Heterobifunctional Peg Synthesis Essay

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  • 2. Experimental Section

    Materials and Instrumentation. PEG with a nominal molar mass of 1,450 g/mol, silver (I) oxide (Ag2O), p-toluenesulfonyl chloride (TsCl), methanesulfonyl chloride, triphenylphosphine (PPh3), 2,2’-dipyridyl disulfide (2-PDS), tris(2-carboxyethyl)phosphine hydrochloride (TCEP), N-hydroxysuccinimide (NHS), sodium azide (NaN3), N-ethyl-N-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), hydrochloric acid (HCl), 2-(N-morpholino) ethanesulfonic acid (MES), N,N- dimethylformamide (DMF), potassium iodide (KI), triethylamine (NEt3), ammonium hydroxide (28% in water), sodium hydrosulfide hydrate (NaSH), sodium chloride (NaCl), and calcium chloride dihydrate were purchased from Sigma-Aldrich (Sigma-Aldrich, Switzerland). Thioacetic acid, potassium bicarbonate, and acetic acid were obtained from Fluka (Fluka, Switzerland). Ammonia (7N in MeOH) was obtained from Brunschwig (Chemie Brunschwig AG, Switzerland). Na-alg (HV Kelton, lot no. 46198 A) was obtained from Kelco (San Diego, CA, USA). The intrinsic viscosity [η] in 0.1 M NaCl at 20 °C and the molar guluronic acid fraction FG have been analyzed as [η]0.1 M NaCl = 930 mL/g and FG = 0.41. Unless otherwise mentioned, all reagents were analytical grade and were used without further purification. Other chemicals and their suppliers were toluene (VWR, Switzerland), dichloromethane (DCM), methanol (MeOH) and diethyl ether (Fisher Scientific, Switzerland), filter cell cake (Macherey-Nagel, Switzerland), and sodium sulfate anhydrous (AppliChem, Germany). 1H and 13C-NMR spectra were recorded on a Bruker AV-400 NMR spectrometer. NMR data were processed by Mnova software (Mestrelab Research, Spain). Gel permeation chromatography (GPC) was carried out on a Waters system (Waters AG, Switzerland) equipped with column heater, manual injector, and refractive index and UV/Vis detector. PEG standards were used for calibration. Separation was achieved combining three columns (Waters Styragel THF HR 2, HR 3, and HR 4) at a flow rate of 1.0 mL/min with THF as the mobile phase at 40 °C. Fourier transform infrared (FTIR) spectra were recorded on a Perkin Elmer spectrometer (Spectrum One) equipped with Spectrum software (version 5.3, Perkin Elmer). Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF/TOF MS) was performed in reflection mode using ABI 4800 MALDI TOF/TOF Analyzer (Applied Biosystems). The matrix solution was alpha-cyano-4-hydroxycinnamic acid (7 mg/mL in ACN/0.1%TFA (1:1 v/v)).

    Synthesis of α-tosyl-ω-hydroxyl PEG (1). PEG (1450 g/mol, 20 g, 13.8 mmol, previously dried by azeotropic distillation in toluene using a Dean-Stark trap) was dissolved in 250 mL of dry toluene. Ag2O (1.5 eq, 4.8 g, 20.7 mmol) and KI (0.2 eq, 458 mg, 2.76 mmol) were added. To this rapidly stirred solution, TsCl (1.05 eq, 2.76 g, 14.5 mmol) was added in one portion. The reaction mixture was left at room temperature (rt) with constant stirring for 12 h before filtration over a filter cell cake and solvent removal by rotary evaporation were performed. The crude product was dissolved in 30 mL DCM and then precipitated by dropwise addition into diethyl ether. The polymer was collected by filtration (22 g, 98%). 1H-NMR (DMSO, δ in ppm): 7.79 (2H, d, J = 8 Hz), 7.49 (2H, d, J = 8 Hz), 4.56 (1H, t, J = 5.4 Hz, OH), 4.11 (2H, t, J = 4.4 Hz, CH2-SO2), 3.49 (128H, s, PEG backbone), 2.43 (3H, s, CH3). 13C-NMR (CDCl3) δ: 145, 133.24, 130.04, 128.21, 72.19, 70.79, 69.39, 61.95, 21.87. (Supporting Information (SI), Figure S1 and Figure S2).

