Design, synthesis and evaluation of ph-dependent hydrolysable emetine analogs as treatment for prostate cancer.
|
|
- Brett Patrick
- 5 years ago
- Views:
Transcription
1 Design, synthesis and evaluation of p-dependent hydrolysable emetine analogs as treatment for prostate cancer. Emmanuel S. Akinboye, 1 Marc D. Rosen, 2 Samuel R. Denmeade, 2 Bernard Kwabi-Addo 3 and ladapo Bakare 1* 1 Department of Chemistry, oward University, 525 College Street W, Washington DC, 20059, USA 2 The Sidney Kimmel Comprehensive Cancer Center at Johns opkins, The Johns opkins University School of Medicine, Baltimore, MD, 21239, USA 3 Department of Biochemistry and Cancer Center, oward University, Washington DC * Address correspondence to this author at the Department of Chemistry, oward University, 525 College Street W, Washington DC, 20059, USA; Tel: ; Fax: ; E- mail: obakare@howard.edu Preparation and characterization of emetine analogs General Information: All solvents and reagents used were bought from commercial sources and used without further purification. Melting points were determined in open capillary tubes on a Mel-Temp melting point apparatus and are uncorrected. The IR spectra were recorded on a Perkin Elmer PE 100 spectrometer with an Atenuated Total Reflectance (ATR) window. The 1 - and 13 C-MR spectra were obtained on a Bruker Avance 400 Mz spectrometer at 400 Mz and 100 Mz, respectively in deuterated chloroform (CDCl 3 ) or deuterated methanol (CD 3 D). Chemical shifts are in δ units (ppm) with TMS (0.00 ppm), CCl 3 (7.27 ppm), or C 3 (3.34 ppm) as the internal standard for 1 -MR, and CDCl 3 (77.00 ppm) or CD 3 D (49.90 ppm) for 13 C-MR. Accurate mass determination was carried out on Agilent 6224 Accurate-Mass TF LC/MS system and also with Voyager-DE-STR (Applied Biosystems) Matrix-assisted laser S1
2 desorption/ionization (MALDI) time-of-flight mass spectrometry. Analytical thin-layer chromatography was performed on EMD precoated silica gel 60 F254 plates. Purity of the compounds was determined with reverse phase-plc. The purity of all the compounds was determined to be 95%. PLC Methods In this study, the reverse phase PLC studies were carried out using the following methods. PLC Method 1 This method was used for analytical reversed-phase PLC of synthetic emetine analogues: PLC Unit: Waters Delta 600 Controller equipped with a variable wavelength UV-vis detector (Waters 2487 Dual λ Absorbance Detector) set to detect at 215 nm and 285 nm and a Luna 5µ C18 reversed phase analytical column (150 X 4.60 mm, Waters). Software: Laura TM Lite 3 PLC Conditions: Flow rate: 1 ml/min; mobile phase A: 50% p M phosphate buffer, 50%. Mobile phase B: 100%. Gradient: 0-2 min 56% mobile phase A and 44% mobile phase B; 2-9 min gradual change to 10% mobile phase A and 90% mobile phase B; 9-26 min 10% mobile phase A and 90% mobile phase B; min gradual change to 56% mobile phase A and 44% mobile phase B; min 56% mobile phase A and 44% mobile phase B. Injection volume 100 µl. S2
3 PLC Method 2 This method was used for analytical reversed-phase PLC of p responsive studies on emetine analogues: PLC Unit: Waters Delta 600 Controller equipped with a variable wavelength UV-vis detector (Waters 2487 Dual λ Absorbance Detector) set to detect at 215 nm and 285 nm and a Waters XBridge 5µ C18 reversed phase analytical column (150 X 4.60 mm, Waters). Software: Empower 2 PLC Conditions: Flow rate: 1 ml/min; mobile phase A: 30% p M phosphate buffer, 70%. Mobile phase B: 100%. Gradient: 0-20 min 100% mobile phase A; min gradual change to 100% mobile phase B; min 100% mobile phase B; Injection volume: 100 µl. General procedure for the synthesis of thiourea analogs 4-6 Synthesis of intermediate isothiocyanate Procedure adapted from report by Wong & Colman 1. To a solution of appropriate amine (16.0 mmol) in TF (15 ml) at 0 o C was added triethylamine (10.0 ml). This was set to moderate stirring and CS 2 (34.0 mmol) was added in drops over about 30 min at 0 o C. The mixture was allowed to stir at this temperature for 15 minutes after which it was stirred at room temperature for 1 h. The reaction temperature was then cooled to 0 o C again while stirring continued and a solution of tosyl chloride (20.8 mmol) in TF was added gently. The reaction mixture was allowed to warm up to room temperature, stirred for 1 h and then 20 ml 1 Cl was added while stirring continued. This was followed by 25 ml diethyl ether and the reaction stirred for S3
4 another 5 minutes. The aqueous layer was separated and extracted with diethyl ether (2 X 20 ml). The combined organic layers were dried over anhydrous a 2 S 4, solvent evaporated invacuo, and the crude product was purified by column chromatography over silica gel with hexanes as eluent. Reaction of isothiocyanate with emetine to produce the thiourea analogs To a stirred solution of pyridine (0.5 ml) in C 2 Cl 2 (15 ml) at room temperature was added emetine dihydrochloride (200 mg, 0.36 mmol). After all the emetine was completely dissolved, the appropriate isothiocyanate (0.72 mmol) was added. The reaction mixture was stirred at room temperature for 8 to 16 h. C 2 Cl 2 (15 ml) was then added to the mixture and the resulting mixture washed with water (2 x 25 ml) and brine (1 x 25 ml). The organic layer was dried over anhydrous MgS 4 followed by solvent removal in-vacuo. The crude product was purified either by precipitation in a diethyl ether/hexane mixture or by column chromatography using C 2 Cl 2 / mixture in appropriate ratio as eluent. Compound 4 was purified by column chromatography over silica gel using gradient elution. 100% C 2 Cl 2 was employed to elute nonpolar impurities followed by elution with 10% in C 2 Cl 2 to obtain the desired product 4. Compounds 5 and 6 were purified by dissolving the crude product in a small amount of ethyl acetate to dissolve it and to this solution was added a 3:7 mixture of diethyl ether and hexanes to precipitate 5 and 6 in pure form. C S S4
5 Isothiocyanatomethyl-benzene Yield: 73%, yellow oil, IR (cm -1 ) 3053, 3033, 2906, 2855, 2167, 2077, 1593, 1496, 1454, 1439: 1 MR (400Mz, CDCl 3 ) δ 4.74 (2, s), (2, m), (3, m); 13 C MR (100 Mz, CDCl 3 ) δ 48.7, 126.0, 126.9, 127.2, 128.4, 129.0, 129.4, S 4 1-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1 α]isoquinol-2-ylmethyl)- 6,7-dimethoxy-3,4-dihydro-1-isoquinoline-2-carbothioic acid benzylamide (4) Yield: 67%, mp = o C. 1 MR (400 Mz, CDCl 3 ) δ 0.89 (3, t, J = 7.4 z), (1, m), (1, m), (3, m), (3, m), 2.09 (1,br s), 2.38 (1, t, J = 12.5 z), 2.51 (1, br s), 2.63 (1, br d, J = 15.6 z), 2.76 (1, dt, J = 3.9, 15.8 z), (2, m), (4, m), (1, m), 3.83 (3, s), 3.84 (3, s), 3.86 (3, s), 3.87 (3, s), 4.92 (2, d, J = 4.7 z), 5.84 (1, t, J = 4.7 z), 6.56 (1, s), 6.58 (1, s), 6.63 (1, s), 6.92 (1, s), (2, m), (3, m); 13 C MR (100 Mz, CDCl 3 ) δ 11.2, 23.8, 27.2, 29.1, 37.8, 38.4, 40.0, 41.3, 50.5, 52.4, 55.9, 56.0, 56.1 (2C), 56.3 (2C), 57.8, 61.4, 108.9, 110.2, 111.1, 111.3, 124.7, 125.9, 127.1, 127.9, 128.0, 128.7, 128.9, 129.2, 130.9, 138.1, 147.3, 147.4, 147.7, 147.8, 182.3; ESI-TF-MS m/z , ([C S + ] + calcd ). t R is 8.39 min (100% purity). S5
6 C S 1-Isothiocyanatomethyl-4-methoxy-benzene Yield: 93%, pale yellow oil, IR (cm -1 ) 3007, 2955, 2837, 2163, 2077, 1611, 1587, 1440, MR (400 Mz, CDCl 3 ) δ 3.83 (3, s), 4.65 (2, s), (2, m), (2, m). 13 C MR (100 Mz, CDCl 3 ) δ 48.3, 55.4, 114.0, 114.4, 128.1, 128.2, 130.3, 131.9, S 5 1-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1 α]isoquinol-2-ylmethyl)- 6,7-dimethoxy-3,4-dihydro-1-isoquinoline-2-carbothioic acid 4-methoxybenzylamide (5) Yield: 48%, mp = o C; 1 MR (400 Mz, CDCl 3 ) δ 0.88 (3, t, J = 7.4 z), (2, m), (3, m), (2, m), (1, m), 2.37 (1, t, J = 12.4 z), (1, m), 2.62 (1, br d, J = 15.6 z), 2.75 (1, dt, J = 4.0, 16.4 z), (6, m), (1, m), 3.76 (3, s), 3.81 (1, s), 3.82 (3, s), 3.83 (3, s), 3.84 (3, s), 3.89 (3, s), (2, m), 5.77 (1, t, J = 4.8 z), 6.55 (1, s), 6.57 (1, s), 6.63 (1, s), 6.85 (2, d, J = 9.6 z), 6.93 (1, s), 7.27 (2, d, J = 9.6 z); 13 C MR (100 Mz, CDCl 3 ) δ 11.2, 23.8, 27.1, 29.1, 37.8, 38.4, 40.0, 50.0, 52.4, 55.4, 55.9, 56.0 (2C), 56.1 (2C), 56.3, 57.8, 61.5, 108.9, 110.2, 111.2, 111.3, 114.2, 114.3, 124.8, 126.3, 128.4, 129.0, 129.2, 129.4, 130.0, S6
