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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Synonyms: 3-Methoxyphenylboronic acid
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Wen Ren ; Yuling Deng ; Jacob D. Ward ; Rebecca Vairin ; Ruoli Bai b ; Hashini I. Wanniarachchi , et al.
Abstract: The synthesis and evaluation of small-molecule inhibitors of tubulin polymerization remains a promising approach for the development of new therapeutic agents for cancer treatment. The natural products colchicine and combretastatin A-4 (CA4) inspired significant drug discovery campaigns targeting the colchicine site located on the beta-subunit of the tubulin heterodimer, but so far these efforts have not yielded an approved drug for cancer treatment in human patients. Interest in the colchicine site was enhanced by the discovery that a subset of colchicine site agents demonstrated dual functionality as both potent antiproliferative agents and effective vascular disrupting agents (VDAs). Our previous studies led to the discovery and development of a 2-aryl-3-aroyl-indole analogue (OXi8006) that inhibited tubulin polymerization and demonstrated low nM IC50 values against a variety of human cancer cell lines. A water-soluble phosphate prodrug salt (OXi8007), synthesized from OXi8006, displayed promising vascular disrupting activity in mouse models of cancer. To further extend structure-activity relationship correlations, a series of 6-aryl-3-aroyl-indole analogues was synthesized and evaluated for their inhibition of tubulin polymerization and cytotoxicity against human cancer cell lines. Several structurally diverse molecules in this small library were strong inhibitors of tubulin polymerization and of MCF-7 and MDA-MB-231 human breast cancer cells. One of the most promising analogues (KGP591) caused significant G2/M arrest of MDA-MB-231 cells, disrupted microtubule structure and cell morphology in MDA-MB-231 cells, and demonstrated significant inhibition of MDA-MB-231 cell migration in a wound healing (scratch) assay. A phosphate prodrug salt, KGP618, synthesized from its parent phenolic precursor, KGP591, demonstrated significant reduction in bioluminescence signal when evaluated in vivo against an orthotopic model of kidney cancer (RENCA-luc) in BALB/c mice, indicative of VDA efficacy. The most active compounds from this series offer promise as anticancer therapeutic agents.
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Keywords: Inhibitors of tubulin polymerization ; Vascular disrupting agents ; Indole synthesis ; Molecular docking ; Antiproliferative agents ; Inhibitors of cell migration
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Purchased from AmBeed: 128796-39-4 ; 10365-98-7 ; 98-80-6 ; 98437-24-2 ; 5720-05-8 ; 64-86-8 ; 13331-27-6 ; 206551-43-1 ; 63139-21-9 ; 622864-48-6 ; 5720-07-0 ; 87199-18-6 ; 30418-59-8 ; 4521-61-3 ; 4521-61-3 ; 87199-18-6 ; 64-86-8 ; 64-86-8 ; 128796-39-4 ; 5720-05-8 ; 64-86-8
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Guo, Sheng ; Wu, Yifan ; Luo, Shao-Xiong Lennon ; Swager, Timothy M. ;
Abstract: Heterogenous catalysts with confined nanoporous catalytic sites are shown to have high activity and size selectivity. A solution-processable nanoporous organic polymer (1-BPy-Pd) catalyst displays high catalytic performance (TON > 200K) in the heterogeneous Suzuki–Miyaura coupling (SMC) reaction and can be used for the preparation of the intermediates in the synthesis of pharmaceutical agents. In comparison to the homogeneous catalyst analogue (2,2′-BPy)PdCl2, the heterogenous system offers size-dependent catalytic activity when bulkier substrates are used. Furthermore, the catalyst can be used to create catalytic impellers that simplify its use and recovery. We found that this system also works for applications in heterogenous Heck and nitroarenes reduction reactions. The metal-binding nanoporous polymer reported here represents a versatile platform for size-selective heterogeneous and recyclable catalysts.
