Expanding the 'aplysinospin cascade' through DNA-templated [2+2] photocycloaddition.

Inspired by the unique ability of nucleic acids to template chemical transformations that are otherwise impossible in solution, we embarked on the generalisation of our DNA-templated [2+2] photo-induced homo- and heterodimerization of aplysinopsins. Our process ensures a straightforward access to cyclobutane containing natural products and analogues thereof. Most importantly, this conceptual biomimetic achievement presents interesting arguments to build a biosynthetic scenario.

Three novel non-nitrogenous cassane diterpenoids from Erythrophleum suaveolens (Guill. et Perr.) Brenan (Fabaceae).

During our research to contribute to the elucidation of the chemical composition of the root bark of E. suaveolens, six non-nitrogenous cassane diterpenoids (1-6) were isolated and identified. Of these secondary metabolites, three have never been previously described: Cassan-13,15-dien-3-oxo-17-oic acid (2), Cassan-15-en-[7,17]-γ-lactone (3) and 6α-hydroxy-cassamic acid (5). The other are known but, never isolated from the root barks of E. suaveolens (Fabaceae): Cassan-13,15-dien-17-oic acid (1), 6α-hydroxy-cassamic acid methyl esther (4) and cassamic acid (6). Their structures were established according to the spectroscopic data (NMR 1D and 2D, HR-ESI-MS and IR), in comparison with those of literature. The originality of this study lies in the fact that three new natural molecules were isolated and identified. In addition, all the isolated compounds (1-6) were reported for the first time from the root barks of E. suaveolens.

Spectroscopic data of new cassane diterpenoids from the root bark of Erythrophleum suaveolens.

The data are related to the research article entitled ''New cassane diterpenoids from the root bark of Erythrophleum suaveolens'' (Jacques et al., 2019). The article provides method of purification and data to determine structure of two novel cassane diterpenoid amines: 3ß-hydroxy-3-methylbutanoyloxy-6α-hydroxy-nor-cassamine (1) and 3ß-hydroxy-3-methylbutanoyloxy-erythrosuamine (2). This data in brief provides IR, NMR and Q-TOF-MS spectra, along with fragmentation pathways that allowed to the identification of both new compounds.

Revisiting Previously Investigated Plants: A Molecular Networking-Based Study of Geissospermum laeve.

Three new monoterpene indole alkaloids (1-3) have been isolated from the bark of Geissospermum laeve, together with the known alkaloids (-)-leuconolam (4), geissolosimine (5), and geissospermine (6). The structures of 1-3 were elucidated by analysis of their HRMS and NMR spectroscopic data. The absolute configuration of geissolaevine (1) was deduced from the comparison of experimental and theoretically calculated ECD spectra. The isolation workflow was guided by a molecular networking-based dereplication strategy using an in-house database of monoterpene indole alkaloids. In addition, five known compounds previously undescribed in the Geissospermum genus were dereplicated from the G. laeve alkaloid extract network and were assigned with various levels of identification confidence. The antiparasitic activities against Plasmodium falciparum and Leishmania donovani as well as the cytotoxic activity against the MRC-5 cell line were determined for compounds 1-5.

