Stefan Chassaing

Characterization of the antiproliferative activity of Xylopia aethiopica

BackgroundXylopia aethiopica, a plant found throughout West Africa, has both nutritional and medicinal uses. The present study aims to characterize the effects of extracts of this plant on cancer cells.ResultsWe report that X. aethiopica extract prepared with 70% ethanol has antiproliferative activity against a panel of cancer cell lines. The IC50 was estimated at 12 μg/ml against HCT116 colon cancer cells, 7.5 μg/ml and > 25 μg/ml against U937 and KG1a leukemia cells, respectively. Upon fractionation of the extract by HPLC, the active fraction induced DNA damage, cell cycle arrest in G1 phase and apoptotic cell death. By using NMR and mass spectrometry, we determined the structure of the active natural product in the HPLC fraction as ent-15-oxokaur-16-en-19-oic acid.ConclusionThe main cytotoxic and DNA-damaging compound in ethanolic extracts of Xylopia aethiopica is ent-15-oxokaur-16-en-19-oic acid.

Marine Pyrrolocarbazoles and Analogues: Synthesis and Kinase Inhibition

Granulatimide and isogranulatimide are alkaloids obtained from marine sources which have been shown to inhibit cell-cycle G2-checkpoint, targeting more particularly checkpoint 1 kinase (Chk1). At a structural level, they possess a characteristic pyrrolocarbazole framework also shared by the well-known rebeccamycin and staurosporine microbial metabolites which have been described to inhibit topoisomerase I and diverse kinases, respectively. This review reports precisely on the synthesis and kinase inhibitory activities of pyrrolocarbazole-based analogues of granulatimide.

Cu(I)-USY as a Ligand-Free and Recyclable Catalytic System for the Ullmann-Type Diaryl Ether Synthesis.

The catalytic potential of copper(I)-exchanged zeolites was evaluated in the Ullmann-type synthesis of diaryl ethers. Among four investigated zeolites (i.e., USY, MOR, β, and ZSM5), Cu(I)-USY was the best catalyst and proved efficient under ligand-free conditions in toluene at 120 °C. Cu(I)-USY was also easy to recover and was recyclable up to five times without significant loss of activity.

Synthesis and biological evaluation of analogs of the marine alkaloids granulatimide and isogranulatimide

A series of pyrrolic analogs and two series of regioisomeric pyrazolic analogs of the marine alkaloids granulatimide and isogranulatimide were prepared. The synthesis of the two first ones was based on the condensation reaction of diversely 5-substituted 3-bromoindoles with pyrrole or pyrazole followed by addition of the intermediates on maleimide or dibromomaleimide, respectively, the so-obtained acyclic adducts being finally photocyclized to the desired analogs. Compounds of the last series were obtained by reacting different 5-substituted-indole-3-glyoxylates with N-Boc-pyrazole-3-acetamide and subsequent photochemical cyclization of the adducts. All the compounds were evaluated for their in vitro growth inhibitory properties toward eight cancer cell lines. Several compounds were also assayed for their ability to abrogate the G2-cell cycle checkpoint or to inhibit a panel of Ser/Thr kinases. Lastly, computer-assisted phase-contrast microscopy (quantitative videomicroscopy) revealed that the three most potent compounds (4a, 9a, 9e), with IC(50) growth inhibitory concentrations ranging between 10 and 20 μM, displayed cytostatic, not cytotoxic, anticancer effects.

Retrochalcone derivatives are positive allosteric modulators at synaptic and extrasynaptic GABAA receptors in vitro

BACKGROUND AND PURPOSE Flavonoids, important plant pigments, have been shown to allosterically modulate brain GABAA receptors (GABAARs). We previously reported that trans‐6,4′‐dimethoxyretrochalcone (Rc‐OMe), a hydrolytic derivative of the corresponding flavylium salt, displayed nanomolar affinity for the benzodiazepine binding site of GABAARs. Here, we evaluate the functional modulations of Rc‐OMe, along with two other synthetic derivatives trans‐6‐bromo‐4′‐methoxyretrochalcone (Rc‐Br) and 4,3′‐dimethoxychalcone (Ch‐OMe) on GABAARs.

Metal-doped Zeolites as Green Catalysts for Organic Synthesis

Metal-doped zeolites prepared by vapor diffusion are excellent heterogeneous catalysts. Copper(I)- exchanged zeolites catalyze for example 1,3-dipolar reactions or Mannich condensation, whereas scandium(III)-exchanged zeolites catalyze the Mukaiyama-type aldolization. These catalysts are easily prepared, stable for months, conveniently recovered by filtration and recyclable. They can be used in safe solvents and even without solvent, and thus fully comply with the Green Chemistry principles. Their ease of handling and their large scope of applications enabled us to introduce the “zeo-click” concept for organic synthesis catalyzed by such green heterogeneous catalysts. Graphical Abstract Metal-doped Zeolites as Green Catalysts for Organic Synthesis

Triazolophthalazines: Easily Accessible Compounds with Potent Antitubercular Activity.

