Céline Rivière

Benzofuran-Based Hybrid Compounds for the Inhibition of Cholinesterase Activity, β Amyloid Aggregation, and Aβ Neurotoxicity

The complex etiology of Alzheimers disease (AD) prompts scientists to develop multitarget strategies to combat causes and symptoms. We therefore designed, synthesized, and tested new hybrid molecules linking a benzofuran ring to a N-methyl- N-benzylamine through a heptyloxy chain, affording a series of potential multifunctional drugs for AD. The cholinesterase inhibitory activity was extended to the inhibition of Abeta fibril formation for 1, 3, and 5. Compound 3 showed an additional neuroprotective effect.

Natural stilbenoids: distribution in the plant kingdom and chemotaxonomic interest in Vitaceae

Stilbenoids, a family of polyphenols known for the complexity of their structure and for their diverse biological activities, occur with a limited but heterogeneous distribution in the plant kingdom. The most prominent stilbene containing plant family, the Vitaceae, represented by the famous wine producing grape vines Vitis vinifera L., is one of the richest sources of novel stilbenes currently known, together with other families, such as Dipterocarpaceae, Gnetaceae and Fabaceae. This review focuses on the distribution of stilbenes and 2-arylbenzofuran derivatives in the plant kingdom, the chemical structure of stilbenes in the Vitaceae family and their taxonomic implication.

Anthocyanin identification and composition of wild Vitis spp. accessions by using LC–MS and LC–NMR

The composition and concentration of anthocyanins of grape berry skins were analyzed in order to assess phenotypic variation between four grape wine varieties belonging to 4 different species: Vitis vinifera, Vitis amurensis, Vitis cinerea and Vitis X champinii. High-performance liquid chromatography coupled to mass spectrometry (LC-MS) and NMR spectroscopy (LC-NMR) were used to separate and identify the structure of anthocyanins present in these species. Combination of LC-MS and LC-NMR data resulted in the identification of 33 anthocyanins. In particular, newly reported cis isomers of p-coumaric-derivatives were identified (petunidin-, peonidin- and malvidin-3-(6-p-coumaroyl)-5-diglucoside). In V. cinerea and V. vinifera, anthocyanins were monoglucoside derivatives whereas in V. amurensis and V. X champinii, both mono- and diglucoside derivatives were identified. Malvidin-, delphinidin- and petunidin-derivatives were, respectively, the most abundant components in V. cinerea and V. vinifera, V. amurensis and V. X champinii.

New stilbene dimers against amyloid fibril formation.

Twenty stilbene derivatives and moracin M extracted from natural products were tested against amyloid-beta peptide (Abeta) aggregation. Results of stilbene monomer derivatives indicated that interaction with resveratrol and piceid was specific. Concerning oligomers, scirpusin A and epsilon-viniferin glucoside demonstrated a strong inhibition of the aggregation process.

Development of HPLC fingerprints for Mallotus species extracts and evaluation of the peaks responsible for their antioxidant activity

Some Mallotus species are used in traditional medicine in Vietnam. To use certain species in Western medicines or as food supplements, they should be identified and quality control should be more strict, for instance, to avoid the erroneous switching of species. In species with interesting activities, the compounds responsible for them should be identified. For these identifications, HPLC fingerprint methodology can be used. In this paper, HPLC fingerprints of different lengths were developed for a number of Mallotus species. Secondly, a multivariate regression model was constructed to model the antioxidant activity of the Mallotus samples from the HPLC fingerprints with the aim to indicate peaks possibly responsible for this activity. For this purpose, after data pretreatment, the calibration technique partial least squares (PLS) was applied.

The polyphenol piceid destabilizes preformed amyloid fibrils and oligomers in vitro: hypothesis on possible molecular mechanisms.

Alzheimer’s disease (AD) is characterized by deposits of amyloid in various tissues. The neuronal cytotoxicity of Aβ peptides is attributed not only to various mechanisms but also to amyloid fibrils and soluble oligomeric intermediates. Consequently, finding molecules to prevent or reverse the oligomerization and fibrillization of Aβ could be of therapeutic value in the treatment of AD. We show that piceid, a polyphenol of the stilbene family, destabilized fibrils and oligomers to give back monomers that are not neurotoxic molecules. The mechanism of this destabilization could be a dynamic interaction between the polyphenol and the Aβ that could open the hydrophobic zipper and shift the reversible equilibrium “random coil⇔β-sheet” to the disordered structure.

