One-Pot Synthesis of 2-Styrylindoles from Ortho -Substituted Chloroenynes

International audienceA facile one pot synthesis of 2-styrylindoles, through Suzuki-arylation of ortho-substituted chloroenynes followed by N-cyclization and N-demethylation has been developed. A variety of 2-styrylindoles were obtained in good to excellent yields and were evaluated for their anticancer properties

Regioselective hydrostannation of diarylalkynes directed by a labile ortho bromine atom: An easy access to stereodefined triarylolefins, hybrids of combretastatin A-4 and isocombretastatin A-4

International audienceA series of triarylolefins bearing the combretastatin A-4 and the isocombretastatin A-4 cores were synthesized and evaluated. The cooperative ortho-effect of a labile bromine atom in the regioselective hydrostannation of unsymmetrical diarylalkynes leading to stereo-defined triarylolefins is presented

Design, synthesis and anticancer properties of 5-arylbenzoxepins as conformationally restricted iso combretastatin A-4 analogs

International audienceA series of novel benzoxepins 6 was designed and prepared as rigid-isoCA-4 analogues according to a convergent strategy using the coupling of N-tosylhydrazones with aryl iodides under palladium catalysis. The most potent compound 6b, having the greatest resemblance to CA-4 and isoCA-4 displayed antiproliferative activity at nanomolar concentrations against various cancer cell lines and inhibited tubulin assembly at a micromolar range. In addition, benzoxepin 6b led to the arrest of HCT116, K562, H1299 and MDA-MB231 cancer cell lines in the G2/M phase of the cell cycle, and strongly induced apoptosis at low concentrations. Docking studies demonstrated that benzoxepin 6b adopt an orientation similar to that of isoCA-4 at the colchicine binding site on -tubulin

N,N-bis-heteroaryl methylamines: Potent anti-mitotic and highly cytotoxic agents

International audienceThe synthesis and evaluation of a series of N,N-bis-heterocyclic-methylamines 1 as isoazaerianin analogues are descriebed. It was demonstrated that the replacement of the 3,4,5-trimethoxyphenyl A-ring present in CA-4, isoCA-4 and isoazaerianin by a quinoline or a quinazoline ring is possible and often beneficiary for a high level of cytotoxicity. We have also showed that a carbazole or an indole nucleus are very effective as Brings in this series, leading to anti-cancer drugs 1 having a sub-nanomolar level of cytotoxicity (1a: IC50 = 70 pM against HCT116 cells). 1a also display a high level of cytotoxicity against four other human cancer cells and inhibited tubulin assembly at a micromolar level. Moreover, at a concentration of 5 nM, 1a arrested the cellular cycle in G2/M phase of the cellular cycle and induced apoptosis of HCT116 cells. It was also showed that after few hours 1a at a concentration of 10 nM totally disrupted endothelial network formation on Matrigel

Conformationnally restricted naphthalene derivatives type isocombretastatin A-4 and isoerianin analogues: Synthesis, cytotoxicity and antitubulin activity

International audienceA novel series of dihydronaphtalene, tetrahydronaphtalene and naphtalene derivatives as restricted-analogues of isoCA-4 were designed, synthesized and evaluated for their anticancer properties. High cell growth inhibition against four tumor cell lines was observed at a nanomolar level with dihydronaphtalenes 1d,e and 1h, tetrahydronaphtalene 2c and naphtalene 3c. Structure activity relationships are also considered. These compounds exhibited a significant inhibitory activity toward tubulin polymerization (IC50 = 2-3 M), comparable to that of isoCA-4. The effect of the lead compounds 1e and 2c on the cancer cells tested was associated with cell cycle arrest in the G2/M phase. Docking studies reveal that these compounds showed a binding mode similar to those observed with their non-constraint isoCA-4 and isoerianin congeners

Usefulness of PKH fluorescent labelling to study leukemic cell proliferation with various cytostatic drugs or acetyl tetrapeptide – AcSDKP

BACKGROUND: PKH67 labelling was compared for classical proliferation assessment (using S phase evaluation) to analyse the cell proliferation of 29 AML patients treated or not with various drugs. Among these drugs, the effect of tetrapeptide AcSDKP or AcSDKP-NH2 on AML cells, stimulated or not by cytokines, was also evaluated in order to determine (i) if AcSDKP was able to inhibit blast cell proliferation as it inhibits haematopoietic progenitors (ii) if AcSDKP-NH2 was more stable than AcSDKP with FBS. METHODS: For PKH labeling, cells were suspended in Diluent C, and rapidly admixed with PKH67 solution at 20 μM PKH67. Staining was stopped by addition of FBS. RESULTS: A good correlation between PKH67 labelling and bromodeoxyuridine incorporation was obtained first with 6/9 patients for control cells, then for 11/17 AML patients treated with classical antileukemic drugs (among whom 4 were also treated with AcSDKP). The effect of AcSDKP was also studied on 7 patients. The discrepancy between both methods was essentially due to an accumulation of cells into different cycle phases measured by BrdUrd incorporation secondary to drug action and PKH67 labelling which measured the dynamic proliferation. This last method allows identifying resistant cells which still proliferate. AcSDKP or AcSDKP-NH2 induced a decrease of leukemic cell proliferation in 5/7 patients when cytokines were added (in order to stimulate proliferation) one day after tetrapeptide AcSDKP or AcSDKP-NH2. No effect on proliferation was noted when cytokines were added to AcSDKP-NH2. CONCLUSION: PKH67 labelling method is a powerful tool for cell proliferation assessment in patients with AML, even in cells treated by various drugs

Contribution de l’anthropologie sensorielle à l’étude du COVID-19

En réponse à la pandémie COVID-19, de nombreux gouvernements ont pris des mesures sans précédent pour éviter un engorgement des unités de réanimation. En raison du lourd impact sociétal et économique de ces initiatives, des indicateurs épidémiologiques précis de la propagation de la maladie sont essentiels aux autorités de santé publique. Dans le même temps, la perturbation des perceptions des odeurs et du goût ont été identifiés comme l’un des symptômes les plus spécifiques de la maladie COV..

Recent smell loss is the best predictor of COVID-19 among individuals with recent respiratory symptoms

In a preregistered, cross-sectional study we investigated whether olfactory loss is a reliable predictor of COVID-19 using a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified univariate and multivariate predictors of COVID-19 status and post-COVID-19 olfactory recovery. Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both univariate and multivariate models (ROC AUC=0.72). Additional variables provide negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms (e.g., fever). Olfactory recovery within 40 days of respiratory symptom onset was reported for ~50% of participants and was best predicted by time since respiratory symptom onset. We find that quantified smell loss is the best predictor of COVID-19 amongst those with symptoms of respiratory illness. To aid clinicians and contact tracers in identifying individuals with a high likelihood of having COVID-19, we propose a novel 0-10 scale to screen for recent olfactory loss, the ODoR-19. We find that numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4<10). Once independently validated, this tool could be deployed when viral lab tests are impractical or unavailable

Economie insulaire et développement durable

Le président de la commission Environnement de l\u27ANEL (Association Nationale des Elus du Littoral) présente son regard de politique et de juriste sur le concept d\u27insularité, ses spécificités, ses forces et faiblesses. Puis il examine comment peut-on inscrire les économies insulaires dans une perspective durable, avec une approche de la diversité des pratiques en la matière