Structure of 4-Tolylboronic acid
CAS No.: 5720-05-8
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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: p-Tolylboronic acid
4.5
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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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Yuan, Gengyang ; Dhaynaut, Maeva ; Lan, Yu ; Guehl, Nicolas J. ; Huynh, Dalena ; Iyengar, Suhasini M. , et al.
Abstract: Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for several neuropsychiatric disorders. An mGluR2 function in etiology could be unveiled by positron emission tomography (PET). In this regard, 5-(2-fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide ([11C]13, [11C]mG2N001), a potent negative allosteric modulator (NAM), was developed to support this endeavor. [11C]13 was synthesized via the O-[11C]methylation of phenol 24 with a high molar activity of 212 ± 76 GBq/μmol (n = 5) and excellent radiochemical purity (>99%). PET imaging of [11C]13 in rats demonstrated its superior brain heterogeneity and reduced accumulation with pretreatment of mGluR2 NAMs, VU6001966 (9) and MNI-137 (26), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [11C]13 selectively accumulated in mGluR2-rich regions and resulted in high-contrast brain images. Therefore, [11C]13 is a potential candidate for translational PET imaging of the mGluR2 function.
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Purchased from AmBeed: 16289-54-6 ; 5521-55-1 ; 22047-25-2 ; 98-80-6 ; 40155-47-3 ; 5720-05-8 ; 879-65-2 ; 98-96-4 ; 31519-62-7 ; 23688-89-3 ; 23611-75-8 ; 33332-25-1 ; 20737-42-2 ; 61442-38-4 ; 17933-03-8 ; 50681-25-9 ; 13924-99-7 ; 40155-43-9 ; 166744-78-1 ; 36070-80-1 ; 4595-61-3 ; 118853-60-4 ; 41110-28-5 ; 40155-42-8 ; 937669-80-2 ; 31462-59-6 ; 16419-60-6 ; 5424-01-1 ; 59-67-6 ; 34604-60-9 ; 27398-39-6 ; 1196151-53-7 ; 19847-12-2 ; 13965-03-2 ; 876161-05-6 ; 27825-21-4 ; 2164-61-6 ; 4604-72-2 ; 98-97-5 ; 24005-61-6 ; 5521-61-9 ; 2516-34-9 ; 2719-27-9 ; 123-90-0 ; 6761-50-8 ; 625-43-4 ; 872-64-0 ; 1309866-36-1 ; 36932-49-7 ; 1528085-68-8 ; 1195533-51-7 ; 13534-79-7
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Structure activity relationship of pyrazinoic acid analogs as potential antimycobacterial agents
Hegde, Pooja V. ; Aragaw, Wassihun W. ; Cole, Malcolm S. ; Jachak, Gorakhnath ; Ragunathan, Priya ; Sharma, Sachin , et al.
Abstract: Tuberculosis (TB) remains a leading cause of infectious disease-related mortality and morbidity. Pyrazinamide (PZA) is a critical component of the first-line TB treatment regimen because of its sterilizing activity against non-replicating Mycobacterium tuberculosis (Mtb), but its mechanism of action has remained enigmatic. PZA is a prodrug converted by pyrazinamidase encoded by pncA within Mtb to the active moiety, pyrazinoic acid (POA) and PZA resistance is caused by loss-of-function mutations to pyrazinamidase. We have recently shown that POA induces targeted protein degradation of the enzyme PanD, a crucial component of the CoA biosynthetic pathway essential in Mtb. Based on the newly identified mechanism of action of POA, along with the crystal structure of PanD bound to POA, we designed several POA analogs using structure for interpretation to improve potency and overcome PZA resistance. We prepared and tested ring and carboxylic acid bioisosteres as well as 3, 5, 6 substitutions on the ring to study the structure activity relationships of the POA scaffold. All the analogs were evaluated for their whole cell antimycobacterial activity, and a few representative mols. were evaluated for their binding affinity, towards PanD, through isothermal titration calorimetry. We report that analogs with ring and carboxylic acid bioisosteres did not significantly enhance the antimicrobial activity, whereas the alkylamino-group substitutions at the 3 and 5 position of POA were found to be up to 5 to 10-fold more potent than POA. Further development and mechanistic anal. of these analogs may lead to a next generation POA analog for treating TB.
