Geneviève Aubert

Synthetic Analogue of Rocaglaol Displays a Potent and Selective Cytotoxicity in Cancer Cells: Involvement of Apoptosis Inducing Factor and Caspase-12

Flavaglines constitute a family of natural anticancer compounds. We present here 3 (FL3), the first synthetic flavagline that inhibits cell proliferation and viability (IC(50) approximately 1 nM) at lower doses than did the parent compound, racemic rocaglaol. Compound 3 enhanced doxorubicin cytotoxicity in HepG2 cells and retained its potency against adriamycin-resistant cell lines without inducing cardiomyocyte toxicity. Compound 3 induced apoptosis of HL60 and Hela cells by triggering the translocation of Apoptosis Inducing Factor (AIF) and caspase-12 to the nucleus. A fluorescent conjugate of 3 accumulated in endoplasmic reticulum (ER), suggesting that flavaglines bind to their target in the ER, where it triggers a cascade of events that leads to the translocation of AIF and caspase-12 to the nucleus and probably inhibition of eIF4A. Our studies highlight structural features critical to their antineoplastic potential and suggest that these compounds would retain their activity in cells refractory to caspase activation.

Discovery of a new family of bis-8-hydroxyquinoline substituted benzylamines with pro-apoptotic activity in cancer cells: synthesis, structure-activity relationship, and action mechanism studies.

Bis-8-hydroxyquinoline substituted benzylamines have been synthesized and screened for their antitumor activity on KB3 cell line model. Synthesis of this series of new analogues was accomplished using a one pot specific methodology which allows the synthesis of both bis- and mono-8-hydroxyquinoline substituted benzylamines. Among the synthesized compounds two compounds (4a and 5a), respectively, named JLK 1472 and JLK 1486, were particularly potent on KB3 cell line. Their CC(50) values being, respectively, 2.6 and 1.3 nM. Screened on a panel of cell lines showing various phenotype alterations, both compounds were found inactive on some cell lines such as PC3 (prostate cell line) and SF268 (neuroblastoma cell line) while highly active on other different cell lines. Mechanistic studies reveal that these two analogues did not affect tubulin and microtubules neither they exert a proteasomal inhibition effect. In contrast 4a and 5a activate specifically caspase 3/7 and not caspase 8 and 9, suggesting that their biological target should be located upstream from caspase 3/7. Moreover their cytotoxic effect is potentiated by the pro-apoptotic effects of TRAIL.

Structure–activity relationships and mechanism of action of antitumor bis 8-hydroxyquinoline substituted benzylamines

A series of twenty six 8-hydroxyquinoline substituted amines, structurally related to compounds 2 and 3, were synthesized to evaluate the effects of structural changes on antitumor activity and understand their mechanism of action. The studies were performed on a wide variety of cancer cell lines within glioma and carcinoma models. The results obtained from chemical models and biological techniques such as microarrays suggest the following hypothesis that a quinone methide intermediate which does not react with DNA but which gives covalent protein thiol adducts. Micro-array analysis showed that the drugs induce the expression of a variety of stress related genes responsible for the cytotoxic and cytostatic effects in carcinoma and glioblastoma cells respectively. The described analogues could represent new promising anti-cancer candidates with specific action mechanisms, targeting accessible thiols from specific proteins and inducing potent anti-cancer effects.

Cytotoxic activities of hexane, ethyl acetate and butanol extracts of marine sponges from Mauritian Waters on human cancer cell lines.

