In vitro biological effects of two anti-diabetic medicinal plants used in Benin as folk medicine.

International audienceBACKGROUND: Extracts from Polygonum senegalensis (Polygonaceae) and Pseudocedrela kotschyi (Meliaceae) are two important traditionally used medicinal plants in rural Benin to treat many diseases and notably type 2 diabetes. The aim of the study was to investigate the alpha-glucosidase inhibition, antioxidant and antibacterial activities of those plants extract: Polygonum senegalensis leaves, and Pseudocedrela kotschyi root. METHODS: Hydro-alcoholic (50%) extracts were analyzed for their phytochemical content and tested for their inhibition potency on alpha-glucosidase from Saccharomyces cerevisiae. Antioxidant activities were assessed using the DPPH, ORAC, FRAP and DCFH-DA (cell based) assay. Finally, the antibacterial activity was evaluated using MIC determination on four Gram-positive cocci (Bacillus subtilis, Clostridium difficile, Enterococcus faecalis, Staphylococcus aureus), three Gram-negative bacilli (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae), and the yeast Candida albicans. RESULTS: Each extract presented significant alpha-glucosidase inhibition and antioxidant activities. Polygonum senegalensis leaf extracts were the most active in each in vitro assay with an IC50 = 1.5 mug/ml for alpha-glucosidase inhibition and an IC50 = 6.8 mug/ml for DPPH scavenging, - 4.5 mumol Fe II/g of dry matter - 9366 mumol Trolox / g DW - for FRAP and ORAC values, respectively. IC50 = 2.3 mug GA / ml for DCFH-DA assay. Concerning its antibacterial activity, a growth inhibitory effect was observed only against three Gram negative bacilli: B. subtilis, E. faecalis, S. aureus and the yeast C. albicans at high concentration. CONCLUSION: The results showed that the semi alcoholic extract of the two studied plants possess alpha-glucosidase inhibitory activity, antioxidant potency, and low antibacterial effect

N-Phenyl-N'-(2-chloroethyl)urea analogues of combretastatin A-4: Is the N-phenyl-N'-(2-chloroethyl)urea pharmacophore mimicking the trimethoxy phenyl moiety ?

A series of novel N-phenyl-N'-(2-chloroethyl)urea derivatives potentially mimicking the structure of combretastatin A-4 were synthesized and tested for their cell growth inhibition and their binding to the colchicine-binding site of beta-tubulin. Compounds 2a, 3a, and 3b were found to inhibit cell growth at the micromolar level on four human tumor cell lines. Flow cytometric analysis indicates that the new compounds act as antimitotics and arrest the cell cycle in G(2)/M phase. Covalent binding of 2a, 3a, and 3b to the colchicine-binding site of beta-tubulin was confirmed also using SDS-PAGE and competition assays

Concept, synthèse et mécanisme d'action de motifs hétéroaromatiques à visée radiochimiothérapeutique interne du mélanome

Le risque de développer un mélanome augmente fortement d'année en année. A partir de cette constatation, notre travail a consisté à la synthèse de molécules pouvant être utilisées en radiochimiothérapie interne du mélanome. Notre recherche s'est d'abord articulée sur une bibliographie récente montrant que des structures de type iodobenzamides ont été développées dans une finalité de radiothérapie. Une pharmacomudulation par substitution du noyau benzènique par un hétérocycle a été envisage e. Deux stratégies ont été réalisées soit à partir d'hétérocycles originaux soit à partir d'un motif acridine (ou acridone) reconnu comme cytotoxique. La 1ère approche a mis en jeu divers polyhétérocycles obtenus par réaction de Friedländer sur le synthon imidazopyridinique. Une évaluation de la cytotoxicité puis des études RMN d'intercalation avec un oligonucléotide de synthèse ont été effectuées. La seconde approche s'est principalement orientée vers la synthèse de iodoacridines et acridones carboxamides analogues du DACA et de l'amsacrine. Une détermination des valeurs d'IC50 de ces composés a été entreprise afin d'évaluer leur cytotoxicité vis-à vis du mélanome. Cette recherche, réalisée au sein de l'UMR INSERM 484 et à l'interface chimie-biologie, sera prolongée par des études de biodistribution.Malignant melanoma has become a serious public health problem in most countries due to its dramatic rise in incidence and mortality. The aim of this work is to conceive new structures that could be used in an internal chemo radionuclide therapy. It was previously reported a series of iodobenzamide derivatives that showed affinity for melanoma tissue. So, we decided the remplacement of the phenyl moiety by a cytotoxic heterocyclic nucleus. Two approaches have been developed. The first one consisted in the synthesis of original polyheterocycles using Friedländer's reaction in imidazo[1,2-a]pyridine serie. We tested their biological effects in vitro on cell lines. In order to test the intercalating properties of these compounds, their interactions with a synthetic oligodeoxynucleotide were studied by NMR spectroscopy. A second approach consisted in using an heterocyclic nucleus known as being cytotoxic : the acridine (or the acridone). Various molecules, structural analogs of two anti-cancer agents : the amsacrine and the DACA, including the functionalities N-[2-(diethylamino)ethyl]carboxamide and iodine have been synthesized. IC50 values showed cytotoxic effects toward melanoma cells. A study of tissue distribution would be effected to completed this work.CLERMONT FD-BCIU-Santé (631132104) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Etude phytochimique de l'espèce Croton (contribution à l'étude de Croton mayumbensis J. Léonard (Euphorbiaceae) du Centrafrique)

