Structure of 4-Phenoxyphenylboronic acid
CAS No.: 51067-38-0
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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.
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Pieterse, Lianie ; Beteck, Richard M. ; Baratte, Blandine ; Jesumoroti, Omobolanle J. ; Robert, Thomas ; Ruchaud, Sandrine , et al.
Abstract: Protein kinases, including CDK9/CyclinT and Haspin, are regarded as potential drug targets in cancer therapy. Findings from a previous study suggested 7-azaindole as a privileged scaffold for producing inhibitors of CDK9/CyclinT and Haspin. Inspired by these findings, the current study synthesized and evaluated thirteen (13) C6-substituted 7-azaindole and twenty (20) C4-substituted structurally related 7H-pyrrolo[2,3-d]pyrimidine derivatives against a panel of protein kinases, including CDK9/CyclinT and Haspin. Eleven of the 7H-pyrrolo[2,3-d]pyrimidine derivatives exhibited activity toward CDK9/CyclinT, while 4 of compounds had activity against Haspin. The best CDK9/CyclinT (IC50 of 0.38 μM) and Haspin (IC50 of 0.11 μM) activities were achieved by compounds 7d and 7f, resp. Hence, these compounds may be valuable starting points for development of new anti-cancer drugs.
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Keywords: 7-Deazapurine ; Anticancer ; CDK9/CylinT ; Haspin ; Protein kinase
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Purchased from AmBeed: 98437-24-2 ; 71597-85-8 ; 3680-69-1 ; 6165-68-0 ; 51067-38-0 ; 87199-18-6
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CAS No. : | 51067-38-0 |
Formula : | C12H11BO3 |
M.W : | 214.02 |
SMILES Code : | OB(O)C1=CC=C(OC2=CC=CC=C2)C=C1 |
MDL No. : | MFCD00093312 |
InChI Key : | KFXUHRXGLWUOJT-UHFFFAOYSA-N |
Pubchem ID : | 2734377 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 16 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 62.78 |
TPSA ? Topological Polar Surface Area: Calculated from |
49.69 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 |
2.35 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.16 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.53 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.42 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.09 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.0 |
Solubility | 0.212 mg/ml ; 0.00099 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.03 |
Solubility | 0.198 mg/ml ; 0.000926 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.55 |
Solubility | 0.0599 mg/ml ; 0.00028 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 |
Yes |
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) |
No |
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) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.94 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 |
0.0 |
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) |
2.19 |
* 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 sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 85℃; for 2h;Inert atmosphere; | To a solution of <strong>[19745-07-4]2,5-dichloropyrazine</strong> (2.91 mmole) in 1,2-dimethoxyethane (9 mL), was added 4-(phenoxyphenyl)lboronic acid (3.49 mmole) and tetrakis(triphenylphosphine)palladium (0.145 mmole) followed by 2M Na2CO3 (3 mL). The resulting mixture was heated at 85 C for 2 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite. The organic extract was dried over Na2SO4 and evaporated in vacuo. The crude product was purifed by biotage chromatography and then with prep TLC eluting with 5percent ethyl acetate and hexane mixture to give 2-chloro-5-(4-phenoxyphenyl)pyrazine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; for 0.166667h;Inert atmosphere; Microwave irradiation; | Example 1Synthesis Example 1Example 1 gives a specific example of the synthesis of the organometallic complex represented by the structural formula (100) in Embodiment 1 which is one embodiment of the present invention, (acetylacetonato)bis[3,5-dimethyl-2-(4-phenoxyphenyl)pyrazinato]iridium(III) (abbreviation: [Ir(dmpoppr)2(acac)]). A structure of [Ir(dmpoppr)2(acac)] is illustrated below. Step 1: Synthesis of 3,5-Dimethyl-2-(4-phenoxyphenyl)pyrazine (abbreviation: Hdmpoppr)First, into a recovery flask equipped with a reflux pipe were placed 1.35 g of <strong>[38557-72-1]2-chloro-3,5-dimethylpyrazine</strong>, 2.02 g of 4-phenoxyphenylboronic acid, 1.00 g of sodium carbonate, 0.043 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 15 mL of water, and 15 mL of acetonitrile, and the air inside the flask was replaced with argon. Heating was performed by microwave irradiation (2.45 GHz, 100 W) of this reaction container for 10 minutes, so that reaction occurred. After that, water was added to this reaction solution, and extraction with dichloromethane was carried out. A solution of the obtained extract was washed with water and dried over magnesium sulfate. After the drying, the solution was filtered. After the solvent of this solution was distilled, the obtained residue was washed with methanol, so that the pyrazine derivative which was the object of the synthesis, Hdmpoppr, was obtained (a white powder in a yield of 89%). Note that a microwave synthesis system (Discover, produced by CEM Corporation) was used for the microwave irradiation. The synthesis scheme of Step 1 is illustrated in the following formulae (e). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 12h;Inert atmosphere; | Compound <strong>[953410-86-1]5-bromo-7-iodo-1H-indazole</strong> 20c (2.0 g, 6.2 mmol), (4-phenoxyphenyl)boric acid (1.46 g, 6.8mmol), cesium carbonate (4.04 g, 12.4 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (453 mg, 0.62 mmol), 1,4-dioxane (50 mL), and water (10 mL) were mixed, degassed, and heated at 100C under nitrogen for 12 hrs. The mixture was cooled to room temperature, and then water (100 mL) was added. Next, the mixture was extracted with ethyl acetate (100 mL*2). The organic phases were combined, and desolventized under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/methanol = 30/1), to produce a target compound 5-bromo-7-(4-phenoxyphenyl)-1H-indazole 20d (1.6 g, white solid), yield: 71%. MS m/z(ESI):365, 367[M+1] |
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