QR inducing activity of natural products as a strategy for cancer chemopreventive activity

Lors de ce travail, diverses stratégies appartenant au domaine de la phytochimie et de la pharmacognosie ont été associées afin d'isoler, de caractériser et d'évaluer l'activité chimiopréventive du cancer de composés naturels isolés à partir d'extraits de Morinda citrifolia L. et de Morinda lucida Bent. Ainsi, un isolement bio-guidé par l'induction de la quinone réductase (QR) dans des hépatocytes murin (Hepa 1c1c7) a conduit à l'isolement de 18 substances naturelles dont 3 composés nouvellement décrits. Au total, 32 anthraquinones présentant diverses activités inductrices de la QR ont été utilisées afin d'élaborer un modèle de relations structures-activité. La rubiadine, l'une des anthraquinones les plus actives identifiées, a été sélectionnée et a permis de mettre en évidence certaines voies de signalisation cellulaire modulant l'activité de la QR. Finalement, le test cellulaire permettant la mesure de l'induction de la QR a été amélioré afin d'en augmenter la sensibilité et la robustesse

Natural compounds analysis using liquid and supercritical fluid chromatography hyphenated to mass spectrometry: Evaluation of a new design of atmospheric pressure ionization source

The MS hyphenation performance of UniSpray®, a new design of atmospheric pressure ionization source was evaluated in both SFC and RPLC modes. Sensitivity, stability, versatility and matrix effects offered by the UniSpray were assessed in positive and negative ionization modes and systematically compared to an electrospray source (ESI) using 120 natural compounds covering an extended chemical space. In a first instance, a multivariate approach was used to screen and optimize the UniSpray source settings to maximize detection sensitivity. The position of the source capillary against the fixed charged rod was highlighted as the major parameter affecting the detection sensitivity. The sensitivity improvement in Unispray vs. ESI strongly depends on the compounds chemical class and the chromatographic mode. For a few compounds (i.e. anabasine, theanine, caproic acid, fumaric acid and protopanaxatriol), up to a 10-fold increase in sensitivity was noticed with UniSpray. The signal stability over multiple injections was also found to be equivalent between both sources with RSD values on peak intensity lower than 14% on>100 injections, in both chromatographic modes. On complex plant extract, the matrix effects occurring from the secondary metabolites were also found to be comparable between ESI and UniSpray, at least in the positive ionization mode. However, a systematic decrease of MS signal intensity was observed in SFC mode when compounds were ionized using UniSpray in the negative ion mode

Cancer chemopreventive activity of compounds isolated from Waltheria indica

Waltheria indica L. is traditionally used in several countries against inflammatory related diseases and cancer, mainly as a decoction of the aerial parts

Anti-inflammatory and quinone reductase-inducing compounds from Beilschmiedia mannii

Previous studies on the therapeutic potential of plant species found in the diet of chimpanzees living in Taï National Park have shown that they could be potential candidates for the search of new molecules useful for humans. Based on the screening of some of these plants, the fruits of; Beilschmiedia mannii; , whose dichloromethane extract showed cancer chemopreventive properties, were selected. Bioactivity-guided fractionation of the extract resulted in the isolation and identification of two; γ; -pyrones, including desmethoxydihydromethysticin (1: ), found in a natural source for the first time, and a new congener, beilschmiediapyrone (2: ), as well as five known alkamides (3: - 7: ). Their structures were established by using nuclear magnetic resonance spectroscopy and mass spectrometry methods. The isolated compounds were evaluated for their cancer chemopreventive potential by using quinone reductase induction and nuclear factor-kappa B inhibition tests in Hepa 1c1c7 and HEK-293/NF-; κ; B-Luc cells, respectively. Among them, compounds 1: and 2: were the most active. The concentrations to double the quinone reductase activity were 7.5 µM for compound 1: and 6.1 µM for compound 2: . Compounds 1: and 2: inhibited nuclear factor-kappa B with IC; 50; values of 2.1 and 3.4 µM, respectively. These results are promising with regard to cancer chemoprevention, especially because this plant is also used for cooking by the local population around the Taï forest

Antioxidants, quinone reductase inducers and acetylcholinesterase inhibitors from Spondias tuberosa fruits

The methanolic extract of umbu (Spondias tuberosa) presented high antioxidant activities in the DPPH, ABTS and ORAC assays, as well as acetylcholinesterase (AChE) inhibition activity. The dichloromethane extract exhibited cancer chemopreventive activity, with a quinone reductase induction in Hepa1c1c7 cells. The localization of the active compounds was performed by HPLC activity-based profiling, and preliminary structural information was obtained by HPLC-PAD-ESI-MS and UHPLC-TOF-HRMS. The main constituents from the methanolic extract were efficiently isolated in a single step by preparative MPLC-UV. Two new natural products were identified, together with five known compounds. The structures of the compounds were elucidated by 2D NMR and ESI-HRMS. The dichloromethane extract was fractionated by SPE and by semi-preparative HPLC-UV-ELSD. Using this approach, one anacardic acid derivative was isolated. However, this compound was not responsible for QR induction. This study highlights the potential of umbu as an active ingredient for functional food formulations

Natural (dihydro)phenanthrene plant compounds are direct activators of AMPK through its allosteric drug and metabolite–binding site

AMP-activated protein kinase (AMPK) is a central energy sensor that coordinates the response to energy challenges to maintain cellular ATP levels. AMPK is a potential therapeutic target for treating metabolic disorders, and several direct synthetic activators of AMPK have been developed that show promise in preclinical models of type 2 diabetes. These compounds have been shown to regulate AMPK through binding to a novel allosteric drug and metabolite (ADaM)–binding site on AMPK, and it is possible that other molecules might similarly bind this site. Here, we performed a high-throughput screen with natural plant compounds to identify such direct allosteric activators of AMPK. We identified a natural plant dihydrophenathrene, Lusianthridin, which allosterically activates and protects AMPK from dephosphorylation by binding to the ADaM site. Similar to other ADaM site activators, Lusianthridin showed preferential activation of AMPKβ1-containing complexes in intact cells and was unable to activate an AMPKβ1 S108A mutant. Lusianthridin dose-dependently increased phosphorylation of acetyl-CoA carboxylase in mouse primary hepatocytes, which led to a corresponding decrease in de novo lipogenesis. This ability of Lusianthridin to inhibit lipogenesis was impaired in hepatocytes from β1 S108A knock-in mice and mice bearing a mutation at the AMPK phosphorylation site of acetyl-CoA carboxylase 1/2. Finally, we show that activation of AMPK by natural compounds extends to several analogs of Lusianthridin and the related chemical series, phenanthrenes. The emergence of natural plant compounds that regulate AMPK through the ADaM site raises the distinct possibility that other natural compounds share a common mechanism of regulation