1 H qNMR Quantification of Annonaceous Acetogenins in Crude Extracts of Annona muricata L. Fruit Pulp.

INTRODUCTION: Annonaceous acetogenins (AAGs) constitute a group of environmental neurotoxins, possibly implicated in sporadic atypical Parkinsonism/dementia complexes. The recent evidencing of complex mixtures of AAGs in edible fruits and derived food products requires efficient and practical analytical tools for an estimation of human exposure. OBJECTIVE: To develop a simple method for the direct quantitation of the majority of AAGs (sub-types 1a and 1b) within crude extracts, using commonly available 1 H-NMR spectrometers, for food control. METHODOLOGY: Method development was carried out on 400 MHz and 300 MHz spectrometers, for routine application on fruits crude extracts of Annona muricata L. The method was validated with annonacin and squamocin as reference compounds. Two internal standards (ISs), fumaric acid and dimethyl fumarate, were successfully used, in deuterated methanol (CD3 OD) and deuterated chloroform (CDCl3 ), respectively. RESULTS: Quantitation was carried out using signals corresponding to the deshielded ethylenic protons characterising most AAGs, at δ 7.18 or δ 6.98 ppm in CDCl3 . The limit of quantification (LOQ) was 2.5 mM, with acceptable accuracy, and the limit of detection (LOD) was 0.5 mM. The AAGs contents measured in seven distinct fruit samples of Annona muricata ranged from 14 µmol to 226 µmol of AAGs per 100 g fresh pulp (i.e. 0.14 mmol to 1.3 mmol of AAGs per fruit). CONCLUSION: A simple, accurate and specific method for quantification of AAGs content was developed and validated for routine application to fruit pulp crude extracts. Copyright © 2017 John Wiley & Sons, Ltd.

Fibrate treatment induced quantitative and qualitative HDL changes associated with an increase of SR-BI cholesterol efflux capacities in rabbits.

Fibrates are widely used as lipid lowering drugs acting as peroxisome proliferator-activated receptors α (PPARα) agonists and modulating the expression of several genes involved in lipid and lipoprotein metabolism. Much less is known on the effect of fibrates in HDL structure and composition. Therefore, we examined whether fenofibrate induces quantitative and/or qualitative modifications in HDL metabolism in the rabbit, an animal that, contrary to rodents and similar to humans, is less sensitive to peroxisome proliferators. We first demonstrated that 3-week treatment with fenofibrate (250 mg/kg/day) induced an important increase in serum apolipoprotein A-I, HDL-cholesterol and HDL-phospholipids concentrations and a relative enrichment in HDL cholesteryl ester content. Moreover, the fatty acid profiles from fenofibrate-treated rabbits displayed a dramatic increase in the serum or HDL C18:3 ω6 to C18:2 ω6 ratio suggesting higher Δ6 desaturase activity. In addition, HDL from fenofibrate-treated animals exhibited higher relative proportions of sphingomyelin, phosphatidylinositol and phosphatidylethanolamine. We then reported that fenofibrate induced major changes in the physical characteristics of HDL, mainly a higher size and a faster mobility on agarose gel electrophoresis. Finally, serum or HDL from treated rabbits exhibited higher capacity to promote cholesterol efflux from Scavenger receptor class B type I (SR-BI)-rich Fu5AH cells compared to controls. Our findings demonstrate that fenofibrate has beneficial effects in rabbits by increasing the mass of the circulating HDL pool and by modifying their composition transforming them as better acceptors of cellular cholesterol through SR-BI pathway. These effects of fenofibrate might contribute to its benefits on the prevention and treatment of atherosclerosis.

Identification of a tetrahydroquinoline analog as a pharmacological inhibitor of the cAMP-binding protein Epac.

The cAMP-binding protein Epac is a therapeutic target for the treatment of various diseases such as cardiac hypertrophy and tumor invasion. This points out the importance to develop Epac inhibitors to better understand the involvement of these cAMP sensors in physiology and pathophysiology. Here, we have developed a functional fluorescence-based high-throughput assay with a Z' value around 0.7 for screening Epac-specific antagonists. We identified an Epac1 inhibitor compound named CE3F4 that blocked Epac1 guanine nucleotide exchange activity toward its effector Rap1 both in cell-free systems and in intact cells. CE3F4 is a tetrahydroquinoline analog that fails to influence protein kinase A holoenzyme activity. CE3F4 inhibited neither the interaction of Rap1 with Epac1 nor directly the GDP exchange on Rap1. The kinetics of inhibition by CE3F4 indicated that this compound did not compete for binding of agonists to Epac1 and suggested an uncompetitive inhibition mechanism with respect to Epac1 agonists. A structure-activity study showed that the formyl group on position 1 and the bromine atom on position 5 of the tetrahydroquinoline skeleton were important for CE3F4 to exert its inhibitory activity. Finally, CE3F4 inhibited Rap1 activation in living cultured cells, following Epac activation by either 8-(4-chlorophenylthio)-2'-O-methyl-cAMP, an Epac-selective agonist, or isoprenaline, a non-selective ß-adrenergic receptor agonist. Our study shows that CE3F4 and related compounds may serve as a basis for the development of new therapeutic drugs.

