Structure of 3-Acetylindole
CAS No.: 703-80-0
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Selective and Cell-Active PBRM1 Bromodomain Inhibitors Discovered through NMR Fragment Screening
Shifali Shishodia ; Raymundo Nuñez ; Brayden P. Strohmier ; Karina L. Bursch ; Christopher J. Goetz ; Michael D. Olp , et al.
Abstract: PBRM1 is a subunit of the PBAF chromatin remodeling complex that uniquely contains six bromodomains. PBRM1 can operate as a tumor suppressor or tumor promoter. PBRM1 is a tumor promoter in prostate cancer, contributing to migratory and immunosuppressive phenotypes. Selective chemical probes targeting PBRM1 bromodomains are desired to elucidate the association between aberrant PBRM1 chromatin binding and cancer pathogenesis and the contributions of PBRM1 to immunotherapy. Previous PBRM1 inhibitors unselectively bind SMARCA2 and SMARCA4 bromodomains with nanomolar potency. We used our protein-detected NMR screening pipeline to screen 1968 fragments against the second PBRM1 bromodomain, identifying 17 hits with Kd values from 45 μM to >2 mM. Structure–activity relationship studies on the tightest-binding hit resulted in nanomolar inhibitors with selectivity for PBRM1 over SMARCA2 and SMARCA4. These chemical probes inhibit the association of full-length PBRM1 to acetylated histone peptides and selectively inhibit growth of a PBRM1-dependent prostate cancer cell line.
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CAS No. : | 703-80-0 |
Formula : | C10H9NO |
M.W : | 159.19 |
SMILES Code : | C1=CC=CC2=C1C(=C[NH]2)C(C)=O |
MDL No. : | MFCD00005626 |
InChI Key : | VUIMBZIZZFSQEE-UHFFFAOYSA-N |
Pubchem ID : | 12802 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 9 |
Fraction Csp3 | 0.1 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 48.49 |
TPSA ? Topological Polar Surface Area: Calculated from |
32.86 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.48 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.15 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.37 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.18 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.85 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.01 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.67 |
Solubility | 0.34 mg/ml ; 0.00214 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.47 |
Solubility | 0.537 mg/ml ; 0.00337 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.61 |
Solubility | 0.0393 mg/ml ; 0.000247 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) |
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) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.74 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 |
0.0 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) |
1.21 |
* 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 |
---|---|---|
89% | 3-acetylindole (15.9 g, 0.10 mol) was added to a dry 250 mL three-necked flask,100 mL of DMF was added,Stirring at 25 C,60 wt% NaH (4.4 g, 0.11 mol) was added in portions,Add after stirring 1h;To the reaction solution was added dropwise dimethyl sulfate (25.2 g, 0.20 mol)After the dropwise addition, the reaction was carried out at 25 C for 1 h.The reaction solution was then poured into 400 mL of ice water and stirred for 1 h,The resulting solid was filtered off and then dried,To give 15.4 g of a pale yellow solid 1-methyl-3-acetylindole,The yield was 89%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | A solution of 0.80 g (5 mmol) of 3-acetylindole in 30 mL of dry THF was added and 0.4 g (2 eq) of NaH in an amount of 60% was added to the flask at 0 C. The mixture was stirred for 15 minutes and 1.3 mL (2 eq) CH3I, the reaction was gradually warmed to room temperature, the reaction 2 hours,TLC showed the disappearance of raw materials; 0 C slowly added ice water to quench the reaction, extracted 2-3 times with ethyl acetate, saturated sodium chloride solutionWashed once, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain 0.73g white solid1- (1-methyl-1H-indol-3-yl) ethanone,Yield: 92.0%. | |
92% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; | To a mixture of 3-acetylindole a (0.157 mol, 25.0 g) in DMF (200 ml) was added potassium carbonate (1.05 equiv., 0.165 mol, 22.8 g) and methyl iodide (1.1 equiv., 0.173 mol, 24.5 g). The mixture was stirred at room temperature overnight. A second portion of both potassium carbonate (2.1 equiv. , 0.330 mol, 45.6 g) and methyl iodide (2.2 equiv. , 0.346 mol, 49.0 g) were added and the mixture was stirred at room temperature for an additional 3 hours. The mixture was concentrated under reduced pressure to 1/5th of the original volume. The residue was dissolved in dichloromethane and washed with water. The organic phase was dried with MgS04 and concentrated in vacuo, affording intermediate b (24.8g, yield = 92%, purity (LC) = 90%). The crude product was used without further purification in the next step. |
80% | General procedure: A mixture of compound 6b (2 g, 11.3 mmol) and KOH (2.5 g, 45.2 mmol) in DMSO (20 mL) was stirring at room temperature for 1 h, followed by addition of iodomethane (1.1 mL, 22.6 mmol). The mixture was allowed to stirring at this temperature for another 4 h and then poured into water, the precipitate was collected by filtration. 9b was obtained as a light yellow solid (1.6 g, 76%). |
80% | To a cold solution of 3-acetylindole 8a (1.0 g, 6.3 mmol) in anhydrous toluene (50 mL), potassium t-butoxide (1.0 g, 8.6 mmol) and TDA-1 (1-2 drops) were added. The reaction mixture was stirred at room temperature for 8 h and then methyl iodide (0.4 mL, 6.3 mmol) was added. TLC analysis (DCM/EtOAc 9/1) revealed that methylation was complete after 2 h. The solvent was evaporated under reduced pressure. The residue was treated with water (50 mL), extracted with DCM (3 × 50 mL), dried (Na2SO4), evaporated under reduced pressure, and purified by column chromatography using DCM/EtOAc (9/1) as eluent. | |
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; | To a mixture of 3-acetylindole 1 (0.157 mol, 25.0 g) in DMF (200 ml) was added potassium carbonate (1.05 equiv. , 0.165 mol, 22.8 g) and methyl iodide (1. 1 equiv. , 0.173 mol, 24.5 g). The mixture was stirred at room temperature overnight. To the mixture was added potassium carbonate (2.1 equiv. , 0.330 mol, 45.6 g) and methyl iodide (2.2 equiv. , 0.346 mol, 49.0 g). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to 1/5 THE original volume. The residue was dissolved in dichloromethane and washed with water. The organic phase was dried with MGS04, concentrated in vacuo, affording intermediate m (purity (LC) = 90%). The crude product was used without further purification in the next step. To a mixture of intermediate m (0.312 mol, 54. 0G) in ethanol (150 ml and water (100 ml) was added acetic acid, sodium salt (2.4 equiv. , 0.748 mol, 61.0 g) and hydroxyl- amine hydrochloride (3 equiv. , 0.935 mol, 65.0 g). The mixture was stirred and heated at reflux for 2.5 hours. The mixture was cooled to room temperature. The reaction mixture was poured into water (750 ml). The precipitate was isolated by filtration and washed with water. The crude precipitate was dissolved in THF (200 ml) and toluene (50 ml) and the mixture was evaporated to dryness (2x), affording intermediate n (purity (LC) = 80 %). The crude product was used as such in the next reaction. Intermediate n (0.312 mol, 58.7g) was dissolved in acetic acid (300 ml). The mixture was stirred and heated at reflux for 2 hours. The mixture was concentrated in vacuo. Toluene (100 ml) added and evaporated to dryness (2x). Crystallization from ethanol (400 ml) gave crude intermediate p (31. 0 g, purity (LC) = 90%). RECRYSTALLIZATION in ethanol (300 ml) afforded p [C. PAPAMICAEL, G. QUeGUINER, J. Bourguignon, G. Dupas Tetrahedron 2001, 57, 5385-5391] as brown crystals (29.4 g, yield = 50%, purity (LC) > 98%). To cooled (0C) dry DMF (40 ML) was added dropwise phosphorus oxychloride (2.5 equiv. , 0.199 mol, 30.6 g) and the reaction mixture was stirred for 0. 5h at 0C. Then, a solution of p (0.080 mol, 15.0 g) in DMF (160 ML) was added. The cooling was removed and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was poured into ice-water (21) and stirred for 0.5 hours. A brown precipitate was isolated by filtration and washed with water. The precipitate was dried for 24 hours in open air, affording intermediate q as a brown powder (6.10 g, yield = 35%, purity (LC) = 95%). A mixture of intermediate q (0.005 mol, 1.13 g), Pd/C-catalyst (10%, 0.50 g) and triethylamine (6.8 equiv. , 0.036 mol, 3.60 g) in TH : F (200 ml) was hydrogenated at atmospheric pressure for 2 hours. The catalyst was removed by filtration. The filtrate was evaporated to give r as a brown powder (0.88g, yield = 92%, purity (LC) > 95%). To a mixture of intermediate r (0.005 mol, 0.880 g) and ethanol (5 ml) was added 3-chloroperoxybenzoic acid (70-75 %, 1.2 equiv. , 0.006 mol, 1.43g). The reaction mixture was heated at reflux for 2 hours. Pyridine (0.5 equiv. , 0.002 mol, 0.190 g) was added and the mixture was heated at reflux for 0. 