7 (2C), (2C), 159.3, ESI-TF-MS m/z , ([C S + ] + calcd ). t R is 8.11 min (100% purity). Cl C S S Cl 6 1-Chloro-4-Isothiocyanatomethyl-benzene Yield: 85%, yellow oil, IR (cm -1 ) 3027, 2953, 2850, 2173, 2069, 1597, 1579, 1491, MR (400 Mz, CDCl 3 ) δ 4.69 (2, s), (2, m), (2, m). 13 C MR (100 Mz, CDCl 3 ) δ 48.7, 128.8, 129.0, 129.5, 129.7, 133.3, (3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1 α]isoquinol-2-ylmethyl)- 6,7-dimethoxy-3,4-dihydro-1-isoquinoline-2-carbothioic acid 4-chloro-benzylamide (6) Yield: 51%, mp = o C; 1 MR (400 Mz, CDCl 3 ) δ 0.88 (3, t, J = 7.4 z), (5, m), (2, m), (1, m), (2, m), 2.61 (1, br d, J = 15.5 z), 2.75 (1, dt, J = 4.0, 16.0 z), (6, m), (1, m), 3.83 (3, s), 3.84 (3, s), 3.86 (3, s), 3.87 (4, s), 4.87 (1, dd, J = 4.9, 14.8 z), 4.95 (1, dd, J = 5.0, 14.7 z), 5.91 (1, t, J = 4.8 z), 6.56 (1, s), 6.58 (1, s), 6.64 (1, s), 6.90 (1, s), 7.28 (4, s). 1 MR (400 Mz, CD 3 D) δ 0.93 (3, t, J = 7.4 z), (2, m), (2, m), (2, S7
8 m), (1, m), 2.12 (1, t, J = 11.2 z), 2.38 (1, t, J = 12.4 z), (1, m), (2, m), (6, m), (1, m), 3.73 (3, s), 3.81 (6, s), 3.82 (3, s), 4.28 (1, br s), (2, m), 6.69 (2, s), 6.74 (2, s), 6.96 (1, br s), 7.17 (2, d, J = 8.4 z), 7.30 (2, d, J = 8.4 z). 13 C MR (100 Mz, CDCl 3 ) δ 11.2, 23.9, 27.2, 29.2, 37.9, 38.5, 39.9, 40.3, 49.5, 52.4, 55.9, 56.0, 56.1 (2C), 56.3 (2C), 58.0, 61.6, 108.9, 110.2, 111.1, 111.3, (2C), (2C), 129.2, 129.3, 130.1, 130.9, 133.5, 136.8, 147.2, 147.4, 147.8, 147.9, ESI-TF-MS m/z , ([C Cl 3 4 S + ] + calcd ). t R is min (100% purity). General procedure for the synthesis of urea analogs 7-9 Synthesis of the isocyanate was carried out as reported by Sigurdsson 2 et al with slight modifications. A solution of Trichloromethyl chloroformate (5.741 mmol) in C 2 Cl 2 (15 ml) was stirred at 0 o C. A solution of an appropriate amine, (3.827 mmol) and 1,8- bis(dimethylamino)-naphthalene or DMAP (7.654 mmol) in C 2 Cl 2 was then added dropwise over a period of 5 to 10 min. Thereafter, the ice bath was removed and the reaction mixture was allowed to warm up to room temperature and then stirred for another 45 min. Solvent and all volatiles were evaporated in-vacuo and fresh C 2 Cl 2 (30 ml) was added followed by 1 Cl solution (20 ml); this was stirred for about 3-5 min. The organic layer was separated and then washed with 1 Cl (3 x 15 ml) and 1 a (1 x 15 ml). It was dried over anhydrous a 2 S 4 and solvent was evaporated in vacuo to give the respective isocyanates that were used without further purification. S8
9 To a solution of a given isocyanate, (0.72 mmol) in C 2 Cl 2 (10 ml), was added a solution of emetine dihydrochloride (200 mg, 0.36 mmol) and DMAP (1.44 mmol) in C 2 Cl 2 (15 ml) at room temperature. The reaction mixture was stirred overnight at room temperature. Additional C 2 Cl 2 (10 ml) was added to the mixture and the resulting mixture washed with water (2 x 25 ml) and brine (1 x 25 ml). The organic layer was dried over anhydrous MgS 4 and the solvent removed in-vacuo. All the products were purified by flash column chromatography using gradient elution beginning with 100 % EtAc and followed with a gradual addition of from 5% to 10 % in EtAc to afford 7-9 in pure form. 7 1-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1 α]isoquinol-2-ylmethyl)- 6,7-dimethoxy-3,4-dihydro-1-isoquinoline-2-carboxylic acid benzylamide (7) Yield: 82%, mp = o C; 1 MR (400 Mz, CDCl 3 ) δ 0.89 (3, t, J = 7.5 z), (2, m), (3, m), (2, m), 1.75 (2, m), (1, m), 2.25 (1, 11.6 z), (1, m), 2.67 (2, br t, J = 15.0 z), (2, m), (1, m), (1, m), 3.83 (3, s), 3.85 (6, s), 3.86 (3, s), 4.42 (2, dd, J = 5.6, 16.8 z), 4.55 (1, dd, J = 5.8, 14.6 z), 4.93 (1, t, J = 5.4 z), 5.60 (1, d, J = 10.0 z), 6.58 (1, s), 6.59 (2, s), 6.91 (1, s), (5, m); 13 C MR (100 Mz, CDCl 3 ) δ 11.4, 23.9, 27.8, 29.4, 36.6, 37.2, 38.1, 38.7, 45.2, 45.4, 51.3 (2C), 52.8, 56.2, 56.3, 56.4 (2C), 61.8, 109.2, 110.5, 111.5, 111.9, 125.6, S9
10 TF-MS m/z , ([C ] + calcd ). t R is 8.48 min (97 % purity) , 127.8, 128.1, 128.9, (2C), (2C), 140.1, 147.6, 147.7, (2C), ESI- 1-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1 α]isoquinol-2-ylmethyl)- 6,7-dimethoxy-3,4-dihydro-1-isoquinoline-2-carboxylic acid 4-methoxy-benzylamide (8) Yield: 75%, mp = o C; 1 MR (400 Mz, CDCl 3 ) δ 0.89 (3, t, J = 7.4 z), (2, m), (2, m), (3, m), (1, m), 2.19 (1, t, J = 12.4 z), 2.67 (1, d, J = 15.2 z), (1, m), (2, m), (3, m), 3.65 (2, d, J = 15.6 z), 3.72 (3, s), 3.81 (3, s), 3.85 (3, s), 3.86 (3, s), 3.92 (3, s), (3, m), 5.05 (1, s), 5.61 (1, d, J = 8.8 z), 6.57 (2, s), 6.59 (1, s), 6.76 (2, d, J = 8.2 z), 6.98 (1, br s), 7.21 (2, d, J = 8.2 z); 13 C MR (100 Mz, CDCl 3 ) δ 11.2, 22.7, 27.5, 30.1, 36.2 (2C), 38.3 (2C), 44.5 (2C), 50.4 (2C), 55.2, 55.3, 55.9, 56.1 (2C), 56.2 (2C), 108.8, 109.9, 111.0, 111.4, (2C), (2C), 129.1, (2C), (2C), (4C), 157.3, 158.9; ESI- TF-MS m/z , ([C ] + calcd ). t R is 9.17 min (98.8 % purity). 8 S10
11 Cl 9 1-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1 α]isoquinol-2-ylmethyl)- 6,7-dimethoxy-3,4-dihydro-1-isoquinoline-2-carboxylic acid 4-chloro-benzylamide (9) Yield: 85%, mp = o C; 1 MR (400 Mz, CDCl 3 ) δ 0.87 (3, t, J = 7.6 z), (2, m), (3, m), (4, m), (1, m), 2.20 (1, t, J = 12.4 z), (1, m), 2.65 (2, t, J = 14.6 z), (2, m), (1, m), 3.62 (1, d, J = 14.0 z), 3.82 (3, s), 3.83 (6, s), 3.84 (3, s), 4.36 (2, dd, J = 5.6, 14.8 z), 4.45 (1, dd, J = 5.8, 15.0 z), 4.93 (1, s), 5.55 (1, d, J = 9.2 z), 6.56 (3, s), 6.87 (1, s), 7.20 (2, s), 7.25 (2, s); 13 C MR (100 Mz, CDCl 3 ) δ 11.0, 23.5, 27.5, 36.3, 37.8 (2C), 38.4, 39.5, 44.3, 51.0 (2C), 52.5 (2C), 55.9 (2C), 56.0, 56.1, 61.4, 108.8, 110.1, 111.2, 111.5, (2C), (2C), 129.0, (2C), (2C), 138.4, 147.4, (3C), 157.3; ESI-TF-MS m/z , ([C Cl ] + calcd ). t R is min (100% purity). General procedure for the preparation of sulfonamide analogs To a stirred solution of dimethyl amino pyridine (DMAP) ( mg, 1.45 mmol) in C 2 Cl 2 (20 ml) was added emetine dihydrochloride (200 mg, 0.36 mmol) at room temperature. After minutes, the appropriate sulfonyl chloride (0.9 mmol) solution in C 2 Cl 2 (5 ml) was added. The reaction mixture was then stirred at room temperature for h. The solvent was removed in- S11
12 vacuo and water (25 ml) was added to the residue to dissolve all the water soluble impurities. The crude product was isolated by extraction into C 2 Cl 2 (3 x 25 ml). The combined organic phase was washed with brine (2 x 20 ml), dried over anhydrous MgS 4 and the solvent evaporated in-vacuo. The crude product was purified by flash column chromatography over silica gel using gradient elution starting with 100% C 2 Cl 2 to remove the least polar impurities and gradually varying this to C 2 Cl 2 : eluent mixture. ptimum components vary from 5 to 20% depending on the specific analog to afford the desired product. S 10 2-(2-Benzenesulfonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-3-ethyl- 9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyridol[2,1-a]isoquinoline (10) The product was purified using flash column chromatography with of 5% in C 2 Cl 2. Yield: 75%, mp = o C; 1 MR (400 Mz, CDCl 3 ) δ 0.87 (3, t, 7.4 z), (2, m), 1.33 (1, t, J = 11.6 z), (1, m), (3, m), (1, m), 2.22 (1, t, J = 12.1 z), (2, m), (1, m), 2.64 (1, d, J = 16.2 z), (1, m), (4, m), 3.73 (3, s), 3.83 (3, s), 3.85 (3, s), 3.89 (3, s), 4.01 (1, dt, J = 3.9, 14.5 z), 5.16 (1, dd, J = 3.6, 11.8 z), 6.21 (1, s), 6.43 (1, s), 6.58 (1, s), 7.07 (1, s), 7.25 (2, t, J = 7.8 z), (1, m), 7.67 (2, dd, J = 1.2, 8.4 z); 13 C MR (100 Mz, CDCl 3 ) δ S12
