Synthesis of benzopyran derivatives as PPARα and/or PPARγ activators.

We describe the synthesis of 26 compounds, small polycerasoidol analogs, that are Lipinski's rule-of-five compliant. In order to confirm key structural features to activate PPARα and/or PPARγ, we have adopted structural modifications in the following parts: (i) the benzopyran core (hydrophobic nucleus) by benzopyran-4-one, dihydrobenzopyran or benzopyran-4-ol; (ii) the side chain at 2-position by shortening to C3, C4 and C5-carbons versus C-9-carbons of polycerasoidol; (iii) the carboxylic group (polar head) by oxygenated groups (hydroxyl, acetoxy, epoxide, ester, aldehyde) or non-oxygenated motifs (allyl and alkyl). Benzopyran-4-ones 6, 12, 13 and 17 as well as dihydrobenzopyrans 22, 24 and 25 were able to activate hPPARα, whereas benzopyran-4-one (7) with C5-carbons in the side chain exhibited hPPARγ agonism. According to our previous docking studies, SAR confirm that the hydrophobic nucleus (benzopyran-4-one or dihydrobenzopyran) is essential to activate PPARα and/or PPARγ, and the flexible linker (side alkyl chain) should containg at least C5-carbon atoms to activate PPARγ. By contrast, the polar head ("carboxylic group") tolerated several oxygenated groups but also non-oxygenated motifs. Taking into account these key structural features, small polycerasoidol analogs might provide potential active molecules useful in the treatment of dyslipidemia and/or type 2 diabetes.

Polycerasoidol, a Natural Prenylated Benzopyran with a Dual PPARα/PPARγ Agonist Activity and Anti-inflammatory Effect.

Dual peroxisome proliferator-activated receptor-α/γ (PPARα/γ) agonists regulate both lipid and glucose homeostasis under different metabolic conditions and can exert anti-inflammatory activity. We investigated the potential dual PPARα/γ agonism of prenylated benzopyrans polycerasoidol (1) and polycerasoidin (2) and their derivatives for novel drug development. Nine semisynthetic derivatives were prepared from the natural polycerasoidol (1) and polycerasoidin (2), which were evaluated for PPARα, -γ, -δ and retinoid X receptor-α activity in transactivation assays. Polycerasoidol (1) exhibited potent dual PPARα/γ agonism and low cytotoxicity. Structure-activity relationship studies revealed that a free phenol group at C-6 and a carboxylic acid at C-9' were key features for dual PPARα/γ agonism activity. Molecular modeling indicated the relevance of these groups for optimal ligand binding to the PPARα and PPARγ domains. In addition, polycerasoidol (1) exhibited a potent anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium in a concentration-dependent manner via RXRα/PPARγ interactions. Therefore, polycerasoidol (1) can be considered a hit-to-lead molecule for the further development of novel dual PPARα/γ agonists capable of preventing cardiovascular events associated with metabolic disorders.

Chemical composition and antimicrobial activity of the essential oils from New Caledonian Citrus macroptera and Citrus hystrix.

The essential oils from the leaves of Citrus macroptera and C. hystrix, collected in New Caledonia, have been analyzed by gas chromatography/mass spectrometry (GC/MS) and evaluated for their antimicrobial activity. A total of 35 and 38 constituents were identified, representing 99.1 and 89.0% of the essential oils, respectively. Both essential oils were rich in monoterpenes (96.1 and 87.0%, resp.), with beta-pinene as major component (33.3 and 10.9%, resp.), and poor in limonene (2.4 and 4.7%, resp.). Other main components of C. macroptera oil were alpha-pinene (25.3%), p-cimene (17.6%), (E)-beta-ocimene (6.7%), and sabinene (4.8%). The essential oil of C. hystrix was characterized by high contents of terpinen-4-ol (13.0%), alpha-terpineol (7.6%), 1,8-cineole (6.4%), and citronellol (6.0%). The antimicrobial activity was evaluated against five bacteria and five fungi strains. Both oils were inactive against bacteria. However, the C. macroptera leaf oil exhibited a pronounced activity against Trichophyton mentagrophytes var. interdigitale, with a minimal-inhibitory concentration (MIC) of 12.5 microg/ml.

In vitro antitumor structure-activity relationships of threo/trans/threo/trans/erythro bis-tetrahydrofuranic acetogenins: correlations with their inhibition of mitochondrial complex I.

Annonaceous acetogenins are known to be cytotoxic against tumor cell lines by virtue of their inhibition of mitochondrial complex I. We decided to conclude part of our recent revisions of the different structure-activity relationships (SARs) found within these compounds with a detailed description of the cytotoxic activity, and correlations with the inhibition of the target enzyme, of the broadest subclass of this family of natural products, the bis-tetrahydrofuranic acetogenins (bis-THF ACGs) of threo/trans/threo/trans/erythro relative configuration. Five naturally occurring ACGs and more than 10 semisynthetic analogs were tested against the MCF-7 (breast), A-549 (lung), HepG2 (liver), HT-29 (colon), MES-SA (ovary), and a multidrug-resistant (MDR-MES-SA/Dx5) cell lines using the MTr cytotoxicity assay to determine if the mitochondrial complex I inhibition correlated with the in vitro antitumor potency of the most common ACGs. Results indicated that a previously observed trend for other subclasses of ACGs between the ED50 of the cytotoxicity assay and the polarity of compounds was not present in this set and that there were several specific interactions that enhanced the antitumor activity. For example, some of the guanacone derivatives prepared were two orders of magnitude more potent than the parent compound for specific cell lines.