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Keywords: Tuberculosis ; Pyrazinoic acid ; pyrazinamide
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Purchased from AmBeed: 16289-54-6 ; 5521-55-1 ; 22047-25-2 ; 98-80-6 ; 40155-47-3 ; 5720-05-8 ; 879-65-2 ; 98-96-4 ; 31519-62-7 ; 23688-89-3 ; 23611-75-8 ; 33332-25-1 ; 20737-42-2 ; 61442-38-4 ; 17933-03-8 ; 50681-25-9 ; 13924-99-7 ; 40155-43-9 ; 36070-80-1 ; 4595-61-3 ; 118853-60-4 ; 41110-28-5 ; 40155-42-8 ; 937669-80-2 ; 98-98-6 ; 31462-59-6 ; 16419-60-6 ; 5424-01-1 ; 59-67-6 ; 34604-60-9 ; 27398-39-6 ; 1196151-53-7 ; 19847-12-2 ; 13965-03-2 ; 876161-05-6 ; 27825-21-4 ; 2164-61-6 ; 4604-72-2 ; 98-97-5 ; 24005-61-6 ; 103-67-3 ; 5521-61-9 ; 2516-34-9 ; 2719-27-9 ; 123-90-0 ; 6761-50-8 ; 625-43-4 ; 872-64-0 ; 36932-49-7 ; 1528085-68-8 ; 1195533-51-7 ; 13534-79-7
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CAS No. : | 5720-05-8 |
Formula : | C7H9BO2 |
M.W : | 135.96 |
SMILES Code : | C1=C(B(O)O)C=CC(=C1)C |
Synonyms : |
p-Tolylboronic acid
|
MDL No. : | MFCD00039138 |
InChI Key : | BIWQNIMLAISTBV-UHFFFAOYSA-N |
Pubchem ID : | 79799 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P362-P403+P233-P405-P501 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 41.23 |
TPSA ? Topological Polar Surface Area: Calculated from |
40.46 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.19 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.33 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.61 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.3 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.24 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.81 |
Solubility | 2.1 mg/ml ; 0.0155 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.64 |
Solubility | 3.15 mg/ml ; 0.0231 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.64 |
Solubility | 3.09 mg/ml ; 0.0227 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.28 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.32 |
* 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 |
---|---|---|
tetrakis(triphenylphosphine)palladium (0); In chloroform; toluene; | Step (b) Preparation of 4-(4'-Methyl-biphenyl-4-yl)-4-oxo-butyric acid methyl ester To a stirred mixture of (4-methylphenyl)boronic acid (0.818 g, 0.00602 mol) and 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.3556 g, 0.00500 mol) in toluene (10 mL) was added tetrakis(triphenylphosphine)-palladium(0) (0.173 g, 0.000150 mol) and 2.0 M aqueous sodium carbonate (5.0 mL, 0.010 mol), and the mixture was heated at reflux under nitrogen for 12 hours and allowed to cool. The mixture was diluted with toluene and dichloromethane (10 mL/10 mL), and filtered through a pad of Celite. The Celite was washed with additional toluene and dichloromethane. Filtrate and washings were combined and washed with 2.0 M aqueous sodium carbonate, brine, 3% aqueous ammonium hydroxide, water, and brine. The organics were dried (Na2SO4) and rotary evaporated. The residue was dissolved in chloroform and purified by column chromatography on silica gel (144 g, 230-400 mesh), eluding with hexanes-acetone (6:1, 17*125 mL) to give 0.98 g of 4-(4'-methyl-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 121-122 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; | Example 112 Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4,4'-dimethyl-[1,1'-biphenyl]-3-carboxamide To a stirred solution <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (200 mg, 0.42 mmol) and p-tolyl boronic acid (86 mg, 0.63 mmol) in dioxane (3 mL), aqueous 2M Na2CO3 solution (0.75 mL, 1.51 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (48 mg, 0.04 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100 C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (150 mg, 73%). LCMS: 488.20 (M+1)+; HPLC: 99.33% ( 254 nm) (Rt; 5.393; Method: Column: YMC ODS-A 150 mm*4.6 mm*5mu; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 muL, Col. Temp.: 30 C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) delta 11.46 (s, 1H), 8.19 (t, 1H), 7.51 (d, 2H, J=8 Hz), 7.37 (s, 1H), 7.25 (d, 2H, J=8 Hz), 7.19 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.81-3.83 (m, 2H), 3.22-3.27 (m, 2H), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.55 (m, 2H), 0.82 (t, 3H, J=6.