13 147.8, 147.6, 147.4, 147.3, 140.8, (2C), (2C), 128.6, (2C), (2C), 111.4, 111.1, 109.2, 108.9, 56.2, 56.0, 55.9, 55.8, 53.4, 52.3 (2C), 41.6, 40.6, 40.0, 37.9, 36.7, 36.2, 29.3, 24.6, 23.6, 11.1; ESI-TF-MS m/z , ([C S + ] + calcd ). t R is 9.29 min (99.8% purity). S Cl 11 2-[2-(4-Chloro-benzenesulfonyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)- 3-ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyridol[2,1-a]isoquinoline (11). The product was purified using flash column chromatography with of 7% in C 2 Cl 2. Yield: 86%, mp = o C; 1 MR (400 Mz, CDCl 3 ) δ 0.87 (3, t, 7.4 z), (3, m), (1, m), (1, m), (2, m), (1, m), (1, m), (2, m), (1, m), 2.63 (1, d, J = 15.4 z), (1, m), (3, m), (1, m), 3.74 (3, s), 3.83, (3, s), 3.84 (3, s), 3.87 (3, s), 3.99 (1, dd, J = 6.4, 15.3 z), 5.15 (1, dd, J = 3.5, 11.8 z), 6.22 (1, s), 6.44 (1, s), 6.56 (1, s), 7.04 (1, s), 7.21 (2, d, J = 8.4 z), 7.58 (2, d, J = 8.4 z); 13 C MR (100 Mz, CDCl 3 ) δ 148.0, 147.7, 147.4, 147.3, 139.4, 138.8, (2C), (2C), (2C), (2C), 111.4, 111.2, 109.2, 108.9, 56.2 (2C), 56.1, 55.9, 55.8, 53.6, 52.3, 41.6, 40.4, 37.9, 36.8, 36.1, 30.9, 29.2, 24.5, 23.6, 11.1; ESI-TF-MS m/z , ([C Cl 2 6 S + ] + calcd ). t R is min (100% purity). S13
14 S 12 2-[6,7-Dimethoxy-2-(4-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinolin-1- ylmethyl]-3-ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyridol[2,1-a]isoquinoline (12) The product was purified using flash column chromatography with of 5% in C 2 Cl 2. Yield: 81%, mp = o C; 1 MR (400 Mz, CDCl 3 ) δ 0.87 (3, t, J = 7.4 z), (2, m), (1, m), (1, m), (2, m), (1, m), (1, m), 2.21 (1, t, J = 12.2 z), (2, m), (1, m), 2.63 (1, d, J = 15.7 z), (1, m), (3, m), (1, m), 3.74 (3, s), 3.75 (3, s), 3.84 (3, s), 3.85 (3, s), 3.88 (3, s), (1, m), 5.14 (1, dd, J = 3.5, 11.7 z), 6.24 (1, s), 6.44 (1, s), 6.58 (1, s), 6.71 (2, d, J = 8.9 z), 7.07 (1, s), 7.59 (2, d, J = 8.9 z) 13 C MR (100 Mz, CDCl 3 ) δ 162.6, 147.7, 147.6, 147.5, 147.4, (2C), (2C), 129.2, (2C), 114.2, 114.1, 111.4, 111.3, 111.1, 110.1, 56.2 (2C), 56.0, 55.9, 55.8, 55.5, 53.2, 52.3, 48.9, 42.9, 39.7, 38.2, 36.7, 36.2, 29.2, 24.6, 23.7, ESI-TF-MS m/z , ([C S + ] + calcd ). t R is 9.55 min (100% purity). S14
15 a +- S S 13 Sodium 1-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1-a]isoquinolin-2- ylmethyl)-6,7-dimethoxy-3,4-dihydro-1-isoquinoline-2-carbodithioate (13). A solution of a (240 mg, 6.00 mmol) in water (1.00 ml) and ethanol (20.00 ml) was added to a solution of emetine dihydrochloride hydrate (1.11 g, 2.00 mmol) in ethanol (10.0 ml) at -8 o C. This was stirred at this temperature for 15min after which CS 2 (0.30 ml, 4.97 mmol) was added. The resulting mixture was stirred at -5 to 1 o C for 2 h and at room temperature for 30 min. The solvent was removed in-vacuo and the residue triturated with acetonitrile and then filtered. The filtrate was evaporated to dryness and the residue dissolved in ethyl acetate (3 ml). To this was added diethyl ether to precipitate 13 as a white solid (950 mg, 82%). Mp: o C; 1 MR (400 Mz, CD 3 D) δ 0.93 (3, t, J = 7.4 z), (1, m), (2, m), (2, m), (1, m), 2.10 (1, t, J = 11.0 z), 2.38 (1, t, J = 12.8 z), 2.50 (1, tb, J = 4.1, 11.6 z ), (2, m), (5, m), 3.35 (1, s), (1, m) 3.80 (3, s), 3.81 (6, br s), 3.84 (3, s), 5.95 (1, dd, J = 5.9, 12.8 z), 6.66 (1, s), 6.69 (1, s), 6.72 (1,s), 7.20 (1,s), 7.25 (1, dd, J = 3.6, 11.8 z). 13 C MR (100 Mz, CD 3 D) δ 216.5, 147.4, 147.3, 147.2, 147.1, 133.0, 131.1, 127.0, 126.5, 112.6, 112.0, 111.0, 110.3, 65.4, 63.3, 61.6, 58.0, 56.5, 56.2, 56.1, 56.0, 55.9, 52.5, 41.7, 41.3, 37.6, 29.4, 27.3, 23.7, MALDI- MS m/z ([C a 4 S 2 + a] + calcd ). S15
16 S S 14 1-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1-a]isoquinolin-2- ylmethyl)-6,7-dimethoxy-3,4-dihydro-1-isoquinoline-2-carbodithioic acid benzyl ester (14): Compound 13 (200 mg, 0.35 mmol) was dissolved in acetonitrile (15 ml) and to this was added a solution of benzyl bromide (0.27 mmol.) in acetonitrile (5 ml). The reaction mixture was stirred for 24 h at room temperature. Solvent was evaporated in vacuo and the residue obtained triturated with water (20 ml), and filtered under suction. The crude product was airdried and then purified by flash chromatography on silica gel using EtAc: (10:1) as eluent. Yield: 45%, mp = o C; 1 MR (400 Mz, CDCl 3 ) δ 0.89 (3, t, J = 7.4 z), (1, m), (3, m), (1, m), (1, m), (1, m), 2.05 (1, t, J = 11.0 z), (2, m), 2.62 (1, d, J = 14.9 z), (1, m), (1, m), (4, m), 3.35 (1, s), (1, m), 3.80 (3, s), 3.84 (3, s), 3.91 (3, s), 3.95 (3, s), 4.54 (1, d, J = 13.1 z), 4.63 (1, d, J = 13.1 z), 6.56 (1, s), 6.58 (2, s), 6.86 (1, dd, J = 3.8, 11.3 z), 6.93 (1, s), (3, m), 7.38 (2, d, J = 6.7 z); 13 C MR (100 Mz, CDCl 3 ) δ 197.1, 148.3, 148.0, 147.8, 147.4, 147.3, 135.8, 135.3, 130.0, 129.5, 128.3, 127.8, 127.6, 126.2, 124.6, 111.5, 111.3, 111.0, 108.8, 62.8, 62.3, 61.4, 56.3, 56.1, 56.0, 55.9, S16
17 52.4, 52.3, 45.2, 43.4, 42.0, 38.9, 37.7, 29.7, 28.0, 23.8, 11.2; ESI-TF-MS m/z ([C S 2 + ] + calcd ). t R is min (98% purity) (3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1-a]isoquinolin-2- ylmethyl)-6,7-dimethoxy-3,4-dihydro-1-isoquinoline-2-carboxylic acid benzyl ester (15): Yield: 46%, mp = o C; 1 MR (400 Mz, CDCl 3 ) δ 0.88 (3, t, J = 7.6 z), (2, m), (7, m), (1, m), (1, m), (1, m), (1, m), (1, m), (1, m), (1, m), (3, m), 3.84 (3, s), 3.89 (6, s), 3.96 (3, s), (1, m), 5.14 (1, d, J = 12.6 z), 5.24 (1, d, J = 12.6 z), 6.56 (1, s), 6.58 (1, s), 6.62 (1, s), 6.98 (1, s), (2, m), (3, m); 13 C MR (100 Mz, CDCl 3 ) δ 9.3, 22.3, 27.0, 29.3, 31.8, 33.1, 37.3, 38.7, 51.1, 52.2, 53.4, 53.8, 55.9, 56.0, 56.1 (2C), 59.7, 67.1, 108.3, 109.4, 111.1, 111.5, 127.7, 127.8, 127.9, 128.5, 128.8, (2C), (2C), 139.2, 147.0, 147.8, 148.4, 148.7, 155.5; MALDI-MS m/z , ([C ] + calcd ). t R is min (100 % purity). S17
18 General Reaction procedure for all the amide analogues of emetine A solution of emetine dihydrochloride (500 mg, 0.89 mmol) in chloroform (10 ml) and triethylamine (2 ml) was stirred for about 5 minutes. To this was added a solution of the appropriate anhydride (3.55 mmol) in chloroform. The reaction mixture was stirred at room temperature for 12 to 20 h. All volatiles and solvent was evaporated in-vacuo from the reaction mixture to obtain a crude solid. Purification methods vary slightly from one analog to another and these are specified below. For compounds 20 and 21 the crude product was dissolved in chloroform (40 ml). This was washed with water (2 x 15 ml) with gentle shaking, brine (1 x 15 ml), dried over anhydrous MgS 4 and the solvent evaporated in vacuo. The residue was dissolved in ethyl acetate (2-4 ml) and pure product was obtained by precipitation with 20% diethyl ether in hexanes at 0 to 10 o C. Product was filtered and washed with cold (0 to 5 o C) 20% ether in hexanes. The solid isolated was further dried in a vacuum oven at 60 o C for 4 hour. 20 S18
19 ylmethyl)-6,7-dimethoxy-3,4-dihydro-1-isoquinolin-2-yl]-4-oxo-butyric acid (20): Yield. 90%, white solid, mp = o C; 1 MR (400 Mz, CD 3 D) δ 0.81 (3, t, J = 7.5 z), (3, m), (2, m), (1, m), 2.14 (1, t, J = 12.4 z), 2.29 (1, t, J = 11.6 z), (2, m), (2, m), (3, m), (1, m), (1, m), (1, m), (1, m), (2, m), (2, m), 3.66 (3, s), 3.68 (3, s), 3.69 (3, s), 3.77 (3, s), 3.98 (1, dd, J = 5.0, 13.5 z), 5.66 (1, dd, J = 3.8, 11.6 z), 6.58 (1, s), 6.59 (1, s), 6.60 (1, s), 6.84 (1, s); 13 C MR (100 Mz, CD 3 D) δ 11.2, 24.3, 28.7, 29.6, 30.6, 30.9, 33.6, 37.0, 38.3, 40.0, 49.7 (2C), 52.8, 55.8, 56.5, 56.6, 56.8, 57.0, 64.2, 110.6, 111.9, 113.0, 113.5, 126.6, 127.1, 129.5, 131.7, 149.3, 149.4, 149.5, 149.6, 174.3, ESI-TF-MS m/z , ([C ] + calcd ). t R is 3.05 min (97.5% purity) [1-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1-a]isoquinolin-2-4-[1-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1-a]isoquinolin-2- ylmethyl)-6,7-dimethoxy-3,4-dihydro-1-isoquinolin-2-yl]-4-oxo-but-2-enoic acid (21): Yield. 90%, white solid, mp = o C 1 MR (400 Mz, CD 3 D) δ 0.86 (3, t, J = 7.1 z), (3, m), (4, m), (1, m), 2.23 (1, t, J = 12.8 z), 2.67 S19
20 (1, br d, J = 12.9 z), (5, m), (1, m), (3, m), 3.82 (4, s), 3.83 (4, s), 3.86 (4, s), 4.07 (1, dd, J = 2.4, 7.1 z), 5.70 (1, br d, J = 8,6 z), 6.10 (1, dd, J = 3.0, 11.9 z), 6.31 (1, dd, J = 3.0, 11.9 z), 6.49 (1, s), 6.51 (1, s), 6.55 (1, s), 6.87 (1, s). 13 C MR (100 Mz, CDCl 3 ) δ 10.3, 22.7, 26.3, 28.4, 34.7 (2C), 35.4, 38.4, 39.4, 45.3, 48.5 (2C), 55.8, 55.9, 56.1, 56.2, 60.4, 109.3, 109.8, 110.8, 111.6, (2C), (2C), 132.5, 135.7, 147.7, 147.9, 148.2, 148.4, 167.2, 169.5; MALDI-MS m/z , ([C ] + calcd ). t R is 3.30 min (99.5% purity) [1-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1-a]isoquinolin-2- ylmethyl)-6,7-dimethoxy-3,4-dihydro-1-isoquinolin-2-yl]-2-methyl-4-oxo-but-2-enoic acid (22): After precipitation with 20% diethyl ether in hexanes, compound 22 was further purified by flash chromatography on silica gel using gradient elution beginning with 100% ethyl acetate followed by an eluent mixture of 50% methanol in ethyl acetate to remove all less polar impurities and 100% methanol eluted compound 22. S20