    Synthesis of α-azide-ω-hydroxyl PEG (2). α-Tosyl-ω-hydroxyl PEG (1, 10 g, 6.23 mmol) and NaN3 (2 g, 31 mmol) were dissolved in 150 mL of dry DMF, and the mixture was stirred overnight at 90 °C under argon atmosphere. After cooling down to rt and filtration, DMF was removed under vacuum. The crude product was dissolved in 100 mL DCM and washed twice with brine and twice with water. The organic layer was dried over sodium sulfate, reduced to a small volume by rotary evaporation, and finally precipitated by dropping into diethyl ether. The polymer was collected by filtration (8.7 g, 95%). 1H-NMR (DMSO, δ in ppm): 4.56 (1H, t, J = 5.6 Hz, OH), 3.6 (2H, t, J = 5 Hz, CH2CH2-N3), 3.5 (127H, s, PEG backbone), 3.4 (2H, t, J = 5 Hz, CH2-N3). 13C-NMR (CDCl3, δ in ppm): 71.9, 70.53, 69.13, 61.65, 50.64 (Figure S3 and Figure S4).

    Synthesis of α-amine-ω-hydroxyl PEG (3). To a solution of α-azide-ω-hydroxyl PEG (2, 5 g, 3.4 mmol) in 100 mL MeOH, PPh3 was added (2.67 g, 10.2 mmol). The reaction mixture was refluxed overnight under argon atmosphere and then cooled down to rt. The solvent was removed by rotary evaporation. The crude product was dissolved in 20 mL DCM and added dropwise into diethyl ether. α-Amine-ω-hydroxyl PEG was collected by filtration (4.7 g, 95%). 1H-NMR (CDCl3, δ in ppm): 3.64 (124H, s, PEG backbone), 3.5 (2H, t, J = 5.4 Hz, CH2CH2-NH2), 2.85 (2H, t, J = 5.4 Hz, CH2-NH2). 13C-NMR (CDCl3, δ in ppm): 73.45, 72.61, 70.55, 61.67, 41.78 (Figure S5 and Figure S6).

    Synthesis of α-azide-ω-thioacetate PEG (4). α-Azide-ω-hydroxyl PEG (2, 10 g, 6.8 mmol) was dissolved in 100 mL DCM. NEt3 (6 mL, 43 mmol) and TsCl (6.3 g, 33 mmol) were added. The mixture was stirred overnight at rt. The solution was then filtered, washed twice with saturated NH4Cl solution and twice with water. The organic layer was dried over sodium sulfate, filtered, reduced to small volume by rotary evaporation, and added dropwise into diethyl ether. The α-azide-ω-tosyl PEG was collected by filtration (10.5 g, 95%). 1H-NMR (DMSO, δ in ppm): 7.78 (2H, d, J = 8 Hz), 7.48 (2H, d, J = 8 Hz), 4.1 (2H, t, J = 4.4 Hz, CH2-SO2), 3.5 (119H, s, PEG backbone), 3.39 (t, J = 5 Hz, CH2-N3), 2.41 (3H, s, CH3) (Figure S7). The thioacetate function was introduced by reaction with sodium carbonate/thioacetic acid. α-Azide-ω-tosyl PEG (5 g, 3.1 mmol) was dissolved in 100 mL of dry DMF, evacuated and purged with argon. To this rapidly stirred solution, potassium carbonate (2.15 g, 15.5 mmol) and thioacetic acid (1.1 mL, 15.5 mmol) were added, and the mixture was stirred at rt overnight. DMF was removed by rotary evaporation. The crude product was dissolved in 100 mL DCM before filtration and treatment with activated charcoal for 2 h. The mixture was filtered over filter cell cake, the filtrate reduced to small volume by rotary evaporation, and added into diethyl ether. α-Azide-ω-thioacetate was collected by filtration as white solid (3.9 g, 83%). 1H-NMR (CDCl3, δ in ppm): 3.63 (129H, s, PEG backbone), 3.58 (2H, t, J= 6.4 Hz, CH2-CH2-S), 3.38 (2H, t, J= 5.2 Hz, CH2-N3), 3.07 (2H, t, J= 6.4 Hz, CH2-S), 2.32 (3H, s, COCH3). 13C-NMR (CDCl3, δ in ppm): 195.59, 71.89, 69.89, 69.13, 50.65, 30.74, 28.98 (Figure S8 and Figure S9).

