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P. Ac2o, DMAP, CH2Cl2; (b) HCl gas, CH2Cl2; (c) Boc2O, TEA, CH2Cl2; (d) LiOH, THF/MeOH. the percentage of apoptotic cells by propidium iodide (nuclear labelling of dead cells) and FITC-Annexin V double-staining followed by flow cytometry analysis (figure 5B and 5C)

, Compound 10 induced a 2.3-fold and 3.7-fold (23.8 ± 4.3% versus 10.4 ± 1.3% and 37.4 ± 4.3% versus 10.2 ± 0.9%) significant increase of the proportion of MDA-MB-231 labelled with FITC-Annexin V after 48h and 72h treatment respectively

, MDA-MB-231 cells were treated for indicated times with 6 µM of 10 or DMSO for control cells. (A) Caspase 3/7 activity was measured by a luminescent method. (B) Double-staining intensity with Propidium Iodide and Annexin V was quantified by flow cytometry and bar graphs show the percentage of apoptotic cells. (C) Dot-plot graphs representative of the flow cytometry analysis: the apoptotic cells annexin V labeled are localized in the lower and upper right quadrants. Data are represented as mean ± standard error of the mean of at least three independent experiments, Fig. 5. Compound 10 induces apoptosis of MDA-MB-231 breast cancer cells

. ***,

, 5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2,5,7,8-tetramethylchroman-6-yl) carbonate (3) To a solution of compound 1 (2.30 g, 5.22 mmol) in dry MeOH (160 mL) was added the phosphoranylidene 2 (1.88 g, 5.22 mmol). The suspension was stirred at room temperature under argon for 24 h, filtered, and washed with cooled MeOH. The filtrate was concentrated under reduced pressure and purified by column chromatography (eluent: cyclohexane/EtOAc, 80:20) to give 2.01 g (3.85 mmol, 74% yield) of white crystals, °C. IR (film) ? (cm -1, issue.2-, pp.839-840, 1093.

. Mhz, CDCl3): ? 1.42 (s, 3H, CH3), 1.55 (s, 9H, t-Bu), 1.89 (m, 1 H, chromane 3-HaHb), vol.2

2. Hz, 6.99 (d, J = 8.7 Hz, 2H, Harom), 7.42 (d, J = 8.7 Hz, 2H, Harom), vol.7

H. and C. , 2 (CH2), 40 (br s, 1H, NH). 13 C NMR (100 MHz, CDCl3): ? 11.9 (CH3), 12.0 (CH3), 12.8 (CH3), vol.8

+. ). , Anal. Calcd for C30H35NO7, 1/3 H2O (527.62): C, 68

, 8-tetramethylchroman-2-yl)methoxy)benzylidene) and the solvent was evaporated. The residue was dissolved in EtOAc (70 mL), the solution was washed with 5% aqueous NaHCO3 solution (2 x 50 mL), water (2 x 50 mL), dried (MgSO4) and concentrated to dryness. The residue was crystallized in EtOH, vol.7, pp.565-566

. Mmol, CDCl3): ? 1.42 (s, 3H, CH3), 1.92 (m, 1 H, chromane 3-HaHb), 2.09 (s, 3H, CH3), 2.10 (m, 1 H, chromane 3-HaHb), °C. IR (film) ? (cm -1, vol.2, p.3415, 1651.

. Hz, 2H, Harom), 7.55 (br t, 1 H, CH=C), 8.11 (br s, 1H, NH). 13 C NMR (100 MHz, CDCl3): ? 11.4 (CH3), 12.0 (CH3), 12.4 (CH3), 20.4 (CH2), 22.7 (CH3), vol.28

+. ). , Anal. Calcd for C25H27NO5, H2O (439.51): C, 68.32

, mg), in order to avoid any ignition of the solvent. A solution of 3 (100 mg, 0.19 mmol) in EtOAc (10 mL) was then added. The mixture was stirred under hydrogen atmosphere for 18 h at room temperature, then filtered on celite ® and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: cyclohexane/EtOAc, 100:0 to 70:30) to afford 5 as a colorless foam (45 mg, 0.09 mmol, 47 % yield, -yl)methyl)phenoxy)methyl)-2,5,7,8-tetramethylchroman-6-yl) carbonate (5) In a round bottom flask was first introduced 10% palladium on carbon, pp.69-71

1. Hz, . Phchahb-;-m,-1h, . Chchahb-;-m,-2h, +. Chchahb, and . Chchahb, 1 Hz, OCH2), 6.85 (d, J = 8.7 Hz, 2H, Harom), 7.07 (d, J = 8.7 Hz, 2H, Harom), 7.95 (br s, 1H, NH). 13 C NMR (100 MHz, CDCl3): ? 11.9 (CH3), 12.0 (CH3), 12.8 (CH3), 20.3 (CH2), 23.1 (CH3), vol.3