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydroxide; In toluene; at 100℃; for 2h;Schlenk technique; | General procedure: An oven-dried Schlenk flask, equipped with a magnetic stir bar, septum and a condenser was charged with acyl chloride (1.0 mmol), arylboronic acid (1.0 mmol), NaOH (4 mmol) and 5.0 mL of toluene. The flask was immersed and stirred in an oil bath at 100 °C. Upon complete consumption of starting materials as determined by GC analysis, the water (10.0 mL) was added. The reaction mixture was extracted with diethyl ether (3 × 5.0 mL). The combined organic layer was collected, dried over anhydrous Na2SO4 and concentrated in vacuum to afford product which was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 9:1 or 8:2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With di-tert-butyl dicarbonate; potassium carbonate; magnesium chloride; nickel dichloride; zinc; In tetrahydrofuran; at 20℃; for 20h; | Weigh 1mmol of p-fluorobenzoic acid and 0.5mmol of p-methylbenzeneboronic acid in the reaction flask, With tetrahydrofuran as solvent, 6.5 mg of nickel chloride (0.05 mmol) 98 mg zinc powder (1.5 mmol), 8 mg of bipyridine (0.05 mmol), 138 mg of potassium carbonate (1.0 mmol), 143 mg of magnesium chloride (1.5 mmol), 109 mg of di-tert-butyl dicarbonate (0.5 mmol), The reaction was stirred at room temperature for 20h, to give the desired product isolated 58mg, yield 54percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
139 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 80℃; | To <strong>[877399-50-3]4-(4-bromopyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester</strong> (208 mg) were added 4-methylphenylboronic acid (95 mg),N,N-dimethylformamide (3.2 mL),2 M aqueous sodium carbonate solution (946 muL) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloride. dichloromethane complex (26 mg) and the mixture was stirred at 80°c. After completion of the reaction,saturated brine was added and the mixture was extracted with ethyl acetate. The solvent was evaporated and the obtained residue was purified by column chromatography (hexane:ethyl acetate)to give 4-[4-(p-tolyl)pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (139 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 50.0℃; for 5.0h;Inert atmosphere; | General procedure: To an oven dried 5 mL microwave vessel was addedPd(dppf)Cl2·CH2Cl2 (4 mol%), halide/pseudohalide (1 equiv),boron coupling partner (1 equiv), and Cs2CO3 (3 equiv). Thevessel was then capped and purged with N2 before addition ofCyrene (1 mL, 0.25 M) and H2O (1.8 mL). The reaction mixturewas heated to 50 C and maintained at this temperature withstirring for 5 h before the vessel was vented and decapped. Thesolution was then diluted with Et2O (10 mL) and washed withwater (2 × 20 mL) and brine (2 × 20 mL). The organics were thenpassed through a hydrophobic frit and concentrated underreduced pressure to give a residue, which was purified by flashchromatography (silica gel) to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With trisodium tris(3-sulfophenyl)phosphine; palladium diacetate; sodium carbonate; In water; acetonitrile; at 100℃;Inert atmosphere; | General procedure: 31 (1 eq.), boronic acid (1.5 eq.) or pinacol ester [for compound14 (1.5 eq.)], Na2CO3 (9 eq.), Pd(OAc)2 (0.05 eq.) and TPPTS (0.15 eq.)were added to a 10mL round-bottom flask, equipped with a stir bar.Next, the flask was evacuated and refilled with argon. This procedure was repeated three times in total. Next, degassed MeCN(2 mL/mmol SM) and H2O (4 mL/mmol SM) were added to the solids under argon. After 5 min of stirring, the mixture was heatedto 100 C in a pre-heated oil bath. When the starting material was fully consumed (usually 1e3 h), the mixture was cooled to ambient temperature, and neutralized (pH ~ 7) with 0.5M aq. HCl. Themixture was evaporated till dryness, resuspended in MeOH and evaporated (three times). Next, the mixture was adsorbed onto Celite (fromMeOH) and eluted over a short silica pad (~5 cm) with 20% MeOH/DCM. The liquid was evaporated in vacuo and purified by column chromatography. |