), B (3), and C1/C2 (4a/4b), from the flowers, along with ascalonisides A1/A2 (6a/6b). The 22-O-methyl derivatives of triquetrosides A1/A2 (2a and 2b) and C1/C2 (5a and 5b) were also isolated, but they are considered extraction artifacts. Large amounts of seven kaempferol glycosides, of which one (7) has a new structure, were also isolated from both flowers and bulbs. The structures of the new compounds were determined by spectral and chemical methods.

Astersedifolioside A-C, three new oleane-type saponins with antiproliferative activity.

A phytochemical analysis of Aster sedifolius has led to the isolation of three novel triterpenoid saponins, based on an oleane-type skeleton and named astersedifolioside A (1), B (2) and C (3). On the basis of chemical, and 2D NMR and mass spectrometry data, the structures of the new compounds were elucidated as 3-O-[alpha-L-rhamnopyranosyl (1-->2)-beta-D-glucopyranosyl] echinocystic acid 28-[O-alpha-L-rhamnopyranosyl (1-->2)-alpha-L-arabinopyranoside] (1), 3-O-[alpha-L-rhamnopyranosyl (1-->2)-beta-D-glucopyranosyl] echinocystic acid 28-[O-beta-D-xylopyranosyl (1-->4)-O-alpha-L-rhamnopyranosyl (1-->2)-alpha-L-arabinopyranoside] (2) and 3-O-[alpha-L-rhamnopyranosyl (1-->2)-beta-D-glucopyranosyl (1-->2)-beta-D-glucopyranosyl] echinocystic acid 28-[O-beta-D-xylopyranosyl (1-->4)-O-alpha-L-rhamnopyranosyl (1-->2)-alpha-L-arabinopyranoside] (3). The isolated compounds showed antiproliferative effect in KiMol, a transformed thyroid cell line.

Structure-activity relationships for euphocharacins A-L, a new series of jatrophane diterpenes, as inhibitors of cancer cell P-glycoprotein.

The Mediterranean spurge Euphorbia characias L. afforded twelve new diterpenes based on a jatrophane skeleton named euphocharacins A-L. Their chemical structures were elucidated by extensive nuclear magnetic resonance and mass spectrometry methods. Euphocharacins A-L were tested as inhibitors of the daunomycin-efflux activity of P-glycoprotein from cancer cells. The results were used to extend the structure-activity relationship established for this class of compounds, highlighting the positive effects of propyl and benzoyl groups at positions 3 and 9, respectively, and evidencing the negative effect of a free hydroxyl group at position 2. Among the tested compounds, euphocharacins C and I showed an activity higher than cyclosporin to inhibit Pgp-mediated daunomycin transport.

Modified jatrophane diterpenes as modulators of multidrug resistance from Euphorbia dendroides L.

The new diterpenoids terracinolides J-L (1-3), 13alpha-OH terracinolide F (8), abeodendroidin F (11) and epiabeodendroidin F (12) have been identified from Euphorbia dendroides L. The new compounds and six co-occurring known terracinolides were tested as inhibitors of the drug-efflux activity of P-glycoprotein from cancer cells. The results were used to extend the structure-activity relationships established for this class of compounds highlighting the relevance of substitution at positions 2, 3, 6, and 15 and disclosing a remarkable tolerance toward connectivity changes in the terpenoid core.