21 Yield. 94%, pale yellow solid, mp = o C; 1 MR (400 Mz, CDCl 3 ) δ 0.84 (3, t, J = 7.4 z), (2, m), (4, m), 1.98 (3, s), 2.17 (1, t, J = 12.7 z), (2, m), (4, m), (3, m), (2, m), 3.84 (9, s), 3.85 (3, s), 4.03 (1, dd, J = 5.8, 13.8 z), 5.73 (1, br d, J = 10.8 z), 6.10 (1, br s), 6.50 (1, s), 6.56 (2, s), 6.57 (1, s), 6.79 (1, br s); 13 C MR (100 Mz, CDCl 3 ) δ 8.7, 10.9, 21.3, 28.7, 36.3, 37.0 (2C), 38.9, 40.0, 45.1 (2C), 48.8 (2C), 56.0, 56.1, 56.3 (2C), 56.4, 109.2, 110.2, 111.2, 111.8, (2C), (3C), (2C), 147.8, 148.0, 148.2, 167.9, 170.2; MALDI-MS m/z , ([C ] + calcd ). t R is 3.72 min (91.5% purity). In order to convert compounds to their respective sodium salt, each compound was dissolved in chloroform (25 ml) and the solution was washed gently with 0.1 a solution (2 x 20 ml). The organic phase was then washed gently with water (1 x 20 ml), brine (2 x 15 ml), dried over anhydrous MgS 4 and the solvent evaporated in-vacuo at a temperature not greater than 45 o C. For compound 24, the residue obtained was further dissolved in ethyl acetate (1.0 ml) and the product precipitated by adding hexanes (15-20 ml). The precipitate was filtered under vacuum and washed with hexanes (15 ml). The solid product obtained was dried under vacuum at 70 o C for 4 hours. The proton and C-13 MR of are identical to that of respectively. S21
22 a Sodium 4-[1-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1- a]isoquinolin-2-ylmethyl)-6,7-dimethoxy-3,4-dihydro-1-isoquinolin-2-yl]-4-oxo-butyrate (24): Yield. 88%, white solid, mp = o C; 1 MR (400 Mz, CD 3 D) δ 0.81 (3, t, J = 7.5 z), (3, m), (2, m), (1, m), 2.14 (1, t, J = 12.4 z), 2.29 (1, t, J = 11.6 z), (2, m), (2, m), (3, m), (1, m), (1, m), (1, m), (1, m), (2, m), (2, m), 3.66 (3, s), 3.68 (3, s), 3.69 (3, s), 3.77 (3, s), 3.98 (1, dd, J = 5.0, 13.5 z), 5.66 (1, dd, J = 3.8, 11.6 z), 6.58 (1, s), 6.59 (1, s), 6.60 (1, s), 6.84 (1, s). 13 C MR (100 Mz, CD 3 D) δ 11.2, 24.3, 28.7, 29.6, 30.6, 30.9, 33.6, 37.0, 38.3, 40.0, 49.7 (2C), 52.8, 55.8, 56.5, 56.6, 56.8, 57.0, 64.2, 110.6, 111.9, 113.0, 113.5, 126.6, 127.1, 129.5, 131.7, 149.3, 149.4, 149.5, 149.6, 174.3, 180.9; MALDI-MS m/z , ([C ] + calcd ). t R is 3.05 min (97.5% purity). S22
23 a Sodium 4-[1-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1- a]isoquinolin-2-ylmethyl)-6,7-dimethoxy-3,4-dihydro-1-isoquinolin-2-yl]-4-oxo-but-2- enoate (25): Yield. 79%, white solid, mp = o C; 1 MR (400 Mz, CD 3 D) δ 0.86 (3, t, J = 7.1 z), (3, m), (4, m), (1, m), 2.23 (1, t, J = 12.8 z), 2.67 (1, br d, J = 12.9 z), (5, m), (1, m), (3, m), 3.82 (4, s), 3.83 (4, s), 3.86 (4, s), 4.07 (1, dd, J = 2.4, 7.1 z), 5.70 (1, br d, J = 8,6 z), 6.10 (1, dd, J = 3.0, 11.9 z), 6.31 (1, dd, J = 3.0, 11.9 z), 6.49 (1, s), 6.51 (1, s), 6.55 (1, s), 6.87 (1, s); 13 C MR (100 Mz, CDCl 3 ) δ 10.3, 22.7, 26.3, 28.4, 34.7 (2C), 35.4, 38.4, 39.4, 45.3, 48.5 (2C), 55.8, 55.9, 56.1, 56.2, 60.4, 109.3, 109.8, 110.8, 111.6, (2C), (2C), 132.5, 135.7, 147.7, 147.9, 148.2, 148.4, 167.2, 169.5; MALDI-MS m/z , ([C ] + calcd ). t R is 3.30 min (99.5% purity). S23
24 a Sodium 4-[1-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2,1- a]isoquinolin-2-ylmethyl)-6,7-dimethoxy-3,4-dihydro-1-isoquinolin-2-yl]-2-methyl-4-oxobut-2-enoate (26): Yield. 80%, pale yellow solid, mp = o C; 1 MR (400 Mz, CDCl 3 ) δ 0.84 (3, t, J = 7.4 z), (2, m), (4, m), 1.98 (3, s), 2.17 (1, t, J = 12.7 z), (2, m), (4, m), (3, m), (2, m), 3.84 (9, s), 3.85 (3, s), 4.03 (1, dd, J = 5.8, 13.8 z), 5.73 (1, br d, J = 10.8 z), 6.10 (1, br s), 6.50 (1, s), 6.56 (2, s), 6.57 (1, s), 6.79 (1, br s); 13 C MR (100 Mz, CDCl 3 ) δ 8.7, 10.9, 21.3, 28.7, 36.3, 37.0 (2C), 38.9, 40.0, 45.1 (2C), 48.8 (2C), 56.0, 56.1, 56.3 (2C), 56.4, 109.2, 110.2, 111.2, 111.8, (2C), (3C), (2C), 147.8, 148.0, 148.2, 167.9, 170.2; MALDI-MS m/z , ([C ] + calcd ). t R is 3.72 min (91.5% purity). a + - a S24
25 Disodium 2-{2-[1-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2-pyrido[2, 1 a]isoquinolin-2-ylmethyl)-6,7-dimethoxy-3,4-dihydro-1-isoquinolin-2-yl]-2-oxoethylidene}-succinate (27): Yield. 79%, yellow solid, mp = o C; 1 MR (400 Mz, DMS-d6) δ 0.83 (3, t, J = 7.4 z), (4, m), (2, m), (2, m), (1, m), 2.11 (1, t, J = 12.5 z), 2.33 (1, br s), (3, m), (4, m), 3.19 (2, s), 3.70 (9, s), 3.80 (3, s), (1, m), 5.62 (1, d, J = 7.8 z), 5.79 (1, br s), 6.63 (1, s), 6.67 (1, s), 6.78 (1, s), 6.82 (1, s); 13 C MR (100 Mz, CDCl 3 ) δ 10.3, 22.7, 22.9, 34.7, 36.1, 38.4, 39.1 (2C), 40.0, 45.6 (2C), 48.2, 51.1, 55.9, 56.1, 56.2, 56.3, 56.6, 108.8, 109.8, 111.1, 111.5, 124.2, 127.3, (2C), 138.2, 147.9, 148.1, 148.2, 148.3, 148.4, 169.9, 171.6, 172.0; MALDI-MS m/z , ([C ] + calcd ). t R is 2.60 min (95.2 % purity). PLC assay for evaluating the p-responsiveness of emetine analogs PLC method 2 was used for this study. Some of the synthetic analogs of emetine (compounds 5, 12, 13, 20-27) were selected to be evaluated for p responsiveness. To each of three different 9 ml vials marked A, B, and C was weighed 2 mg of each analog. Aqueous phosphate solutions (2 ml, 0.1 M) buffered at p s 5.5, 6.5 and 7.4 was added to dissolve the sample in each of vials A, B and C, respectively, affording sample solutions of concentration 1.0 mg/ml. Compounds 5, 12 and 24 were not expected to be p responsive under the slightly acidic conditions employed in this study. owever, in order to confirm our hypothesis they were also evaluated. All samples were incubated at 37 o C and aliquots were removed at various time points and analysed by S25
26 PLC. Data from the chromatograms obtained are shown in Supporting Table 1 and Supporting Table 2. Supporting Table 1: p- Responsiveness of emetine pro-drugs 13, 21, 22, 25, 26 and 27 in aqueous solutions of p 5.5 and 6.5; and stability in aqueous solutions of p 7.4 to 8.0. % Emetine = Percent composition of emetine in the mixture due to acid initiated hydrolysis at different time points after incubation at 37 o C. Compounds %Emetine at p 5.5 at different time points %Emetine at p 6.5 at different time points % Emetine at p 7.4 to 8.0 over 72 hrs 0 hr 24 hrs 48 hrs 0 hr 24 hrs 48 hrs 0 hrs 24 hrs 48hrs % 55.9% 94.5% 0.0% 5.2% 13.2% 0.0% 0.0% 0.0% % % 35.5% 52.1% 0.0% 0.0% 0.0% % % 76.8% 82.7% 0.0% 0.0% 0.0% % 19.2% 27.1% 0.0% 8.2% 17.1% 0.0% 0.0% 0.0% % 61.5% 77.3% 0.0% 24.9% 49.2% 0.0% 0.0% 0.0% % 33.9% 42.1% 0.0% 13.4% 21.1% 0.0% 0.0% 0.0% S26
27 Supporting Table 2: Stability of emetine analogs 5, 12 and 24 in aqueous solutions of p 5.5 and 7.4 over a period of 72 hrs at 37 o C. These compounds are not expected to be p-responsive at mildly acidic p of 5.5 and the duration of incubation employed for this study. % Emetine = Percent composition of emetine in the mixture due to acid initiated hydrolysis at different time points after incubation at 37 o C. Compounds % Emetine at p 5.5 at different time points % Emetine at p 7.4 at different time points 24 hrs 48hrs 72 hrs 24 hrs 48hrs 72 hrs 5 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 0.0% 0.0% 0.0% 0.0% % 0.0% 3.0% 0.0% 0.0% 0.0% Biological Assays Cytotoxicity Assay General information The human androgen independent and dependent prostate cancer cell lines PC3 and LCaP respectively were purchased from the American Type Culture Collection (Manassas, VA). All cells were grown in cell culture flasks in RPMI culture medium with phenol red (GIBC) supplemented with only 10% fetal bovine serum, 1% L-glutamine and 1% Penicillin- Streptomycin. Cells were cultured in a humidified atmosphere of 95% air and 5% carbon dioxide at 37 o C. To sub-culture cells for experiments, cells growing as monolayer cultures were S27