A cardiac-specific robotized cellular assay identified families of human ligands as inducers of PGC-1α expression and mitochondrial biogenesis.

BACKGROUND: Mitochondrial function is dramatically altered in heart failure (HF). This is associated with a decrease in the expression of the transcriptional coactivator PGC-1α, which plays a key role in the coordination of energy metabolism. Identification of compounds able to activate PGC-1α transcription could be of future therapeutic significance. METHODOLOGY/PRINCIPAL FINDINGS: We thus developed a robotized cellular assay to screen molecules in order to identify new activators of PGC-1α in a cardiac-like cell line. This screening assay was based on both the assessment of activity and gene expression of a secreted luciferase under the control of the human PGC-1α promoter, stably expressed in H9c2 cells. We screened part of a library of human endogenous ligands and steroid hormones, B vitamins and fatty acids were identified as activators of PGC-1α expression. The most responsive compounds of these families were then tested for PGC-1α gene expression in adult rat cardiomyocytes. These data highly confirmed the primary screening, and the increase in PGC-1α mRNA correlated with an increase in several downstream markers of mitochondrial biogenesis. Moreover, respiration rates of H9c2 cells treated with these compounds were increased evidencing their effectiveness on mitochondrial biogenesis. CONCLUSIONS/SIGNIFICANCE: Using our cellular reporter assay we could identify three original families, able to activate mitochondrial biogenesis both in cell line and adult cardiomyocytes. This first screening can be extended to chemical libraries in order to increase our knowledge on PGC-1α regulation in the heart and to identify potential therapeutic compounds able to improve mitochondrial function in HF.

Detection, characterization, and screening of heme-binding molecules by mass spectrometry for malaria drug discovery.

Drug screening for antimalarials uses heme biocrystallization inhibition methods as an alternative to parasite cultures, but they involve complex processes and cannot detect artemisinin-like molecules. The described method detects heme-binding compounds by mass spectrometry, using dissociation of the drug-heme adducts to evaluate putative antiplasmodial activity. Applied to a chemical library, it showed a good hit-to-lead ratio and is an efficient early stage screening for complex mixtures like natural extracts.

Acaricidal activity of tonka bean extracts. Synthesis and structure-activity relationships of bioactive derivatives.

The acaricidal effects of tonka bean, Dipterix odorata, extracts were investigated on Dermatophagoides pteronyssinus, the European house dust mite, and compared with benzyl benzoate as a standard acaricidal compound. A cyclohexane extract was the most effective, with an EC(50) = 0.075 g/m(2) after a 24 h period, as compared with benzyl benzoate (0.025 g/m(2)). Bioassay-guided fractionation of this extract led to the isolation of coumarin (1). Pharmacomodulation of this compound led us to test 20 analogues (2-21), which were either synthesized or purchased.

NMR determination of absolute configuration of butenolides of annonaceous type.

We report herein the first determination of the absolute configuration of the annonaceous butenolides by a NMR method. This technique uses a chiral solvating agent (CSA), the so-called Pirkle's reagent, at low temperature and low concentration, allowing one to apply this method to other natural products as well. Indeed, the presence of basic sites (e.g. tetrahydrofuran, hydroxyl) did not interfere with the major solvation of the reagent with the lactone moiety. A new model is proposed which allowed us to confirm the (S) absolute configuration of the butenolide of annonaceous acetogenins. Furthermore this method can be successfully applied to the measure of the diastereomeric (or enantiomeric) excess of the same butenolide containing compounds.