The ocean is an exceptional source of natural products with many of them exhibiting novel structural features and bioactivity. As one of the most interesting phylum with respect to pharmacological active marine compounds, Poriferas have been investigated widely in the last few decades. A total of 60 organic extracts (hexane, ethyl acetate and butanol) from 20 species of marine sponges from Mauritius were screened at 50μg/ml in an in vitro screening assay against 9 human cancer cell lines. From these tested extracts, many exhibited pronounced cytotoxic effect at least in one of the cell lines and cell type cytotoxic specificity was observed. 27% of ethyl acetate, 11% of hexane and 2% of butanol extracts were found to possess a cytotoxicity ≥75% on 9 different cancer cell lines with the sponges Petrosia sp. 1, Petrosia sp. 2, Pericharax heteroraphis and Jaspis sp. being the most active. Overall, the HL-60cells were much more sensitive to most of the extracts than the other cell lines. We further evaluated the properties of the ethyl acetate (JDE) and hexane extract (JDH) of one sponge, Jaspis sp. on KB cells. JDE displayed a smaller IC(50) than JDH. Clonogenic assay confirmed the antiproliferative effect of both extracts while mitochondrial membrane potential change and microscopic analysis demonstrated extracts-induced apoptosis. Treatment with 100ng/ml of JDE led to a significant increase of cells (24h: 4.02%; 48h: 26.23%) in sub-G1 phase. The cytotoxic properties of the tested extracts from these sponges suggest the presence of compounds with pharmacological potential and are currently undergoing fractionation to isolate the active constituents.

Synthesis and biological investigation of the β-thiolactone and β-lactam analogs of tetrahydrolipstatin

The synthesis of β-thiolactone and β-lactam analogs of tetrahydrolipstatin is described from a common late-stage β-lactone derivative. These analogs, and a cis-disubstituted β-lactone analog of tetrahydrolipstatin, were screened for activity against porcine pancreatic lipase and for inhibition of cell growth of a panel of four human cancer lines.

Design, synthesis and antiproliferative activities of biarylolefins based on polyhydroxylated and carbohydrate scaffolds.

A series of diversely substituted biarylolefins based on carbohydrate and dihydroxyethylene scaffolds were synthesized and evaluated for antiproliferative activity against a panel of human tumor cell lines. Among the thirty-five yet unknown biarylolefins prepared, six displayed potent antiproliferative activities with IC(50) values in the micromolar and submicromolar range. As a new type of antiproliferative agent, the most potent compound 26 showed an IC(50) value of 70 nM against SK-OV3 cell line (ovarian cancer). All the synthesized compounds exhibited a poor or modest tubulin polymerization inhibitory activity suggesting another mode of action for these compounds. Molecular docking simulations to the colchicine binding site of tubulin of representative compounds have been used to explain the lack of activity as inhibitors of tubulin polymerization.

Ethyl acetate extract of the Mauritian sponge Jaspis sp. induces cell arrest in human promyelocytic leukemia cells.

Marine sponges are considered as a gold mine of new natural products possessing numerous biological activities. We examined the cytotoxic properties of the ethyl acetate extract (JDE) of the previously unrecorded sponge, Jaspis sp. collected from Mauritius Waters. JDE displayed an interesting IC50 of 0.057±0.04μg/mL on HL-60 cells evaluated by MTS assay. Mitochondrial membrane potential change, microscopic analysis and DNA fragmentation assays also confirmed JDE induced apoptosis on HL-60 cells. Annexin V staining demonstrated that JDE induced apoptosis at different concentrations. Treatment with 100ng/mL of JDE led to an accumulation of cells in G2/M phase after 24 h, causing a significant increase of cells (24h: 5.84%; 48h: 13.41%) in sub-G1 phase suggesting that JDE can induce cell cycle arrest in G2/M phase.

Synthesis and Anti-Proliferative Activity of Novel Quinolin-8-ol Derivatives

Through the coupling of substituted benzaldehydes with 8-hydroxy 5-amino methyl quinoline scaffold, a series of new derivatives has been synthesized. In vitro growth inhibitory effects on cancer cell line model have been evaluated. Discussion on the chemical reactivity of these new polycyclic aromatic analogs to generate alkylating species led to the hypothesis that the presence of an imine moiety impedes the formation of quinone methide intermediate and consequently abolishes in part their antiproliferative activity.