28 released from the tissue culture flasks by treatment with 0.05% trypson/edta. Cell population density was determined with aid of coulter counter (Beckman) and/or hemocytometer. For all the in-vitro experiments, cells were used during the logarithmic growth phase. Screening of emetine analogs for cytotoxicity in LCaP and PC3 cell lines. For the initial determination of the cytotoxicity of emetine and its analogs in LCaP and PC3, the cells were plated at a density of 6 X 10 3 in 100 µl of medium per well and 2.5 X 10 3 in 100 µl medium per well respectively in 96-well plates. These cells were incubated for 24 hours to allow attachment to the tissue culture plates. Serial dilutions (0.02 mm, 0.1 mm, 0.2 mm, 2 mm, 10 mm, 20 mm) of each drug (emetine and its analogs) were made in sterile DMS and these were further diluted to micromolar scale (0.02 µm, 0.1 µm, 0.2 µm, 2 µm, 10 µm, 20 µm) using RPMI medium. 100 µl of each drug concentration was added in eight replicates to cells in the 96 well-plate providing final drug concentrations of 0.01 µm, 0.05 µm, 0.1 µm, 1 µm, 5 µm, and 10 µm respectively of each drug and uniform DMS concentration of 0.1% v/v in all drug-treated medium. A vehicle and blank control of 0.2% v/v and 0.0% v/v DMS in RPMI medium were made and 100 µl of these was also added in eight replicates to the cells plated in 100 µl of medium in the 96 well-plate. Thus, the vehicle control is 0.1% DMS and blank control is 0% DMS. Each experiment was repeated at least twice. Population of viable cells was determined on day zero and each of the 3 rd, 5 th, and 7 th day of incubating the cells with the drugs using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay. S28
29 The Cell Titer 96 on-radioactive Cell Proliferation Assay produced by Promega Corporation was employed for this study. This is based on cellular conversion of a tetrazolium salt into a formazan product that can be measured easily using a 96-well plate reader. To carry out each cell proliferation assay, spent medium was removed from the cells on each of day zero, 3 rd, 5 th and 7 th day. 100 µl of fresh culture medium was added to each well followed by 15 µl Promega Dye Solution. This was incubated for 3 hours at 37 o C followed by addition of 100 µl of Solubilization/Stop Solution to each well and incubation at room temperature for 1 hour. Absorbance was recorded at 570 nm using SpectraMax Plus384 absorbance micro-plate reader (Molecular Devices). In both the vehicle and blank control, the growth of LCaP and PC3 were found to be in the logarithmic phase from day zero to the 7 th day. Further, for each cell line, both the vehicle and blank control have equal quantitative proliferation rate in all assays carried out (Supporting Figure 1). A. B. S29
30 Supporting Figure 1. Growth curve of LCaP (A) and PC3 (B) treated with 0.1% v/v DMS in culture medium (Vehicle control) and 0.0% v/v DMS in RPMI culture medium (Blank control). This is monitored over a 7-day period. This indicates that cell death does not result from 0.1% v/v DMS concentration in RPMI culture medium. Proliferation of these cells is in the logarithmic growth phase. IC 50 values were calculated based on the vehicle control for both cell lines. In vivo toxicity study to establish the safety of the prodrug of emetine in mice Mice were purchased from Taconic. Mouse care and treatment was done in line with the guidelines of the Animal Care and Use Committee of the Johns opkins University School of Medicine. Eight weeks old male Balb/c mice were injected intravenously with different doses of emetine, 13 and 26. Each drug was given to the mice at doses 33 mg/kg, and 100 mg/kg, and each experiment or dosage was done in triplicate. Drug solutions were made in 1% DMS in saline, and mice received 0.2 ml bolus of each dose per day for five days. Mice in the control experiment received 0.2 ml of 1% DMS in saline at every dosage. References 1. Wong, R.; Dolman, S. J. Isothiocyanates from tosyl chloride mediated mediated decomposition of in situ generated dithiocarbamic acid salts. J. rg. Chem. 2007, 72, S30
31 2. Sigurdsson, S. T.; Seeger, B.; Kutzke, U.; Eckstein, F. A mild and simple method for the preparation of isocyanates from aliphatic amines using trichloromethyl chloroformate. synthesis of an isocyanate containing an activated disulfide. J. rg. Chem. 1996, 72, S31
Electronic Supplementary Information
Electronic Supplementary Material (ESI) for ChemComm. This journal is The Royal Society of Chemistry 2015 Electronic Supplementary Information ovel pseudo[2]rotaxanes constructed by selfassembly of dibenzyl
More informationSupporting Information. Efficient copper-catalyzed Michael addition of acrylic derivatives with primary alcohols in the presence of base
Supporting Information Efficient copper-catalyzed Michael addition of acrylic derivatives with primary alcohols in the presence of base Feng Wang, a Haijun Yang, b Hua Fu, b,c * and Zhichao Pei a * a College
More informationSynthetic chemistry-led creation of a difluorinated biaryl ether non-nucleoside reverse transcriptase inhibitor
upplementary Material for rganic & Biomolecular Chemistry ynthetic chemistry-led creation of a difluorinated biaryl ether non-nucleoside reverse transcriptase inhibitor Lyn. Jones* Amy Randall, scar Barba
More informationSupporting Information. for. Access to pyrrolo-pyridines by gold-catalyzed. hydroarylation of pyrroles tethered to terminal alkynes
Supporting Information for Access to pyrrolo-pyridines by gold-catalyzed hydroarylation of pyrroles tethered to terminal alkynes Elena Borsini 1, Gianluigi Broggini* 1, Andrea Fasana 1, Chiara Baldassarri
More informationSupporting Information. Radical fluorination powered expedient synthesis of 3 fluorobicyclo[1.1.1]pentan 1 amine
Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry. This journal is The Royal Society of Chemistry 2015 Supporting Information Radical fluorination powered expedient synthesis
More informationph Switchable and Fluorescent Ratiometric Squarylium Indocyanine Dyes as Extremely Alkaline Sensors
ph Switchable and Fluorescent Ratiometric Squarylium Indocyanine Dyes as Extremely Alkaline Sensors Jie Li, Chendong Ji, Wantai Yang, Meizhen Yin* State Key Laboratory of Chemical Resource Engineering,
More informationSolid Phase Peptide Synthesis (SPPS) and Solid Phase. Fragment Coupling (SPFC) Mediated by Isonitriles
Solid Phase Peptide Synthesis (SPPS) and Solid Phase Fragment Coupling (SPFC) Mediated by Isonitriles Ting Wang a and Samuel J. Danishefsky a,b,* alaboratory for Bioorganic Chemistry, Sloan- Kettering
More informationUse of degradable cationic surfactants with cleavable linkages for enhancing the. chemiluminescence of acridinium ester labels. Supplementary Material
Use of degradable cationic surfactants with cleavable linkages for enhancing the chemiluminescence of acridinium ester labels Supplementary Material Anand atrajan*and David Wen Siemens Healthcare Diagnostics
More informationThiol-Activated gem-dithiols: A New Class of Controllable. Hydrogen Sulfide (H 2 S) Donors
Thiol-Activated gem-dithiols: A New Class of Controllable Hydrogen Sulfide (H 2 S) Donors Yu Zhao, Jianming Kang, Chung-Min Park, Powell E. Bagdon, Bo Peng, and Ming Xian * Department of Chemistry, Washington
More informationSupporting Information for. Boronic Acid Functionalized Aza-Bodipy (azabdpba) based Fluorescence Optodes for the. analysis of Glucose in Whole Blood
Supporting Information for Boronic Acid Functionalized Aza-Bodipy (azabdpba) based Fluorescence Optodes for the analysis of Glucose in Whole Blood Yueling Liu, Jingwei Zhu, Yanmei Xu, Yu Qin*, Dechen Jiang*
More informationZinc Chloride Promoted Formal Oxidative Coupling of Aromatic Aldehydes and Isocyanides to α- Ketoamides
Supporting information for Zinc Chloride Promoted Formal xidative Coupling of Aromatic Aldehydes and Isocyanides to α- Ketoamides Marinus Bouma, Géraldine Masson* and Jieping Zhu* Institut de Chimie des
More informationMasatoshi Shibuya,Takahisa Sato, Masaki Tomizawa, and Yoshiharu Iwabuchi* Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Oxoammonium ion/naclo 2 : An Expedient, Catalytic System for One-pot Oxidation of Primary Alcohols to Carboxylic Acid with Broad Substrate Applicability Masatoshi Shibuya,Takahisa Sato, Masaki Tomizawa,
More informationAll chemicals were obtained from Aldrich, Acros, Fisher, or Fluka and were used without