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Keywords: nanoporous organic polymer ; heterogeneous catalyst ; Suzuki−Miyaura coupling reaction ; size-selective reaction ; catalyst processing
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Purchased from AmBeed: 128796-39-4 ; 10365-98-7 ; 98-80-6 ; 556-96-7 ; 171663-13-1 ; 71597-85-8 ; 402-43-7 ; 2042-37-7 ; 22385-77-9 ; 16419-60-6 ; 15862-18-7 ; 87199-15-3 ; 171408-84-7 ; 643-58-3 ; 591-50-4 ; 76911-73-4 ; 398-36-7 ; 14871-92-2 ; 5720-07-0 ; 945976-76-1 ; 366-18-7 ; 2920-38-9 ; 623-00-7 ; 24973-49-7 ; 588-59-0 ; 128796-39-4 ; 5723-93-3 ; 17057-88-4 ; 126485-55-0
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CAS No. : | 10365-98-7 |
Formula : | C7H9BO3 |
M.W : | 151.96 |
SMILES Code : | C1=C(C=CC=C1OC)B(O)O |
Synonyms : |
3-Methoxyphenylboronic acid
|
MDL No. : | MFCD00161359 |
InChI Key : | NLLGFYPSWCMUIV-UHFFFAOYSA-N |
Pubchem ID : | 2734370 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 47A 6-(3-Methoxyphenyl)-2-naphthalenecarbonitrile A solution of Example 28B (300 mg, 1 mmol), palladium (II) acetate (22 mg, 0.1 mmol) and 1-1'-bis(diphenyphosphino)ferrocene (111 mg, 0.2 mmol) was stirred in DMF (3 mL) for 15 min, treated with Cs2CO3 (813 mg, 2.5 mmol) and 3-methoxyphenylboronic acid (228 mg, 1.5 mmol), stirred for 20 min at 80 C., cooled, treated with pH 7 buffer (10 mL) and extracted with diethyl ether. The ether extracts were dried (MgSO4), concentrated and purified on silica gel with 10% ethyl acetate/hexane to provide 140 mg of the title compound as a white solid. MS (DCI/NH3) m/e 277 (M+NH4)+. | |
With caesium carbonate; In ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 47A 6-(3-Methoxyphenyl)-2-naphthalenecarbonitrile A solution of Example 28B (300 mg, 1 mmol), palladium (II) acetate (22 mg, 0.1 mmol) and 1-1'-bis(diphenyphosphino)ferrocene (111 mg, 0.2 mmol) was stirred in DMF (3 mL) for 15 min, treated with Cs2CO3 (813 mg, 2.5 mmol) and 3-methoxyphenylboronic acid (228 mg, 1.5 mmol), stirred for 20 min at 80 C., cooled, treated with pH 7 buffer (10 mL) and extracted with diethyl ether. The ether extracts were dried (MgSO4), concentrated and purified on silica gel with 10% ethyl acetate/haexane to provide 140 mg of the title compound as a white solid. MS (DCI/NH3) m/e 277 (M+NH4)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With copper diacetate; triethylamine; In dichloromethane; | Intermediate 25: 2-Chloro-5-(3-methoxyphenoxy)pyrimidine A mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (l .Og, 7.66mmol), 3-methoxyphenyl boronic acid (1.16g, 7.66mmol), copper (II) acetate (1.39g, 7.66mmol), triethylamine(5.34mL, 7.66mmol) and powdered 4A molecular sieves in dichloromethane (30mL) was stirred under air for 3 days. A calcium chloride guard tube was used to protect the reaction from moisture. The reaction mixture was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgS04), the solvent removed under reduced pressure and the crude product was purified by flash chromatography, using 0-15percent ethyl acetate:hexane as eluent, to provide 2-chloro-5- (3-methoxyphenoxy)-pyrimidine (0.448g, 25percent) as yellow oil.Mass: (ES+) 237 (M+H)+ NMR: deltaEta (CDC13) 3.82 (3H, s), 6.63 (2H, m), 6.81 (IH, br d), 7.33 (IH, t) and 8.39 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.15% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In ethanol; toluene; at 120℃; for 0.25h;Microwave irradiation; | 6-(3-methoxy-phenyl)-pyrazin-2ylamine To a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (0.5 g, 3.85 mmol) in a mixture of toluene/ethanol (4:1 , 10 ml), 3-methoxyphenylboronic acid (0.64 g, 4.24 mmol), tetrakis(triphenylphosphino)palladium(0) (0.13 g, 0.11 mmol) and cesium carbonate (2.51 g, 7.71 mmol) are added, degassed briefly and irradiated