Le Croton mayumbensis J. Léonard fait partie de la famille des Euphorbiaceae et du genre Croton, tous les 2 connus pour contenir des diterpènes, n'a jusqu'alors fait l'objet d'aucune étude phytochimique. Les écorces de cette plante sont utilisées par les tradipraticiens de la République Centrafricaine dans le traitement des infections microbiennes et l'amibiase. Nos travaux ont porté sur le fractionnement des extraits par différentes techniques de chromatographie telles que la chromatographie sur colonne et la chromatographie gazeuse couplée à la spectrométrie de masse. Cette étude a permis d'identifier un composé connu, le lup-20(29)-ene-3b-ene-3-ol ou lupeol (E) et quatre composés majoritaires originaux appartenant à la classe des furanoditerpènes : ce sont 3 furanoclérodanes et un furanolabdane. Ces composés correspondent à une lactone diterpénique naturelle de la famille du néo-clérodane, le méthyl 15,16-époxy-12-oxo-néo-clerodan-5(10),13(16),14-trien-20,6b-olide-18-oate dénommée Centrafricine I (A) ainsi qu'à un furanolabdane, Centrafricine II (B) et 2 furanoclérodanes, Centrafricine III (C) et Centrafricine IV (D). Les structures de tous les composés ont été déterminées sur la base d'analyses de données spectroscopiques : spectrométrie de masse, COSY, RMN 1H, RMN 13C (1D et 2D) et par comparaison avec les données rapportées dans la littérature.CLERMONT FD-BCIU-Santé (631132104) / SudocSudocFranceSenegalFRS

Synthesis and Biological Evaluation of Indoloquinolines and Pyridocarbazoles: A New Example of Unexpected Photoreduction Accompanying Photocyclization

International audienceIndoloquinoline alkaloid cryptolepine and pyridocarbazole alkaloid ellipticine are of great interest because in vitro and in vivo studies revealed their good cytotoxic properties. In order to obtain some biologically active analogs of these compounds, we developed a synthesis based on the photocyclization of tertiary N-substituted enaminones derived from 1,3-cyclohexandione and 3 or 6-aminoquinoline. The angular cyclized compounds thus obtained were tested in vitro on K 562 cells and A 2780 doxorubicin sensitive and resistant cells. All compounds were less effective than doxorubicin in sensitive cells but their activity wasn’t decreased by MDR resistance

Synthesis of Polyfused Heterocycle Derivatives Containing the Dipyridoimidazole Core by Friedländer’s Reaction: Access to Analogs of Ellipticine

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Synthesis and in Vitro Cytotoxic Evaluation of New Derivatives of Pyrido[1,2-a]benzimidazolic Ring System: The Pyrido[1,2:1,2]imidazo[4,5-h]quinazolines

International audienceAccess to the original series of pyrido[1',2':1,2]imidazo[4,5-h]quinazoline was developed from a 1,3-dicarbonyl unit with some “N-C-N” bisnucleophilic reagents and the derivatives obtained were evaluated for in vitro cytotoxic activities against HL60 and A2780 cells. All compounds exhibited cytotoxic activitise on resistant cell lines (MDR+; HL60R and A2780R) with no resistance phenomena

A Photochemical Approach to Pyridopyrroloquinoline Derivatives as New Potential Anticancer Agents

International audienceIndoloquinoline alkaloid cryptolepine and pyridocarbazole alkaloid ellipticine are of great interest becausein vitro and in vivo studies revealed their good cytotoxic properties. In order to obtain some biologically activeanalogs of these compounds, we developped a synthesis based on the photocyclisation of tertiary N-methylatedenaminones derived from cyclopentane-1,3-dione and 3 or 6-aminoquinoline. The angular cyclised compoundsthus obtained were submitted to Beckmann rearrangement, preceded by the formation of a Z oxime. Finally, thed -lactame ring was oxidized using 10% palladium/carbon in diphenylether and pyridopyrroloquinolines wereobtained. These compounds and the intermediate lactams and cyclopentanopyrroloquinolines were tested in vitroon K 562 cells and A 2780 doxorubicine sensitive and resistant cells. All compounds were less effective than doxorubicine in sensitive cells but their activity wasn’t decreased by MDR resistance

Efficient Synthesis of New Polyfunctionalized Thiadiazaacenaphthylenes from Imidazo[1,2-a]pyridines

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New Opportunities with the Duff Reaction

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