Tuberculosis (TB) remains one of the major causes of death worldwide, in particular because of the emergence of multidrug‐resistant TB. Herein we explored the potential of an alternative class of molecules as anti‐TB agents. Thus, a series of novel 3‐substituted triazolophthalazines was quickly and easily prepared from commercial hydralazine hydrochloride as starting material and were further evaluated for their antimycobacterial activities and cytotoxicities. Four of the synthesized compounds were found to effectively inhibit the Mycobacterium tuberculosis (M.tb) H37Rv strain with minimum inhibitory concentration (MIC) values <10 μg mL−1, whereas no compounds displayed cytotoxicity against HCT116 human cell lines (IC50>100 μm). More remarkably, the most potent compounds proved to be active to a similar extent against various multidrug‐resistant M.tb strains, thus uncovering a mode of action distinct from that of standard antitubercular agents. Overall, their ease of preparation, combined with their attractive antimycobacterial activities, make such triazolophthalazine‐based derivatives promising leads for further development.

Cinnamic Derivatives in Tuberculosis

Tuberculosis (TB) is a threat to worldwide public health, mainly caused by Mycobacterium tuberculosis (M.tb.) bacteria species. Despite the availability of effective treatment, tuberculosis is responsible for more than three million deaths annually worldwide. The high susceptibility of human immunodeficiency virus-infected persons to the disease (Nunn et al., 2005), the emergence of multi-drug-resistant (MDR-TB) strains (Rastogi et al., 1992, Kochi et al., 1993; Bloch et al., 1994) and extensively drug-resistant (XDR-TB) ones have brought this infectious disease into the focus of urgent scientific interest. For this reason, there is a growing need and urgency to discover new classes of chemical compounds acting with different mechanisms from those currently used. Cinnamic acid (1; Fig. 1) and derivatives have a century-old history as antituberculosis agents. For example, gradual improvement was observed when the TB-patients were treated with cinnamic acid (1) prepared from storax (Warbasse, 1894). Furthermore, in 1920s, ethylcinnamate (2) (Jacobson, 1919), sodium cinnamate (3) (Corper et al., 1920) and benzylcinnamate (4) (Gainsborough, 1928) were reported to be efficacious in the treatment of TB (Fig. 1). Nevertheless, we feel that this class of molecules remained underutilized until recent years. Particularly in the last two decades, there has been huge attention towards various natural and unnatural cinnamic derivatives and their antituberculosis efficacy. This chapter provides a comprehensive literature compilation concerning the synthesis so as the antituberculosis potency of various cinnamic acid, cinnamaldehyde and chalcone derivatives. We envisage that our effort in this chapter contributes a much needed and timely addition to the literature of medicinal research.

Red-emitting, EtTP-5-based organic nanoprobes for two-photon imaging in 3D multicellular biological models

Biocompatible and biostable EtTP-5-loaded organic core–shell nanoparticles have been successfully evaluated for their potential as red-emitting fluorescent nanoprobes for two-photon imaging. Readily formed by Flash NanoPrecipitation, EtTP-5-based nanoprobes proved to penetrate well into multicellular spheroids and were easily imaged through several cell layers within these complex, 3D tissue models.

Synthesis and multistate characterization of bis-flavylium dications – symmetric resorcinol- and phloroglucinol-type derivatives as stochastic systems

Two symmetric bis-flavylium dications were readily synthesized and further evaluated for their multistate profile. Both systems were shown to be fully stochastic and behave like a single compound suggesting that the two flavylium moieties do not communicate via the bridge linking them. Global pKa values of ca. 4 regarding the acid–base reaction between flavylium cation and quinoidal base were calculated using a stopped flow technique. It was further demonstrated that the equilibrium between AH+–AH+ and indistinguishable flavylium-quinoidal base isomers AH+–A (A–AH+) can be calculated by subtracting 0.3 pH units from the observed acid–base constant. On the other hand, the equilibrium between both flavylium-quinoidal base isomers and the bis-quinoidal base A–A is obtained by adding 0.3 pH units. Moreover, both systems do not have a cis–trans isomerization barrier and the rate constants of interconversion between flavylium cation and quinoidal base as a function of pH are fitted with a mono-exponential and follow a bell-shaped curve. The systems proved also to be photochromic and from the fitting of the bell-shaped curve, flash photolysis measurements and quantum yields, it is possible to calculate all rate and equilibrium constants and construct a global energy-level diagram. It was also proved that the rate constant to form both isomers AH+–Ct from the bis-flavylium upon a pH jump from 1 to less acidic solutions is twice that of the observed value and the formation of the bis-trans-chalcone from both isomers AH+–Ct is equal to the observed rate constant. An energy-level diagram of all the multistate species was constructed from the equilibrium constants.