Potential antioxidant compounds in Mallotus species fingerprints. Part I: Indication, using linear multivariate calibration techniques

Some Mallotus species are used in traditional medicine in Vietnam and China. Some also show interesting activities, such as antioxidant and cytotoxic ones. Combining fingerprint technology with data-handling techniques allows indicating the peaks potentially responsible for given activities. In this study it is aspired to indicate from chromatographic fingerprints the peaks potentially responsible for the antioxidant activity of several Mallotus species. Relevant information was extracted using linear multivariate calibration techniques, both before and after alignment of the fingerprints with correlation optimized warping (COW). From the studied techniques, stepwise multiple linear regression is least recommended as it made an inadequate variable selection. Principal component regression theoretically can take largely varying variables uncorrelated to the antioxidant activity into account. However, in practice in the actual case study this problem was limited. These problems in principle do not occur using partial least squares (PLS) models. Of the tested PLS methods, orthogonal projections to latent structures was preferred because of its simplicity, reproducibility, reduced model complexity and improved interpretability of the regression coefficients, yielding a clearer view on the individual contribution of the compounds. Furthermore, reducing analysis times from 60min to 35 and 22.5min resulted in the same main compounds, indicated responsible for the antioxidant activity. Models built after alignment by COW did not result in additional information.

Rosmarinic Acid and Its Methyl Ester as Antimicrobial Components of the Hydromethanolic Extract of Hyptis atrorubens Poit. (Lamiaceae).

Primary biological examination of four extracts of the leaves and stems of Hyptis atrorubens Poit. (Lamiaceae), a plant species used as an antimicrobial agent in Guadeloupe, allowed us to select the hydromethanolic extract of the stems for further studies. It was tested against 46 microorganisms in vitro. It was active against 29 microorganisms. The best antibacterial activity was found against bacteria, mostly Gram-positive ones. Bioautography enabled the isolation and identification of four antibacterial compounds from this plant: rosmarinic acid, methyl rosmarinate, isoquercetin, and hyperoside. The MIC and MBC values of these compounds and their combinations were determined against eight pathogenic bacteria. The best inhibitory and bactericidal activity was found for methyl rosmarinate (0.3 mg/mL). Nevertheless, the bactericidal power of rosmarinic acid was much faster in the time kill study. Synergistic effects were found when combining the active compounds. Finally, the inhibitory effects of the compounds were evaluated on the bacterial growth phases at two different temperatures. Our study demonstrated for the first time antimicrobial activity of Hyptis atrorubens with identification of the active compounds. It supports its traditional use in French West Indies. Although its active compounds need to be further evaluated in vivo, this work emphasizes plants as potent sources of new antimicrobial agents when resistance to antibiotics increases dramatically.

Potential antioxidant compounds in Mallotus species fingerprints. Part II: fingerprint alignment, data analysis and peak identification.

Some Mallotus species are commonly used as traditional medicine (TM) ingredients in Vietnam and China, but only a few are studied for their activities. In Part I, high-performance liquid chromatography (HPLC) fingerprints of 39 Mallotus samples (17 species) were developed and, because of the complexity of and the large differences between the samples, it was chosen to analyse the unaligned fingerprints. The peaks, potentially responsible for the antioxidant activity in given Mallotus species, were indicated by the regression coefficients from an orthogonal projections to latent structures (O-PLS) model. In the present study, an in depth discussion on the need for alignment of the Mallotus fingerprints for the indication of the potentially active compounds is made, as well as an experimental analysis and identification of the previously indicated peaks by HPLC-mass spectrometry (HPLC-MS). Additionally, to thoroughly study and discuss the alignment problem, the modelling and prediction of the antioxidant activity of green tea samples based on HPLC fingerprints were also considered.

Design, synthesis, and biological evaluation of new 5-HT4 receptor agonists: application as amyloid cascade modulators and potential therapeutic utility in Alzheimer's disease.

Serotonin 5-HT(4) receptor (5-HT(4)R) agonists are of particular interest for the treatment of Alzheimers disease because of their ability to ameliorate cognitive deficits and to modulate production of amyloid beta-protein (Abeta). However, despite the range of 5-HT(4)R agonists synthesized to date, potent and selective 5-HT(4)R agonists are still lacking. In the present study, two libraries of molecules based on the scaffold of ML10302, a highly specific and partial 5-HT(4)R agonist, were efficiently prepared by parallel supported synthesis and their binding affinities and agonist activities evaluated. Furthermore, we showed that, in vivo, the two best candidates exhibited neuroprotective activity by increasing the level of the soluble form of the amyloid precursor protein (sAPPalpha) in the cortex and hippocampus of mice. Interestingly, one of these compounds could also inhibit Abeta fibril formation in vitro.