Supplemental Data Alexander et al. Experimental Procedures General Methods for Inhibitor Synthesis All chemicals were obtained from Aldrich, Acros, Fisher, or Fluka and were used without further purification,
More informationSupporting Information
Electronic Supplementary Material (ESI) for MedChemComm. This journal is The Royal Society of Chemistry 2015 Supporting Information Synthesis and Biological Evaluation of D- gluconhydroximo-1, 5-lactam
More informationRameshwar Prasad Pandit and Yong Rok Lee * School of Chemical Engineering, Yeungnam University, Gyeongsan , Korea
Electronic Supplementary Material (ESI) for rganic & Biomolecular Chemistry. This journal is The Royal Society of Chemistry 2014 Novel ne-pot Synthesis of Diverse γ,δ-unsaturated β-ketoesters by Thermal
More informationSupporting Information
Supporting Information Synthesis and biological evaluation of Aryl-hospho-Indole (AI) as novel IV-1 non-nucleoside reverse transcriptase inhibitors. François-René Alexandre a *, Agnès Amador a, Stéphanie
More informationSupporting Information. for. Pd-catalyzed decarboxylative Heck vinylation of. 2-nitro-benzoates in the presence of CuF 2
Supporting Information for Pd-catalyzed decarboxylative Heck vinylation of 2-nitro-benzoates in the presence of CuF 2 Lukas J. Gooßen*, Bettina Zimmermann, Thomas Knauber Address: Department of Chemistry,
More informationSupporting Information
Supporting Information Wiley-VCH 2008 69451 Weinheim, Germany Supporting Information Enantioselective Cu-catalyzed 1,4-Addition of Various Grignard Reagents to Cyclohexenone using Taddol-derived Phosphine-Phosphite
More informationSupporting Information
Electronic Supplementary Material (ESI) for ChemComm. This journal is The Royal Society of Chemistry 2015 Supporting Information Enzyme-activatable Probe with a Self-immolative Linker for Rapid and Sensitive
More informationSupporting Information
Supporting Information Unconventional Passerini Reaction towards α-aminoxyamides Ajay L. Chandgude, Alexander Dömling* Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV
More informationSupporting Information. for. Synthesis of 2,1-benzisoxazole-3(1H)-ones by basemediated. photochemical N O bond-forming
Supporting Information for Synthesis of 2,1-benzisoxazole-3(1H)-ones by basemediated photochemical N O bond-forming cyclization of 2-azidobenzoic acids Daria Yu. Dzhons and Andrei V. Budruev* Address:
More informationChristophe Lincheneau, Bernard Jean-Denis and Thorfinnur Gunnlaugsson* Electronic Supplementary Information
Self-assembly formation of mechanically interlocked [2]- and [3]catenanes using lanthanide ion [Eu(III)] templation and ring closing metathesis reactions Christophe Lincheneau, Bernard Jean-Denis and Thorfinnur
More informationSupporting Materials. Experimental Section. internal standard TMS (0 ppm). The peak patterns are indicated as follows: s, singlet; d,
CuBr-Catalyzed Efficient Alkynylation of sp 3 C-H Bonds Adjacent to a itrogen Atom Zhiping Li and Chao-Jun Li* Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, Quebec H3A
More informationDevelopment of a near-infrared fluorescent probe for monitoring hydrazine in serum and living cells
Supporting Information for Development of a near-infrared fluorescent probe for monitoring hydrazine in serum and living cells Sasa Zhu, Weiying Lin,* Lin Yuan State Key Laboratory of Chemo/Biosensing
More informationSUPPLEMENTAL FIGURE 1 Structures and IC50 values of compounds 13 32
SUPPLEMETAL FIGURE 1 Structures and IC50 values of compounds 13 32 THE JURAL F UCLEAR MEDICIE Vol. 53 o. 11 ovember 2012 Synthesis of [ 19 F]1 ([ 19 F]--(2-{4-[5-(benzyloxy)pyridin-2-yl]piperazin-1-yl}-2-oxoethyl)-
More informationSupporting Information. Copyright Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2007
Supporting Information Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2007 Supporting Information General. NMR spectra for identification of intermediates and final compoundswere recorded
More informationSynthesis and Blastocyst Implantation Inhibition Potential of Lupeol Derivatives in Female Mice
Supporting Information Rec. Nat. Prod. 9:4 (2015) 561-566 Synthesis and Blastocyst Implantation Inhibition Potential of Lupeol Derivatives in Female Mice Anita Mahapatra 1*, Purvi Shah 1, Mehul Jivrajani
More informationPreparation, isolation and characterization of N α -Fmoc-peptide isocyanates: Solution synthesis of oligo-α-peptidyl ureas
SUPPORTING INFORMATION Preparation, isolation and characterization of N α -Fmoc-peptide isocyanates: Solution synthesis of oligo-α-peptidyl ureas Vommina V. Suresh Babu*, Basanagoud S. Patil, and Rao Venkataramanarao
More informationSchwartz s reagent-mediated regiospecific synthesis of 2,3-disubstituted indoles from isatins
Electronic Supplementary Information (ESI) Schwartz s reagent-mediated regiospecific synthesis of 2,3-disubstituted indoles from isatins A. Ulikowski and B. Furman* Institute of Organic Chemistry, Polish
More informationElectronic Supplementary Material
Electronic Supplementary Material PAMAM Dendrimers Bearing Electron-Donating Chromophores: Fluorescence and Electrochemical Properties Bing-BingWang a, Xin Zhang a, Ling Yang a, Xin-Ru Jia* a, Yan Ji a,
More informationAnalytical Method for 2, 4, 5-T (Targeted to Agricultural, Animal and Fishery Products)
Analytical Method for 2, 4, 5-T (Targeted to Agricultural, Animal and Fishery Products) The target compound to be determined is 2, 4, 5-T. 1. Instrument Liquid Chromatograph-tandem mass spectrometer (LC-MS/MS)
More informationManganese powder promoted highly efficient and selective synthesis of fullerene mono- and biscycloadducts at room temperature
Supplementary Information Manganese powder promoted highly efficient and selective synthesis of fullerene mono- and biscycloadducts at room temperature Weili Si 1, Xuan Zhang 1, Shirong Lu 1, Takeshi Yasuda
More informationEnantioselective synthesis of anti- and syn-β-hydroxy-α-phenyl carboxylates via boron-mediated asymmetric aldol reaction
Enantioselective synthesis of anti- and syn-β-hydroxy-α-phenyl carboxylates via boron-mediated asymmetric aldol reaction P. Veeraraghavan Ramachandran* and Prem B. Chanda Department of Chemistry, Purdue
More informationSupporting Information
Electronic Supplementary Material (ESI) for rganic Chemistry Frontiers. This journal is the Partner rganisations 2016 Supporting Information Fangyi Li, Changgui Zhao, and Jian Wang* Department of Pharmacology
More informationLewis acid-catalyzed regioselective synthesis of chiral α-fluoroalkyl amines via asymmetric addition of silyl dienolates to fluorinated sulfinylimines
Supporting Information for Lewis acid-catalyzed regioselective synthesis of chiral α-fluoroalkyl amines via asymmetric addition of silyl dienolates to fluorinated sulfinylimines Yingle Liu a, Jiawang Liu
More informationSupporting Information
Supporting Information Synthesis of N-Heteropolycyclic Compounds Including Quinazolinone Skeletons by Using Friedel-Crafts Alkylation Bu Keun Oh, Eun Bi Ko, Jin Wook Han* and Chang Ho Oh* Department of
More informationRuthenium-Catalyzed C H Oxygenation on Aryl Weinreb Amides
Supporting Information Ruthenium-Catalyzed C H xygenation on Aryl Weinreb Amides Fanzhi Yang and Lutz Ackermann* Institut für rganische und Biomolekulare Chemie Georg-August-Universität Tammannstrasse
More informationAn Unusual Glycosylation Product from a Partially Protected Fucosyl Donor. under Silver Triflate activation conditions. Supporting information
An Unusual Glycosylation Product from a Partially Protected Fucosyl Donor under Silver Triflate activation conditions Robin Daly a and Eoin M. Scanlan* a e-mail: eoin.scanlan@tcd.ie a Trinity Biomedical
More informationTenofovir disoproxil fumarate (Tenofoviri disoproxili fumaras)
C 19 H 30 N 5 O 10 P. C 4 H 4 O 4 Relative molecular mass. 635.5. Chemical names. bis(1-methylethyl) 5-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}-5-oxo-2,4,6,8-tetraoxa-5-λ 5 - phosphanonanedioate
More informationAcyl Radical Reactions in Fullerene Chemistry: Direct Acylation of. [60]Fullerene through an Efficient Decatungstate-Photomediated Approach.