in microwave at 120°C for 15 minutes. The reaction mixture is passed through celite, washed with dichloromethane, the filterate is concentrated and purified by column using silica gel (60-120) mesh to get the product as yellow solid (0.34 g, 44.15 percent); TLC: Pet ether/Ethylacetate(7/3) Rf - 0.2; 1H NMR: 400 MHz, DMSO-d6: delta [ppm] 8.27 (s, 1 H), 7.83 (s, 1H), 7.57-7.52 (m, 2H), 7.37 (t, J = 7.88 Hz, 1 H), 7.00-6.97 (m, 1 H), 6.51 (br s, 2H), 3.80 (s, 3H); LCMS: Mass found (M+, 202.3) Method: A-0.1 percent TFA in H20, B-0.1 percent TFA in ACN: Flow - 2.0ml/min. Column: XBridge C8 (50 X 4.6 mm, 3.5 pm), +ve mode Rt (min): 2.48 area percent -98.79 (Max), 99.35 (254 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A suspension of 3-bromobenzaldehyde (200 mg; commercial) and (3-cyanophenyl)boronic acid neopentyl glycol ester (325 mg; commercial) in toluene/EtOH (2.3 mL; 1 : 1) was treated with sat. aq. Na2C03 (2.3 mL) and degassed by bubbling with nitrogen for 5 min. The suspension was treated with Pd(PPh3)4 (28 mg) and refluxed overnight in a sealed tube. The reaction mixture was allowed to reach rt and diluted with water and EA. The aq. layer was extracted with EA and the combined org. layers were washed with brine, dried over MgS04, filtered and evaporated under reduced pressure. After purification by CC (Hept/EA 2: 1 to 1 : 1), the title compound was obtained as an off-white solid (325 mg; quantitative yield). Starting from 3-methoxyphenylboronic acid (50 mg), 2-bromoisonicotinaldehyde (61 mg), tetrakis-(triphenylphosphine)-palladium (15 mg) and K2C03 (136 mg), and proceeding in analogy to Preparation A, 2-(3-methoxyphenyl)isonicotinaldehyde was obtained. The latter was reacted without purification with (R)-5-(2-aminoethyl)-3-(3-oxo-3,4-dihydro- 2H-benzo[£][l,4]thiazin-6-yl)oxazolidin-2-one (77 mg; prepared according to WO 2009/104147), in analogy to Example 1, affording after purification by prep-HPLC (Method 1), the title compound as a colourless powder (39 mg; 24percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; triphenylphosphine; In 1,4-dioxane; water; at 90℃; | A mixture of <strong>[33930-63-1]4-bromo-2-methylisoquinolin-1(2H)-one</strong> (100 mg, 0.42 mmol), and (3-methoxyphenyl)boronic acid (70 mg, 0.46 mmol), PPh3 (66 mg, 0.25 mmol), Na2CO3 (133 mg, 1.26 mmol), and Pd(dppf)Cl2 (62 mg, 0.084 mmol) in dioxane (2.5 mL) and water (0.5 mL) was heated overnight at 90° C. Extractive work up with ethyl acetate followed by preparative TLC (PE:EA=1:1) gave the title compound (18 mg, 0.07 mmol) as a white solid in 17percent yield. 1H NMR (DMSO, 400 MHz): delta 8.30 (d, 1H, J=7.68), 7.68 (t, 1H, J=7.56), 7.50-7.55 (m, 3H), 7.40 (t, 1H, J=7.44), 6.97-7.00 (m, 3H), 3.78 (s, 3H), 3.54 (s, 3H). MS (m/z, relative intensity): 266 (M+, 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | A mixture of N-boc-2-(4-bromophenyl)ethylamine, the desiredarylboronic acid (a-m) (1.2 equiv), tetrakis(triphenylphosphine)-palladium(0) (0.04 equiv), Na2CO3 (5 equiv) in degassed toluene/H2O (5/2) was refluxed for 18 h. The reaction mixture was filteredthrough Celite and concentrated in vacuo. The resulting residuewas dissolved in in EtOAc (200 mL), washed with H2O (200 mL 2) and brine (200 mL). The organic layer was dried with anhydrousNa2SO4 and concentrated in vacuo. The residue was purified by columnchromatography on SiO2. Using Method E, 13 (1.00?g, 3.3?mmol), 3-methoxyphenylboronic acid (0.61?g, 4.0?mmol), tetrakis(triphenylphosphine)palladium(0) (0.15?g, 0.1?mmol), Na2CO3 (1.77?g, 16.7?mmol) in toluene/H2O (33?ml/13.3?ml), followed by 4.0?M HCl in dioxane (2.50?ml, 10.0?mmol) gave 4i as a white solid (0.47?g, 53%): Rf?=?0.00 (EtOAc 9: acetone 1): 1H NMR (DMSO-d6, 400?MHz) delta 2.93-3.07 (m, NH3CH2CH2), 3.79 (OCH3), 7.01 (d, J?=?8.7?Hz, 1 ArH), 7.33 (d, J?=?8.1?Hz, 2 ArH), 7.56-7.60 (m, 4 ArH), 8.27 (s, NH3); 13C NMR (DMSO-d6, 75?MHz) delta 33.0 (NCH2CH2), 55.6 (CH3), 114.8, 126.8, 128.1, 129.7, 132.7, 136.3, 138.7, 159.3 (12 ArC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