    Synthesis of α-thiol-ω-hydroxyl PEG (5). α-Tosyl-ω-hydroxyl PEG (1, 5 g, 3.1 mmol) in 80 mL of distilled water was treated with NaSH (7.5 g, 0.1 mol). The solution was kept under argon atmosphere, stirred for 6 h at rt, and subsequently at 60 °C for 2 h. The reaction mixture was neutralized (pH = 7) by slow addition of HCl, extracted three times with 50 mL DCM, and dried over sodium sulfate anhydrous. The organic phase was reduced to a small volume by rotary evaporation, and then added dropwise into diethyl ether. α-Thiol-ω-hydroxyl PEG was collected by filtration (3.8 g, 84%). 1H-NMR (DMSO: δ in ppm): 3.62 (124H, s, PEG backbone), 2.66 (2H, t, J= 8 Hz, CH2-SH), 1.57 (t, J = 8 Hz, SH). 13C-NMR (CDCl3, δ in ppm): 72.78, 72.19, 70.78, 61.93, 24.48 (Figure S10 and Figure S11).

    Synthesis of α-thioacetate-ω-hydroxyl PEG (6). α-Tosyl-ω-hydroxyl PEG (1, 10 g, 6.23 mmol) was dissolved in 150 mL of dry DMF, evacuated and purged with argon. To the rapidly stirred solution, potassium carbonate (4.3 g, 31.1 mmol) and thioacetic acid (2.2 mL, 31.1 mmol) were added. The mixture was stirred at rt overnight. DMF was removed by rotary evaporation. The crude product was dissolved in 50 mL DCM before treatment with activated charcoal for 2 h, filtration over filter cell cake, reduction to small volume by rotary evaporation, and precipitation in diethyl ether. The polymer was collected by filtration (8 g, 86%). 1H-NMR (DMSO: δ in ppm): 4.56 (1H, t, J = 5.6 Hz, OH), 3.5 (129H, s, PEG backbone), 3.01 (2H, t, J = 6.6 Hz, CH2S), 2.33 (3H, s, SCOCH3). 13C-NMR (CDCl3, δ in ppm): 195.58, 72.75, 70.47, 69.89, 61.79, 30.73, 28.97 (Figure S12 and Figure S13).

    Synthesis of α-pyridyldithio-ω-hydroxyl PEG (7). α-Thioacetate-ω-hydroxyl PEG (6, 2 g, 1.3 mmol) and 2-PDS (5 eq, 1.44 g, 6.5 mmol) were dissolved in 30 mL ammonia (7 M in MeOH). The solution was stirred at rt under nitrogen for 96 h. Nitrogen was bubbled through the solution to remove ammonia, and MeOH was removed by rotary evaporation. The crude polymer was dissolved in 10 mL DCM and added dropwise into diethyl ether. α-Pyridyldithio-ω-hydroxyl PEG was recovered by filtration as slightly yellowish solid (1.97 g, 94%). 1H-NMR (DMSO, δ in ppm): 8.45–7.22 (4H, pyridyl protons), 4.55 (1H, t, J = 5.4 Hz, OH), 3.61 (2H, t, J = 6 Hz, CH2CH2-S), 3.5 (126H, PEG backbone), 3.02 (2H, t, J = 6 Hz, CH2-S). 13C-NMR (CDCl3, δ in ppm): 160.41, 149.48, 137.10, 120.58, 119.58, 72.50, 70.55, 68.91, 61.69, 38.44 (Figure S14 and Figure S15).

    Synthesis of α-azide-ω-pyridyldithio PEG (8). α-Azide-ω-thioacetate PEG (4, 2 g, 1.3 mmol) and 2-PDS (5 eq, 1.44 g, 6.5 mmol) were dissolved in 30 mL ammonia (7 N in MeOH). The solution was stirred at rt under nitrogen for 96 h. Nitrogen gas was then bubbled through the solution to remove ammonia. MeOH was evaporated under vacuum. The crude polymer was dissolved in 10 mL DCM and added dropwise into diethyl ether. The α-azide-ω-pyridyldithio was recovered by filtration as slightly yellowish solid (1.9 g, 93%). 1H-NMR (DMSO, δ in ppm): 8.5–7.2 (4H, m, pyridyl protons), 3.64-3.59 (4H, m, CH2CH2-S and CH2CH2-N3), 3.5 (131H, s, PEG backbone), 3.39 (t, J = 5 Hz, CH2-N3), 3.02 (2H, t, J = 6 Hz, CH2-S). 13C-NMR (CDCl3): 160.4, 149.48, 137.1, 120.59, 119.59, 71.95, 70.54, 69.13, 50.66, 38.43 (Figure S16 and Figure S17).

