Total Synthesis of the Marine Macrolide Amphidinolide F

International audienceA new and efficient convergent approach toward the synthesis of amphidinolide F is described through the assembly of three fragments. The two trans-tetrahydrofurans were built by a diastereoselective C-glycosylation with titanium enolate of bulky N-acetyloxazolidinethiones. The side chain was inserted by a Liebeskind–Srogl cross-coupling reaction. A sulfone condensation/desulfonylation sequence, a Stille cross-coupling, and a macrolactonization were applied to connect the fragments

Synthesis of 3,5-Disubstituted 1,2-Dioxolanes through the Use of Acetoxy Peroxyacetals

International audienceThe synthesis of acetoxy-endoperoxyacetal derivatives allowed the formation of functionalized 3,5-disubstituted-1,2-dioxolanes through the formation of reactive peroxycarbenium species under Lewis acid mediation. The introduction of a neutral nucleophile such as allylsilanes, silanes, or silyl enol ethers was accomplished with moderate to good yields. The two studied Lewis acids, TiCl4 and SnCl4, gave contrasted results. The higher diastereoselectivity towards the trans diastereomer in experiments with TiCl4 as Lewis acid was explained by a faster degradation of the cis isomer product, conducting generally to lower yields. A rationalization of this result was supported by calculation

Chemicals Possessing a Neurotrophin-Like Activity on Dopaminergic Neurons in Primary Culture

BACKGROUND:Neurotrophic factors have been shown to possess strong neuroprotective and neurorestaurative properties in Parkinson's disease patients. However the issues to control their delivery into the interest areas of the brain and their surgical administration linked to their unability to cross the blood brain barrier are many drawbacks responsible of undesirable side effects limiting their clinical use. A strategy implying the use of neurotrophic small molecules could provide an interesting alternative avoiding neurotrophin administration and side effects. In an attempt to develop drugs mimicking neurotrophic factors, we have designed and synthesized low molecular weight molecules that exhibit neuroprotective and neuritogenic potential for dopaminergic neurons. PRINCIPAL FINDINGS:A cell-based screening of an in-house quinoline-derived compound collection led to the characterization of compounds exhibiting both activities in the nanomolar range on mesencephalic dopaminergic neurons in spontaneous or 1-methyl-4-phenylpyridinium (MPP(+))-induced neurodegeneration. This study provides evidence that rescued neurons possess a functional dopamine transporter and underlines the involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in these processes. CONCLUSION:Cell-based screening led to the discovery of a potent neurotrophic compound possessing expected physico-chemical properties for blood brain barrier penetration as a serious candidate for therapeutic use in Parkinson disease

Biodereplication of antiplasmodial extracts: application of the amazonian medicinal plant piper coruscans kunth

Improved methodological tools to hasten antimalarial drug discovery remain of interest, especially when considering natural products as a source of drug candidates. We propose a biodereplication method combining the classical dereplication approach with the early detection of potential antiplasmodial compounds in crude extracts. Heme binding is used as a surrogate of the antiplasmodial activity and is monitored by mass spectrometry in a biomimetic assay. Molecular networking and automated annotation of targeted mass through data mining were followed by mass-guided compound isolation by taking advantage of the versatility and finely tunable selectivity offered by centrifugal partition chromatography. This biodereplication workflow was applied to an ethanolic extract of the Amazonian medicinal plant Piper coruscans Kunth (Piperaceae) showing an IC50 of 1.36 ug/mL on the 3D7 Plasmodium falciparum strain. It resulted in the isolation of twelve compounds designated as potential antiplasmodial compounds by the biodereplication workflow. Two chalcones, aurentiacin (1) and cardamonin (3), with IC50 values of 2.25 and 5.5 uM, respectively, can be considered to bear the antiplasmodial activity of the extract, with the latter not relying on a heme-binding mechanism. This biodereplication method constitutes a rapid, efficient, and robust technique to identify potential antimalarial compounds in complex extracts such as plant extracts

Lauflumide (NLS-4) Is a New Potent Wake-Promoting Compound

Psychostimulants are used for the treatment of excessive daytime sleepiness in a wide range of sleep disorders as well as in attention deficit hyperactivity disorder or cognitive impairment in neuropsychiatric disorders. Here, we tested in mice the wake-promoting properties of NLS-4 and its effects on the following sleep as compared with those of modafinil and vehicle. C57BL/6J mice were intraperitoneally injected with vehicle, NLS-4 (64 mg/kg), or modafinil (150 mg/kg) at light onset. EEG and EMG were recorded continuously for 24 h after injections and vigilance states as well as EEG power densities were analyzed. NLS-4 at 64 mg/kg induced significantly longer wakefulness duration than modafinil at 150 mg/kg. Although no significant sleep rebound was observed after sleep onset for both treatments as compared with their vehicles, modafinil-treated mice showed significantly more NREM sleep when compared to NLS-4. Spectral analysis of the NREM EEG after NLS-4 treatment indicated an increased power density in delta activity (0.75–3.5 Hz) and a decreased power in theta frequency range (6.25–7.25 Hz), while there was no differences after modafinil treatment. Also, time course analysis of the delta activity showed a significant increase only during the first 2 time intervals of sleep after NLS-4 treatment, while delta power was increased during the first 9 time intervals after modafinil. Our results indicate that NLS-4 is a highly potent wake-promoting drug with no sign of hypersomnia rebound. As opposed to modafinil, recovery sleep after NLS-4 treatment is characterized by less NREM amount and delta activity, suggesting a lower need for recovery despite longer drug-induced wakefulness

Архетип влюблённого в поэзии крымских ханов

<p>This article is focused on the seasonal variation in the contents of 5-methoxycanthin-6-one from the leaves of <i>Zanthoxylum chiloperone</i> (Rutaceae). Based on the pharmacological interest presented by 5-methoxycanthin-6-one, its seasonal variation in <i>Z. chiloperone</i> leaves was analysed in order to determine the best time for harvesting, optimising the 5-methoxycanthin-6-one content. The seasonal dynamics of canthinone alkaloids can be the key to improve the isolation from natural sustainable sources, such as leaves. Complementarily, this study describes the phytochemistry of leaf from this Ruraceae species.</p

Grignard Reagents and Iron

International audienc

Amphidinolides F and C2: An Odyssey in Total Synthesis

International audienceAmphidinolides F, C, C2, and C3 are marine natural products isolated from dinoflagellates amphidinium species. They share the same macrolactone core, the difference between them residing at the side chain level. A predominant feature of these amphidinolides is the presence of two trans-THF rings inside the macrolactone core, titanium mediated C-glycosylation being applicable to build these motives. Thus, the original strategy for their total synthesis was based on the assembly of three main fragments corresponding to C 1-C 9 , C 10-C 19 , and C 20-C 29 or C 20-C 34 disconnections. Whereas synthesis of all fragments was successful, the C-glycosylation reaction between C 19 and C 20 turned out to be an issue. Therefore, a second route was designed. The new disconnection between C 17 and C 18 was based on a sulfone addition and a desulfonylation sequence. Our convergent strategy allowed the total synthesis of amphidinolide F and enabled a new unifying route towards the synthesis of amphidinolides C, C2, and C3 using a late-stage divergent approach. Although unsatisfying yields at some critical steps, our work culminated into the first total synthesis of amphidinolide C2