360 mg | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; at 85.0℃; for 16.0h;Inert atmosphere; | A. 5-Chloro-6-(3-methoxyphenyl)pyridazin-3(2H)-one. To a 50-mL round-bottom flask was placed a solution of <strong>[17285-36-8]5,6-dichloro-2,3-dihydropyridazin-3-one</strong> (990 mg, 6.00 mmol) and (3- methoxyphenyl)boronic acid (900 mg, 5.91 mmol) in EtOH (45 mL) and water (9 mL) then Na2C03 (1062 mg, 10.02 mmol) and Pd(PPh3)4 (288 mg, 0.24 mmol) were added under nitrogen. The reaction was stirred for 16 h at 85°C, cooled to rt, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with EtO Ac/petroleum ether (2: 1) affording 360 mg of the title compound as a white solid. Mass Spectrum (LCMS, ESI pos): Calcd. for CiiH10ClN2O2+: 237.0 (M+H); Found: 237.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere; | General procedure: A mixture of (4-(tert-butyl)phenyl)boronic acid (7.5 mmol),K2CO3 (20 mmol), Pd[P(C6H5)3]4 (0.25 mmol), and compound 14(5 mmol) in DMF was stirred at 120 C for 24 h under an argonatmosphere. The reaction was diluted with H2O (30 mL) andextracted with ethyl acetate (20 mL 2). The organic phases werecombined, washed with brine (30 mL 3), dried over anhydrousNa2SO4, and concentrated under vacuum to yield the crude product,which was purified by flash column chromatography (0e10%ethyl acetate in petroleum ether). |
68.5% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 24h;Inert atmosphere; | Under argon protection,<strong>[121554-10-7]5-bromo-2-iodo-benzonitrile</strong> (1.5 g, 5 mmol), 3-methoxybenzeneboronic acid (1.1 g, 7.5 mmol), K2CO3 (2.8 g, 20 mmol), tetratriphenylphosphine palladium (0.3 g , 0.3mmol) and DMF (6mL) was added to a 30mL two-necked flask, reacted at 120 C for 24h, after TLC monitoring reaction was completed, cooled to room temperature, diluted with 30mL of ethyl acetate, added 30mL of water, oscillated, water The extract was extracted with ethyl acetate (25 mL×3).Purified on silica gel column (V ethyl acetate: V petroleum ether = 1:20)The white solid 2-(3'-methoxy-phenyl)-5-bromo-benzonitrile (a3) 1.0 g was obtained in a yield of 68.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With palladium diacetate; potassium carbonate; triphenylphosphine; In water; N,N-dimethyl-formamide; at 100℃; for 3h;Inert atmosphere; Sealed tube; Microwave irradiation; | <strong>[16870-28-3]2-hydroxy-4-iodobenzoic acid</strong> (50 mg, 0.189 mmol), 3-methoxyphenylboronic acid (34.5 mg, 0.227 mmol), PPh3 (7.4 mg, 0.028 mmol), K2CO3 (91.4 mg, 0.662 mmol), Pd(AcO)2 (2.12 mg, 0.0095 mmol), 1:1 DMF: H2O (2 ml) were used. In this case, prior to chromatographic purification, the residue from evaporating the filtrate was resuspended in acetonitrile. The precipitate was separated from the liquid phase and the latter was discarded. The solid was then purified by flash chromatography (gradient elution with AcOEt: CH3CN:H2O:CH3OH mixture, 70:5:2.5:2.5 to 60:10:10:10). 100 was obtained in the form of a brown solid. Yield after purification: 86 % (25 mg). 1H NMR (500 MHz, methanol-d4) delta 7.92 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.19-7.16 (m, 1H), 7.13 (m, 1H), 7.09 (bs, 1H), 7.08 (m, 1H), 6.92 (dd, J = 8.3, 2.6 Hz, 1H), 3.82 (s, 3H, OCH3). 13C NMR (126 MHz, methanol-d4) delta 174.7 (CO), 163.0 (C), 161.4 (C), 148.3 (C), 142.8 (C), 132.2 (CH), 130.9 (CH), 120.4 (CH), 118.5 (CH), 115.8 (CH), 115.7 (C), 114.5 (CH), 113.7 (CH), 55.7 (CH3). HRMS (TOF, ES-): Calculated for C14H11O4: (M-H)-: m/z 243.0657. 243.0659 found (deviation 0.8 ppm). m.p. (C): 185.1. |