    Synthesis of α-amine-ω-thiol PEG (9). To a solution of α-azide-ω-thioacetate PEG (4, 2 g, 1.3 mmol) in 50 mL dry MeOH, PPh3 was added (1.7 g, 6 mmol), and the reaction mixture was heated to reflux overnight under argon. After cooling down to rt and solvent removal by rotary evaporation, the resulting solid was dissolved in 10 mL DCM, and then added dropwise into diethyl ether. α-Amine-ω-thiol PEG was collected by filtration (1.8 g 95%). 1H-NMR (CDCl3, δ in ppm): 3.88 (2H, t, J = 4.8), 3.64 (131H, s, PEG backbone), 3.15 (2H), 2.67 (2H, CH2-SH), 1.56 (1H, t, J = 8 Hz, SH). 13C-NMR (CDCl3, δ in ppm): 71.95, 70.56, 69.64, 69.15, 41.76, 24.5 (Figure S18 and Figure S19).

    Synthesis of α-thioacetate-ω-mesyl PEG (10). To a chilled (0 °C) solution of α-thioacetate-ω-hydroxyl PEG (6, 3 g, 1.9 mmol) in dry DCM (30 mL) methanesulfonyl chloride (252 mg, 170 µL, 2.2 mmol) was added. NEt3 (506 mg, 697 µL, 5 mmol) was slowly added to this rapidly stirred solution. The reaction was allowed to proceed for 2 h before dropwise addition of the solution into diethyl ether. White solid α-thioacetate-ω-mesyl PEG was collected by filtration and dried under vacuum (3 g, 97%). 1H-NMR (DMSO, δ in ppm): 4.3 (2H, t, J = 4.4 Hz, CH2-O-SO2), 3.68 (2H, t, J = 4.4 Hz, CH2-CH2-O-SO2), 3.52 (121H, s, PEG backbone), 3.17 (3H, s, CH3-SO2), 3.01 (2H, t, J = 6.4 Hz, CH2-S-CO), 2.33 (3H, s, CH3-CO-S). 13C-NMR (CDCl3, δ in ppm): 195.7, 70.84, 70.52, 69.55, 69.22, 37.95, 30.79. 29.04 (Fig S20 and Fig S21).

    Synthesis of α-amine-ω-pyridyldithio PEG (11). α-Thioacetate-ω-mesyl PEG (10, 2 g, 1.3 mmol), and 2-PDS (1.44 g, 6.5 mmol) were dissolved in 150 mL ammonia (7 N in MeOH/ 28% in H2O (2:1 v/v)). The solution was stirred at rt under nitrogen for 96 h. Nitrogen was then bubbled through the solution to remove ammonia. MeOH was evaporated under vacuum. The polymer was extracted from the aqueous solution three times by 30 mL DCM and dried over sodium sulfate. The organic phase was reduced to a small volume by rotary evaporation, and finally added dropwise into cold diethyl ether. α-Amine-ω-pyridyldithio PEG was collected by filtration (1.9 g, 96%). 1H-NMR (CDCl3, δ in ppm): 8.5–7 (4H, t, pyridyl protons), 3.64 (133H, PEG backbone), 2.99 (2H, t, J = 6.6 Hz, CH2-S), 2.89 (2H, t, J = 6.2 Hz, CH2-NH2). 13C-NMR (CDCl3, δ in ppm): 160.4, 149.49, 137.11, 120.58, 119.59, 72.34, 70.54, 68.93, 41.79, 38.44 (Figure S22 and Figure S23).

    Synthesis of Na-alg-PEG. Na-alg (100 mg), NHS (28 mg, 0.24 mmol), and MES (125 mg, 0.6 mmol) were dissolved in 10 mL of distilled water. A solution of H2N-PEG-SH (9, 230 mg, 0.16 mmol in 1 mL H2O) was added. After stirring for 15 min at rt, 330 mg of EDC was added and stirring was continued for 30 min at rt, followed by addition of NaOH (120 µL, 6 M) and 10 min incubation at rt. Purification was achieved by dialysis against distilled water for 4 days. The water was replaced three times/day. During the first 3 days, NaOH (20 µL, 6 M), NaCl (800 µL, 5 M), and TCEP (1 mL, 1M) were added twice daily to the Na-alg-PEG solution inside the dialysis tube (MWCO 14,000 g/mol). The purified polymer solution was filtered (0.22 µm) and lyophilized. The degree of grafting, which refers to the percentage of reacted carboxylate groups on Na-alg, was determined by 1H-NMR (D2O, δ in ppm): 4.7 (s, alginate protons), 3.6 (PEG protons).

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