Supporting information Acyl Radical Reactions in Fullerene Chemistry: Direct Acylation of [60]Fullerene through an Efficient Decatungstate-Photomediated Approach. Manolis D. Tzirakis and Michael rfanopoulos
More informationSupplementary Materials Contents
Supplementary Materials Contents Supporting information... S1 1. General Information & Materials... S2 2. General Procedure for ptimization of Amidation of Aryl Bromides with Copper/,-Dimethylglycine Catalytic
More informationSupporting Information
Investigation of self-immolative linkers in the design of hydrogen peroxide metalloprotein inhibitors Jody L. Major Jourden, Kevin B. Daniel, and Seth M. Cohen* Department of Chemistry and Biochemistry,
More informationImproved Carbonylation of Heterocyclic Chlorides and Challenging Aryl Bromides
Albaneze-Walker et al S-1 Improved Carbonylation of Heterocyclic Chlorides and Challenging Aryl Bromides Jennifer Albaneze-Walker*, Charles Bazaral, Tanya Leavey, Peter G. Dormer, and Jerry A. Murry Department
More informationDirect Aerobic Carbonylation of C(sp 2 )-H and C(sp 3 )-H Bonds through Ni/Cu Synergistic Catalysis with DMF as the Carbonyl Source
Direct Aerobic Carbonylation of C(sp 2 )-H and C(sp 3 )-H Bonds through Ni/Cu Synergistic Catalysis with DMF as the Carbonyl Source Xuesong Wu, Yan Zhao, and Haibo Ge* Table of Contents General Information...
More informationp-toluenesulfonic Acid-Mediated 1,3-Dipolar Cycloaddition of
Supporting Information for: p-toluenesulfonic Acid-Mediated 1,3-Dipolar Cycloaddition of Nitroolefins with NaN 3 for Synthesis of 4-Aryl-NH-1,2,3-triazoles Xue-Jing Quan, Zhi-Hui Ren, Yao-Yu Wang, and
More informationCatalytic decarboxylative alkylation of β-keto acids with sulfonamides via the cleavage of carbon nitrogen and carbon carbon bonds
Catalytic decarboxylative alkylation of β-keto acids with sulfonamides via the cleavage of carbon nitrogen and carbon carbon bonds Cui-Feng Yang, Jian-Yong Wang and Shi-Kai Tian* Joint Laboratory of Green
More informationA Hierarchy of Aryloxide Deprotection by Boron Tribromide. Supporting Information
A Hierarchy of Aryloxide Deprotection by Boron Tribromide Sreenivas Punna, Stéphane Meunier and M. G. Finn* Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
More informationSupporting Information
Electronic Supplementary Material (ESI) for ChemComm. This journal is The Royal Society of Chemistry 2018 Supporting Information Facile Three-Step Synthesis and Photophysical Properties of [8]-, [9]-,
More informationSUPPORTING INFORMATION. Transition metal-promoted synthesis of 2-aryl/heteroaryl-thioquinazoline: C-S
1 SUPPORTING INFORMATION Transition metal-promoted synthesis of 2-aryl/heteroaryl-thioquinazoline: C-S Bond formation by Chan-Lam Cross-Coupling Reaction SATYA KARUNA PULAKHANDAM a, NARESH KUMAR KATARI
More informationThermal shift binding experiments were carried out using Thermofluor 384 ELS system. Protein
Supplementary Methods Thermal shift assays Thermal shift binding experiments were carried out using Thermofluor 384 ELS system. Protein unfolding was examined by monitoring the fluorescence of ANS (1-anilinonaphthalene-8-
More informationmm C3a. 1 mm C3a Time (s) C5a. C3a. Blank. 10 mm Time (s) Time (s)
125 I-C5a (cpm) Fluorescnece Em 520nm a 4000 3000 2000 1000 c 0 5000 4000 3000 2000 Blank C5a C3a 6 0.3 mm C3a 7 9 10 11 12 13 15 16 0.3 mm C5a 0 300 600 900 1200 Time (s) 17 Fluorescnece Em 520nm Fluorescnece
More informationFluorescent probes for detecting monoamine oxidase activity and cell imaging
Fluorescent probes for detecting monoamine oxidase activity and cell imaging Xuefeng Li, Huatang Zhang, Yusheng Xie, Yi Hu, Hongyan Sun *, Qing Zhu * Supporting Information Table of Contents 1. General
More informationSupporting Information. Nitrodibenzofuran: a One- and Two-Photon Sensitive Protecting Group that is Superior to
Supporting Information Nitrodibenzofuran: a One- and Two-Photon Sensitive Protecting Group that is Superior to Brominated Hydroxycoumarin for Thiol Caging in Peptides M. Mohsen Mahmoodi, Daniel Abate-Pella,
More informationNaoya Takahashi, Keiya Hirota and Yoshitaka Saga* Supplementary material
Supplementary material Facile transformation of the five-membered exocyclic E-ring in 13 2 -demethoxycarbonyl chlorophyll derivatives by molecular oxygen with titanium oxide in the dark Naoya Takahashi,
More informationNitro-Grela-type complexes containing iodides. robust and selective catalysts for olefin metathesis
Supporting Information for Nitro-Grela-type complexes containing iodides robust and selective catalysts for olefin metathesis under challenging conditions. Andrzej Tracz, 1,2 Mateusz Matczak, 1 Katarzyna
More informationEur. J. Org. Chem WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, 2009 ISSN X SUPPORTING INFORMATION
Eur. J. rg. Chem. 2009 WILEY-VC Verlag Gmb & Co. KGaA, 69451 Weinheim, 2009 ISS 1434 193X SUPPRTIG IFRMATI Title: ew GM1 Ganglioside Derivatives for Selective Single and Double Labelling of the atural
More informationSupplemental Material
Supplemental Material General Methods Unless otherwise indicated, all anhydrous solvents were commercially obtained and stored under nitrogen. Reactions were performed under an atmosphere of dry nitrogen
More informationSupplementary Notes. HTS compatible FRET-based conformational sensors clarify membrane receptor activation
Supplementary otes TS compatible FRET-based conformational sensors clarify membrane receptor activation Pauline Scholler 1,2,3,4, David Moreno-Delgado 1,2,3, athalie Guillet-Lecat 1,2,3, Etienne Doumazane
More informationSupporting Information. for. Synthesis of dye/fluorescent functionalized. dendrons based on cyclotriphosphazene
Supporting Information for Synthesis of dye/fluorescent functionalized dendrons based on cyclotriphosphazene Aurélien Hameau 1,2, Sabine Fuchs 1,2, Régis Laurent 1,2, Jean-Pierre Majoral* 1,2 and Anne-Marie
More informationSupporting Information for. Use of the Curtius Rearrangement of Acryloyl Azides in the Synthesis of. 3,5-Disubstituted Pyridines: Mechanistic Studies
Supporting Information for Use of the Curtius Rearrangement of Acryloyl Azides in the Synthesis of 3,5-Disubstituted Pyridines: Mechanistic Studies Ta-Hsien Chuang* a, Yu-Chi Chen b and Someshwar Pola
More informationTriptycene-Based Small Molecules Modulate (CAG) (CTG) Repeat Junctions
Electronic Supplementary Material (ESI) for Chemical Science. This journal is The Royal Society of Chemistry 2015 Triptycene-Based Small Molecules Modulate (CAG) (CTG) Repeat Junctions Stephanie A. Barros
More informationSupporting Information
Zinc-Mediated Addition of Diethyl Bromomalonate to Alkynes for the Cascade Reaction towards Polysubstituted Pyranones and Tetracarbonyl Derivatives Anne Miersch, Klaus Harms, and Gerhard Hilt* Fachbereich
More informationPyridazine N-Oxides as Precursors of Metallocarbenes: Rhodium-Catalyzed Transannulation with Pyrroles. Supporting Information
Pyridazine N-Oxides as Precursors of Metallocarbenes: Rhodium-Catalyzed Transannulation with Pyrroles Vinaykumar Kanchupalli, Desna Joseph and Sreenivas Katukojvala* Department of Chemistry, Indian Institute
More informationSupporting Information Synthesis of 2-Aminobenzonitriles through Nitrosation Reaction and Sequential Iron(III)-Catalyzed C C Bond Cleavage of 2-Arylin
Supporting Information Synthesis of 2-Aminobenzonitriles through Nitrosation Reaction and Sequential Iron(III)-Catalyzed C C Bond Cleavage of 2-Arylindoles Wei-Li Chen, Si-Yi Wu, Xue-Ling Mo, Liu-Xu Wei,
More informationSupporting Information for:
Supporting Information for: Tunable Heptamethine-Azo Dye Conjugate as an IR Fluorescent Probe for the Selective Detection of Mitochondrial Glutathione over Cysteine and Homocysteine Soo-Yeon Lim, 1 Keum-Hee
More informationSupplemental Information. Reactivity of Monovinyl (Meth)Acrylates Containing Cyclic Carbonates
Supplemental Information Reactivity of Monovinyl (Meth)Acrylates Containing Cyclic Carbonates Kathryn A. Berchtold a, Jun Nie b, Jeffrey W. Stansbury c, d, and Christopher N. Bowman c, d, a Materials Science
More informationElectronic Supplementary Information
Electronic Supplementary Information A Novel and Facile Zn-mediated Intramolecular Five-membered Cyclization of β-tetraarylporphyrin Radicals from β-bromotetraarylporphyrins Dong-Mei Shen, Chao Liu, Qing-Yun
More informationSupporting Information
Supporting Information A single design strategy for dual sensitive ph probe with a suitable range to map ph in living cells Kang-Kang Yu, Ji-Ting Hou, Kun Li, * Qian Yao, Jin Yang, Ming-Yu Wu, Yong-Mei
More informationSupporting Information
Supporting Information Developing novel activity-based fluorescent probes that target different classes of proteases Qing Zhu, Aparna Girish, Souvik Chattopadhaya and Shao Q Yao * Departments of Chemistry
More informationIssue in Honor of Prof. Edmund Lukevics ARKIVOC 2006 (v) 86-91