, 33 (br s, 1H, CH=C), 7.55 (d, J = 8.1 Hz, 2H, Harom), 7.85 (br s, 3H, NH3 + ), 11.34 (br s, 1H, NH). 13 C NMR (100 MHz, DMSO-d6): ? 11, 14.6 (CH3), 15.6 (CH3), 20.0 (CH2), 21.6 (CH3), 25.7 (CH2), 27.0 (CH2), 28.1 (CH2), vol.7

, (S)-10 and (R)-10 were prepared in three steps from respectively (S)-7 and (R)-7. These compounds showed the same spectral data than the racemic compound 10

, Anal. Calcd for C31H41ClN2O4, 2/3 H2O: C, 67, D +11.6 (c 0.1 in CHCl3:MeOH, vol.9, p.31

, D -11.6 (c 0.1 in CHCl3:MeOH, 9:1). Anal. Calcd for C31H41ClN2O4

, 57 mmol) in methyl methacrylate (100 mL, 937.87 mmol) was cooled in an ice bath and paraformaldehyde (6.00 g, 100.00 mmol) was added. The mixture was stirred under argon for 15 minutes and acetic acid (5.50 mL, 95.99 mmol) and dibutylamine (3.80 mL, 22.55 mmol) were added and the reaction medium was stirred at 0°C for further 15 minutes. Ice bath was removed and the mixture was heated at reflux for 48 h. The yellow solution was cooled down to room temperature, and then let at 4°C for 12 h. The resulting suspension was filtered and the crystals were washed with cooled MeOH and cooled Et2O to give after drying 19.15 g (77.10 mmol, 42% yield) of white crystals, pp.105-107, 1128.

. Mhz and . Dmso-d6, 5 (CH2), 25.6 (CH3), 30.4 (CH2), ? 11.5 (CH3), 18.8 (CH3), 19.8 (CH3), vol.20

, Found: C, 72.69; H, 8.16. 5.1.10 methyl 6-(6-bromohexanoyl)-2,5,7,8-tetramethylchromane-2-carboxylate (13) Preparation of the intermediate acyl chloride: a solution of 6-bromohexanoic acid (19.60 g, 100 mmol) and thionyl chloride (21.6 mL, 291 mmol) in dry CH2Cl2

, The organic layer was then washed twice with water (80 mL), and with a 5% aqueous solution of potassium bicarbonate (10 x 30 mL) to remove the excess of hydrolyzed acyl chloride, and then with water (50 mL). The organic layer was dried (MgSO4), filtered and concentrated under vacuum to give a brownish liquid which was further purified by column chromatography (eluent: cyclohexane/EtOAc, 100/0 to 88/12) to afford 6.00 g (14.11 mmol, 70% yield) of a colorless liquid which crystallized upon storage at 4 °C, Friedel-Crafts acylation: To the above solution were added AlCl3 (10.50 g, 78.00 mmol) and anhydrous dichloromethane (10 mL). A solution of 12 (5.00 g, 20.13 mmol) in CH2Cl2 (35 mL) was then added dropwise in 20 minutes at 0 °C. 15 minutes after the end of the addition were added EtOAc (250 mL) and water (80 mL), vol.1, 1138.

]. Br,

H. , Found: C, 59.36, vol.87

H. , , vol.87

, To a suspension of LiAlH4 (1.82 g, 48.00 mmol) in dry Et2O (30 mL) under argon was added AlCl3 (4.27 g, 32.02 mmol). Five minutes later, a solution of AlCl3 (2.14 g, 16.05 mmol) and 13 (6.82 g, 16.03 mmol) in dry Et2O (90 mL) was slowly added. The mixture was stirred under argon at room temperature for 2 h, and the reaction was then quenched with cold water (140 mL) and 6 M aqueous H2SO4 solution (80 mL). The aqueous layer was extracted twice with EtOAc (100 mL), and the combined organic layers were washed with 2 M Na2CO3 aqueous solution (70 mL), dried (MgSO4) and the solvent was removed under vacuum to give a yellow liquid which was purified by column chromatography

. Mhz, CDCl3): ? 1.23 (s, 3H, CH3), 1.46 (m, 6H, linker CH2), 1.66-2.08 (m, 5H, linker CH2 + chromane 3-CH2 + CH2OH), vol.2

, 55 mmol) and NaN3 (1.63 g, 25.1 mmol) in dry DMF (50 mL) was heated at 80 °C for 3 h. The mixture was cooled to room temperature then diluted with EtOAc (60 mL), washed with water (5 x 30 mL) and with brine (2 x 30 mL). The organic layer was then dried (MgSO4), and the solvent was removed under vacuum to afford 3.76 g (10.88 mmol, 87% yield) of 15 as a colorless liquid which was used without further NMR, MHz, CDCl3) : ? 12.2 (CH3), 15.1 (CH3), 16.0 (CH3), 20.7 (CH2), 22.9 (CH3), vol.12

