Synthesis of 2-Prenylated Alkoxylated Benzopyrans by Horner-Wadsworth-Emmons Olefination with PPARα/γ Agonist Activity.

We have synthesized series of 2-prenylated benzopyrans as analogues of the natural polycerasoidol, a dual PPARα/γ agonist with anti-inflammatory effects. The prenylated side chain consists of five or nine carbons with an α-alkoxy-α,ß-unsaturated ester moiety. Prenylation was introduced via the Grignard reaction, followed by Johnson-Claisen rearrangement, and the α-alkoxy-α,ß-unsaturated ester moiety was introduced by the Horner-Wadsworth-Emmons reaction. Synthetic derivatives showed high efficacy to activate both hPPARα and hPPARγ as dual PPARα/γ agonists. These prenylated benzopyrans emerge as lead compounds potentially useful for preventing cardiometabolic diseases.

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.

Two-Photon Absorption and Cell Imaging of Fluorene-Functionalized Epicocconone Analogues.

Epicocconone 1 is a natural chromophore isolated from the fungus Epicoccum nigrum that has shown applications in proteomics and fluorescent microscopy thanks to its unique pro-fluorescence properties. The modification of the skeleton of the natural product by replacing the triene side chain by a fluorenyl scaffold can noticeably increase the fluorophore's absorption coefficient. The synthesis of the analogues of the natural product has been made possible by the use of a palladium-catalyzed carbonylation reaction, allowing the construction of the ß-keto-dioxinone key intermediate. Two-photon absorption cross-section measurements of the fluorenyl epicocconone analogues show a structure dependency with values ranging from 60 to 280 GM and live cell imaging show intense staining of intracellular vesicle-like structures around the nucleus.

Epicocconone-Hemicyanine Hybrids: Near Infrared Fluorophores for Protein Staining and Cell Imaging.

The development of new near infrared (NIR) dyes is crucial for diverse applications and especially bioimaging, as they absorb and emit light in the "therapeutic window" (650-950 nm). We report here a new family of NIR fluorophores that has been obtained by hybridising hemicyanines with epicocconone. Emission wavelengths of these hybrid dyes is in the range 715-795 nm and is combined with large Stokes' shifts (75-95 nm). The absorption and emission wavelength can be modulated according to the hemicyanine moiety and adding sulfonic acid moieties enhances water solubility. We demonstrate their application in the sensitive detection of proteins in gel electrophoresis and the staining of specific cellular organelles in confocal microscopy. These results are particularly encouraging and bring forward a new fluorescent skeleton for chemical biology.

Synthesis of pyrido[2,1-a]isoquinolin-4-ones and oxazino[2,3-a]isoquinolin-4-ones: new inhibitors of mitochondrial respiratory chain.

Benzo[a]quinolizine is an important heterocyclic framework that can be found in numerous bioactive compounds. The general scheme for the synthesis of these compounds was based on the preparation of the appropriate dihydroisoquinolines by Bischler-Napieralski cyclization with good yields, followed by the Pemberton method to form the oxazinones or pyridones derivatives via acyl-ketene imine cyclocondensation. All the synthesized compounds were assayed in vitro for their ability to inhibit mitochondrial respiratory chain. Most of the tested compounds were able to inhibit the integrated electron transfer chain, measured as NADH oxidation, which includes complexes I, III and IV, in the low micromolar range. Oxazino[2,3-a]isoquinolin-4-ones displayed greater activity than their pyrido[2,1-a]isoquinolin-4-ones analogs. Indeed, the presence of a furan ring in C2 position of oxazino[2,3-a]isoquinolin-4-ones provided the compound (1g) with the most potent biological activity. Therefore, these compounds and especially the oxazinone derivatives are in the tendency of the new less toxic antitumor agents that target mitochondrial electron transport chain in a middle range potency.

Quinoline compounds decrease in vitro spontaneous proliferation of peripheral blood mononuclear cells (PBMC) from human T-cell lymphotropic virus (HTLV) type-1-infected patients.

In vitro spontaneous proliferation is the immunological hallmark of peripheral blood mononuclear cells (PBMC) from HTLV-1-infected individuals. Quinoline compounds down regulate in vitro cell proliferation of HTLV-1 transformed cell lines. In the present study we assessed the capacity of quinolines to inhibit spontaneous cell proliferation of PBMC from HTLV-1-infected individuals. Twenty-two quinolines were evaluated. Toxicity was first assessed on PBMC from healthy donors by using both the Trypan blue technique and Tetrazolium Salt (XTT) method and then the antiproliferative effect was measured by a classic lymphoproliferative assay on PBMC from three HTLV-1-infected individuals, in the presence of decreasing concentrations of quinolines (from 100microM to 0.8microM), after 5 days of culture. We found that 14 out of 22 compounds were non-toxic to PBMC from uninfected individuals at 100, 50 and 10microM. Four compounds presented a capacity to inhibit more than 80% of the spontaneous proliferation: 7 at 25microM and 10, 20 and 23 at 100microM. Our results indicate that some quinolines block spontaneous proliferation of PBMC from HTLV-1-infected individuals.

Biological evaluation of substituted quinolines.

Several quinolines were synthesized and evaluated in vitro against several parasites (Trypanosoma brucei, T. cruzi, Leishmania infantum, L. amazonensis, Plasmodium falciparum). Then, they were evaluated in vitro (at 10 microM), against HTLV-1 transformed cells. A few of them displayed interesting activities, comparable to the reference drugs.

Substituted quinolines induce inhibition of proliferation of HTLV-1 infected cells.

Several quinolines were synthesized and evaluated against HTLV-1 infected cells. Some of them were able to inhibit HTLV-1 cell-growth at 10 microM. Some structure-activity relationships were observed.