Issue in onor of Prof. Edmund Lukevics ARKIVC 2006 (v) 86-91 Polycyclic heterocycles with acidic - groups VIII 1 The synthesis of some binuclear - acids with free rotary 1,2,4- triazole, 6-azauracil and
More informationDevelopment of a Cell-penetrating Peptide that Exhibits Responsive. Changes in its Secondary Structure in the Cellular Environment
Development of a Cell-penetrating Peptide that Exhibits Responsive Changes in its Secondary Structure in the Cellular Environment iroko Yamashita, 1 Takuma Kato, 2 Makoto ba, 2 Takashi Misawa, 1 Takayuki
More informationNovel D-erythro N-Octanoyl Sphingosine Analogs As Chemo- and Endocrine. Resistant Breast Cancer Therapeutics
Page 11 of 32 Cancer Chemotherapy and Pharmacology Novel D-erythro N-Octanoyl Sphingosine Analogs As Chemo- and Endocrine Resistant Breast Cancer Therapeutics James W. Antoon, Jiawang Liu, Adharsh P. Ponnapakkam,
More informationAllenylphosphine oxides as simple scaffolds for. phosphinoylindoles and phosphinoylisocoumarins
Supporting Information for Allenylphosphine oxides as simple scaffolds for phosphinoylindoles and phosphinoylisocoumarins G. Gangadhararao, Ramesh Kotikalapudi, M. Nagarjuna Reddy and K. C. Kumara Swamy*
More informationAn efficient methodology to introduce o-(aminomethyl) phenyl-boronic acids into peptides: alkylation of secondary amines
Electronic Supplementary Material (ESI) for ew Journal of Chemistry. This journal is The Royal Society of Chemistry and the Centre ational de la Recherche Scientifique 2016 An efficient methodology to
More informationAn Orthogonal Array Optimization of Lipid-like Nanoparticles for. mrna Delivery in Vivo
Supporting Information An rthogonal Array ptimization of Lipid-like Nanoparticles for mrna Delivery in Vivo Bin Li, Xiao Luo, Binbin Deng, Junfeng Wang, David W. McComb, Yimin Shi, Karin M.L. Gaensler,
More informationSupporting Information. First synthetic entry to the trimer stage of 5,6-dihydroxyindole polymerization: orthoalkynylaniline-based
Supporting Information First synthetic entry to the trimer stage of 5,6-dihydroxyindole polymerization: orthoalkynylaniline-based access to the missing 2,7 :2,7 -triindole Luigia Capelli, Paola Manini,*
More informationStereoselective Aza-Darzens Reactions of Tert- Butanesulfinimines: Convenient Access to Chiral Aziridines
Stereoselective Aza-Darzens Reactions of Tert- Butanesulfinimines: Convenient Access to Chiral Aziridines Toni Moragas Solá, a Ian Churcher, b William Lewis a and Robert A. Stockman* a Supplementary Information
More informationSupporting information for
Supporting information for A Coordination Gelator that Shows a Reversible Chromatic Change and a Sol-Gel Phase Transition Behavior upon xidative / Reductive Stimuli Shin-ichiro Kawano, orifumi Fujita,
More informationSupplementary Material
10.1071/C15460_AC CSIR 2016 Australian Journal of Chemistry 69 (3), 328-335 Supplementary Material Synthesis and Characterization of Bradykinin Derivatives Based on a β-cyclodextrin Core Rachel J. Stephenson,
More informationPAPRIKA EXTRACT SYNONYMS DEFINITION DESCRIPTION FUNCTIONAL USES CHARACTERISTICS
PAPRIKA EXTRACT Prepared at the 77 th JECFA, published in FAO JECFA Monographs 14 (2013), superseding tentative specifications prepared at the 69 th JECFA (2008). An ADI of 0-1.5 mg/kg bw was allocated
More informationNational Defense Academy, Hashirimizu, Yokosuka, , Japan
Suppoing Information for Reaction of Arynes with Amino Acid Esters Kentaro kuma, a * ahoko Matsunaga, a oriyoshi agahora, a Kosei Shioji, a and Yoshinobu Yokomori b a Depament of Chemistry, Faculty of
More informationOrvinols with Mixed Kappa/Mu Opioid Receptor Agonist Activity
Supporting Information Orvinols with Mixed Kappa/Mu Opioid Receptor Agonist Activity Greedy, Benjamin M.; Bradbury, Faye.; Thomas, Mark P.; Grivas, Konstantinos; Cami-Kobeci, Gerta; Archambeau, Ashley.;
More informationElectronic Supplementary Information
Electronic Supplementary Material (ESI) for Chemical Communications. This journal is The Royal Society of Chemistry 2018 Electronic Supplementary Information A ratiometric fluorescence probe for peroxynitrite
More informationNeuroprotective and Antioxidant Constituents from Curcuma zedoaria Rhizomes
Supporting Information Rec. Nat. Prod. 9:3 (2015) 349-355 Neuroprotective and Antioxidant Constituents from Curcuma zedoaria Rhizomes Omer Abdalla Ahmed Hamdi 1, Lo Jia Ye 2, Muhamad Noor Alfarizal Kamarudin
More informationInhibition of glyoxalase I: the first low-nanomolar tight-binding inhibitors. Swati S. More ξ and Robert Vince*
S1 Inhibition of glyoxalase I: the first low-nanomolar tight-binding inhibitors Swati S. More ξ and Robert Vince* Center for Drug Design, Academic ealth Center, and Department of Medicinal Chemistry, College
More informationSupporting Information
Supporting Information A Regioselective Ring-Expansion of Isatins with In-situ Generated α-aryldiazomethanes; Direct Access to Viridicatin Alkaloids Yellaiah Tangella,, Kesari Lakshmi Manasa,, Namballa
More informationElectronic Supporting Information
Electronic Supplementary Material (ESI) for ChemComm. This journal is The Royal Society of Chemistry 2014 The First Peripherally Masked Thiol Dendrimers : A Facile and Highly Efficient Functionalization
More informationA Novel Synthesis of Arylpyrrolo[1,2-a]pyrazinone Derivatives
Molecules 2004, 9, 574-582 molecules ISS 1420-049 http://www.mdpi.org A ovel Synthesis of ylpyrrolo[1,2-a]pyrazinone Derivatives Fei Wang*, Jiawei Wang and Shoufang Zhang School of Pharmaceutical Engineering,
More informationSupporting Information
Supporting Information Wiley-VCH 2008 69451 Weinheim, Germany Enantioselective Rhodium-catalyzed Addition of Arylboronic Acids to α-ketoesters Hai-Feng Duan, Jian-Hua Xie, Xiang-Chen Qiao, Li-Xin Wang,
More informationSupporting Information
Supporting Information B(C 6 F 5 ) 3 -catalyzed Regioselective Deuteration of Electronrich Aromatic and Heteroaromatic compounds Wu Li, Ming-Ming Wang, Yuya Hu and Thomas Werner* Leibniz-Institute of Catalysis
More informationTitle Revision n date
A. THIN LAYER CHROMATOGRAPHIC TECHNIQUE (TLC) 1. SCOPE The method describes the identification of hydrocortisone acetate, dexamethasone, betamethasone, betamethasone 17-valerate and triamcinolone acetonide
More informationCopyright Wiley-VCH Verlag GmbH, D Weinheim, Angew. Chem
Copyright Wiley-VCH Verlag GmbH, D-69451 Weinheim, 2000. Angew. Chem. 2000. Supporting Information for Salen as Chiral Activator : Anti vs Syn Switchable Diastereoselection in the Enantioselective Addition
More informationEthyl 2-hydroxy-4-methyl-1-((prop-2-yn-1-yloxy)methyl)cyclohex-3-enecarboxylate (16):
General methods: 1 H NMR and 13 C NMR spectra were recorded in CDCl 3 or CDCl3 and CCl 4 as solvent on 300 MHz or 500 MHz spectrometer at ambient temperature. The coupling constant J is given in Hz. The
More informationDirect ortho-c H Functionalization of Aromatic Alcohols Masked by Acetone Oxime Ether via exo-palladacycle
Direct ortho-c H Functionalization of Aromatic Alcohols Masked by Acetone Oxime Ether via exo-palladacycle Kun Guo, Xiaolan Chen, Mingyu Guan, and Yingsheng Zhao* Key Laboratory of Organic Synthesis of
More informationOn the Utility of S-Mesitylsulfinimines for the Stereoselective Synthesis of Chiral Amines and Aziridines
n the Utility of S-Mesitylsulfinimines for the Stereoselective Synthesis of Chiral Amines and Aziridines Caroline Roe, a Toni Moragas Solá, a Leonid Sasraku-eequaye, b eather obbs, c Ian Churcher, c David
More informationBase-promoted acetal formation employing aryl salicylates
Base-promoted acetal formation employing aryl salicylates Pinmanee Boontheung, Patrick Perlmutter*, and Evaloni Puniani School of Chemistry, Monash University, PO Box 23, Victoria 3800 Australia E-mail:
More informationReaction of difluorocarbene with acetylene ethers generates novel fluorinated 5- and 7-membered carbacycles.
Electronic Supplementary Information (ESI) Reaction of difluorocarbene with acetylene ethers generates novel fluorinated 5- and 7-membered carbacycles. Poh Wai Chia, Davide Bello, Alexandra M. Z. Slawin
More informationSimple copper/tempo catalyzed aerobic dehydrogenation. of benzylic amines and anilines
Simple copper/tempo catalyzed aerobic dehydrogenation of benzylic amines and anilines Zhenzhong Hu and Francesca M. Kerton,* Department of Chemistry, Memorial University of Newfoundland, St. John s, NL,
More informationThe synthesis of condensed imidazoles II. A simple synthesis of some 1,5-diaryl-3-[2-(naphtho[2,3-d]imidazol-2-yl)]formazans and its derivatives 1
The synthesis of condensed imidazoles II. A simple synthesis of some 1,5-diaryl-3-[2-(naphtho[2,3-d]imidazol-2-yl)]formazans and its derivatives 1 Iveta Fryšová *, Jan Slouka, and Jan laváč Department
More informationA pillar[2]arene[3]hydroquinone which can self-assemble to a molecular zipper in the solid state
A pillar[2]arene[3]hydroquinone which can self-assemble to a molecular zipper in the solid state Mingguang Pan, Min Xue* Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China Fax:
More information