Explaining primary healthcare pharmacy expenditure using classification of medications for chronic conditions.

BACKGROUND: The Valencian Autonomous Community (Spain) has implemented a scheme of purchasing services with the participation of public and private providers. Five districts are managed using public-private partnership. The financing model is capitation and inter-center invoice. The pharmaceutical benefits are not included in the per capita assignment. OBJECTIVES: Modeling and explaining pharmacy expenditure using electronic prescriptions drug data. METHODS: A database of electronic prescription corresponding to 625,246 patients between November 2008 and October 2009 was used to run four linear models that explain the pharmaceutical expenditures. We take as dependent variable the neperian log of total pharmacy annual cost per patient in the primary health setting. The independent variables used combined demographics with revised classification in 18 chronic conditions obtained from the anatomical therapeutic chemical classification index (ATC). RESULTS: The retrospective model selected included: gender, pharmaceutical co-payment status and 8 dummy variables for the number of chronic conditions of each patient from 1 to 8 or more. The goodness-of-fit achieved is measured in R(2) of 57%. CONCLUSIONS: These models must be considered in the current capitation system for pharmaceutical budgeting in a primary care setting established at regional level, as is the case in the Valencian Autonomous Community. The use of diagnostics and information regarding hospital encounters appears to be a complementary option for refining models of capitation of pharmaceutical and total health expenditure.

New antitumoral acetogenin 'Guanacone type' derivatives: isolation and bioactivity. Molecular dynamics simulation of diacetyl-guanacone.

We describe herein the isolation and semisynthesis of four acetogenin derivatives (1-4) as well as their ability to inhibit the mitochondrial respiratory chain and several tumor cell lines. In addition, four nanoseconds (ns) of MD simulation of compound 4, in a fully hydrated POPC bilayer, is reported.

Guanaconetins, new antitumoral acetogenins, mitochondrial complex I and tumor cell growth inhibitors.

The antitumoral activity of a series of acetylated bis-tetrahydrofuranic acetogenins with a threo/trans/threo/trans/erythro relative configuration was characterized by four new natural and two semisynthetic, 15,24,30-trioxygenated acetogenins that were found to inhibit mitochondrial complex I enzyme as well as growth of several tumor cell lines. Placement of acetyl groups along the alkyl chain modulated the potency of the bis-tetrahydrofuranic acetogenins and could be important for future utilization of these compounds as chemotherapeutic agents.

Acetogenins from Annonaceae: recent progress in isolation, synthesis and mechanisms of action.

The aim of the present review is to summarise the knowledge about newly isolated acetogenins (ACGs) in the last six years. It will also report the total syntheses that have allowed either the confirmation or the revision of some structures, together with the biological activities and mechanism of action of such interesting natural products. In fact, of the 417 isolated compounds reviewed, over 176 have been added during the period from 1998 to 2004.

Tucumanin, a beta-hydroxy-gamma-lactone bistetrahydrofuranic acetogenin from Annona cherimolia, is a potent inhibitor of mitochondrial complex I.

A new beta-hydroxy-gamma-methyl-gamma-lactone bistetrahydrofuranic acetogenin, tucumanin, with the infrequent symmetrical threo/trans/threo/trans/threo relative configuration at the tetrahydrofuran rings was isolated from Annona cherimolia (Annonaceae) seeds. The inhibitory potency on the mitochondrial complex I of acetogenins with this relative configuration (tucumanin and asimicin)was compared with that shown by the corresponding pairs with an asymmetrical threo/trans/threo/trans/erythro relative configuration (laherradurin/rolliniastatin-2, and itrabin/molvizarin). All these compounds act as selective inhibitors of mitochondrial complex I in the 0.18 - 1.55 nM range.

Clasificacion de usuarios de centros para mayores y un modelo de financiacion de acuerdo con dependencia / Clasification of users for centre for older

El propósito es adecuar la financiación de los geriátricos a las necesidades. Tiempo de Atención Directa (TAD) de los usuarios. La población está constituida por los usuarios de plazas públicas de la Comunidad Valenciana, año 1996, extrayéndose una muestra de 611 individuos. Se identificaron aquellas características de dependencia que mayor influencia tienen en el TAD para clasificar a los residentes. Se obtuvo la complejidad de cada una de las residencias del estudio, calculándose una ecuación para la financiación. Las características que más influyeron fueron el deterioro físico, la demencia y los factores de riesgo. La explicación de la variabilidad del TAD fue del 76 por ciento. Los usuarios se clasificaron en siete grupos de dependencia desde 10,7 minutos/día a 237 minutos/día TAD. Este TAD permitió establecer los pesos de complejidad de atención. La financiación de residencias (25 y 100 plazas), obtuvo, en promedio, unos costes fijos anuales de 72.121 y unos costes variables de 5487 plaza/año y 589 complejidad/año