, Acetylation of ?-D-glucose: procedure reported by Wolfrom and Thompson [23] was adapted as follows: to a suspension of ?-D-glucose (3.00 g, 16.65 mmol) in acetic anhydride (20.46 mL, 216.47 mmol) was added sodium acetate (1.50 g, 18.32 mmol) under argon. The mixture was refluxed during 2 h and cooled to room temperature before being cooled in an ice bath. Water (50 mL) was added and the suspension was filtered, washed with water (3 x 20 mL), and carefully dried to give 3.618 g (9.27 mmol, 56% yield) of white powder which was used in the next step without further purification

, 5-dioxopyrrolidin-3-ylidene)methyl)phenoxy)methyl)-2,5,7,8-tetramethylchroman-6-yl)hexyl)-1H-1,2,3-triazol-4-yl)methoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (30) To a mixture of 28 (138 mg, 0.26 mmol) and 29 (100 mg, 0.26 mmol) were added t-BuOH (20 mL) and MeOH (2 mL) and sonication was applied. To the resulting solution was added a mixture of CuSO4 (58 mg, 0.36 mmol) and sodium ascorbate (71 mg, 0.36 mmol) in water (0.5 mL). The reaction mixture was stirred under argon at room temperature for 12 h, and the solvents were evaporated. The residue was dissolved in EtOAc (30 mL) and the solution was washed with water (3 x 20 mL), dried (MgSO4) and concentrated under vacuum to give a yellow residue which was purified by column chromatography, pp.88-90

, 14 (s, 3H, chromane CH3), 2.19 (s, 3H, chromane CH3), 2.59 (m, 2H, linker CH2), 2.66 (m, 2H, chromane 4-H), 3.59 (d, J = 2.3 Hz, 2H, CH2CO), 3.74 (X part of an ABX system, 1H, glucose 5-H), 3.95, 4.04 (AB system, J = 12.6 Hz, 2H, OCH2), 5.01 (dd, J = 9.5, 8.0 Hz, 1H, glucose 2-H), 5.10 (t, J = 9.6 Hz, 1H, glucose 4-H), 5.20 (t, J = 9.5 Hz, 1H, glucose 3-H), 6.99 (d, J = 8.9 Hz, 2H, Harom), 7.42 (d, J = 8.9 Hz, 2H, Harom), 7.50 (br s, 1H, triazole H), vol.2, 1217.

, 3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1, vol.2

, 09 mL, 1.15 mg/mL) was added at room temperature and stirred under argon for 1 h. Amberlite ® IR 120H was added until neutral pH and the suspension was filtered to give after evaporation an orange liquid which was purified by reverse-phase column chromatography, p.1

. Tfa)/meoh, to 10:90) to afford after lyophilisation 31 as a white powder 71 mg (0.09 mmol, 100 % yield). M.p. 126-128 °C. IR (ATR): ? (cm -1 ) 3387, vol.525, 1043.

1. Hz, 11 (s, 1H, triazole H), 11.34 (s, 1H, NH). 13 C NMR (100 MHz, DMSO-d6): ? 11, AB part of an ABX system, J = 11.8, 6.2, 1.6 Hz, 2H, glucose 6-H + 6'-H), 3.59 (d, J = 2.1 Hz, 2H, CH2CO), 4.03, 4.08 (AB system, J = 10.1 Hz , 2H, OCH2), 4.14 (br s, 4H, 4 x OH, vol.12

. Mcf-7 and . Mda-mb-231, These cell lines were grown at 37 °C under 5% CO2 in Dulbecco's Modified Eagle Medium (DMEM, Gibco ® , Thermo Fisher Scientific, Villebon-sur-Yvette, France) for MCF-7 and Hs578T, and Roswell Park Memorial Institute (RPMI) 1640 medium (Gibco ® ) for MDA-MB-231 and MDA-MB-453. These phenol red containing media were supplemented with 2 mM L-glutamine, MDA-MB-453 and Hs578T human breast cancer cell lines were obtained from American Type Culture Collection

, MDA-MB-453 and Hs578T cells were seeded at the appropriate density in their respective medium supplemented with 10% FCS and incubated for 24 h to allow for cell attachment. For crystal violet staining, cells were seeded in 96-well plates at a density of 1.5 x 10 4 cells/well (MDA-MB-231, MCF-7 and Hs578T cells) or 2 x 10 4 cells/well (MDA-MB-453 cells), p.2

, This staining solution was filtered prior to use with a syringe-driven filter unit (0.2 µm pore size, VWR international, Radnor, PA, USA) to eliminate dye precipitates. Cells were then washed with distilled water to remove excess dye. The plates were dried and the dye was dissolved in 10% acetic acid. Cell number was determined by absorbance at 595 nm with a VICTOR? X3 multilabel plate reader

, At the end of the treatment, culture medium containing the non-adherent cells was collected. Adherent cells were washed with PBS, trypsined (0.05% trypsin-EDTA in PBS buffer, Gibco ® ) and resuspended in a medium containing 10% FCS

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