5H. The reaction mixture was cooled to room temperature and evaporated in vacuo to dryness. The residue was mixed with acetic anhydride (10 ml) and heated at reflux for 4 h and evaporated to dry. The residue was dissolved in 2N potassium hydroxide (50 ml) and stirred for LH. The pH of the reaction mixture was adjusted to 1 by the addition of concentrated hydrochloric acid. A brown precipitate was isolated by filtration. The precipitate was washed with a saturated sodium bicarbonate solution (2x 10 ml), water, isopropanol and diisopropyl ether, affording intermediate s as a brown powder (0.680 g, yield = 71 %, purity (LC) >95%). A mixture OF S (0.001 mol, 0.2 g), copper (II) acetate (2 equiv. , 0.002 mol, 0.366g), 4-acetylphenylboronic acid (2 equiv. , 0.002 mol, 0.328 g) and powdered molecular sieves (4A) in DMF/PYRIDINE (9/1) (3ML) was heated in a stoppered flask at 80C overnight. The molecular sieves were removed by filtration and washed with acetonitrile. The combined filtrates was evaporated under reduced pressure and the crude mixture was purified with by preparative HPLC affording compound 122 (0.066g, yield= 21%, purity (LC) >95%). | |
In tetrahydrofuran; | a 3-Acetyl-1-methyl-1H-indole 3-Acetyl-1H-indole (4.00 g, 0.025 mol) was dissolved in dry THF (100 ml), and treated with 80% sodium hydride (0.794 g, 0.0263 mol) with stirring under At. After 0.5 h, methyl iodide (2.36 ml, 0.038 mol) was added. After 20 h, the reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was then dried (Na2 SO4), and evaporated under reduced pressure to give the title compound as a pale brown oil which crystallized on standing (4.20 g, 97%). 1 H NMR (250 MHz, CDCl3), delta 8.40 (m, 1H), 7.70 (s, 1H), 7.30 (m, 3H), 3.85 (s, 3H), 2.52 (s, 3H). | |
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; | To a mixture of 3-acetylindole 1 (0.157 mol, 25.0 g) in DMF (200 ml) was added potassium carbonate (1.05 equiv., 0.165 mol, 22.8 g) and methyl iodide (1.1 equiv., 0.173 mol, 24.5 g). The mixture was stirred at room temperature overnight. To the mixture was added potassium carbonate (2.1 equiv. , 0.330 mol, 45.6 g) and methyl iodide (2.2 equiv. , 0.346 mol, 49.0 g). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to 1/5th of the original volume. The residue was dissolved in dichloromethane and washed with water. The organic phase was dried with MgS04, concentrated in vacuo, affording intermediate m (purity (LC) = 90%). The crude product was used without further purification in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tetrabutylammomium bromide; sodium hydroxide; In 2-methyltetrahydrofuran; for 3.5h;Reflux; | General procedure: A mixture of 3-acetylindole (6,32 mmol,1 g), tetra-n-butylammoniumbromide (1.5 mol%) and the alkyl halide (1 equiv., 6.32 mmol) in6 mL of 2-methyltetrahydrofuran and 8 mL of a 25% aqueous sodiumhydroxide solution is heated to reflux temperature for 3.5 hours (reactionprogress is also monitored by TLC analysis). Afterward, the contents of theflask is allowed to cool to room temperature, while it separates into twolayers. Diethyl ether is added (10 mL) and the mixture is transferred intoa separation funnel. The organic phase is isolated and dried over MgSO4,whereupon the solvent is evaporated invacuo, furnishing the N-alkylatedindole as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 130℃; for 3h;Inert atmosphere; | General procedure: One point zero equivalent of a ketone compound 1(or a ketone compound 1?), 1.2 equivalents of an alkyl halide or an aryl halide, 3.0 equivalents of potassium carbonate, and five times the theoretical amount of dimethyl sulfoxide were mixed and stirred while heating in a nitrogen atmosphere at 130 C. for 3 hours. After cooling the reaction mixture to room temperature, ion-exchanged water was added, and the thus precipitated solid was collected by filtration, which was thoroughly washed and dried to give a ketone compound 2 (or a ketone compound 2?). |
Tags: 703-80-0 synthesis path| 703-80-0 SDS| 703-80-0 COA| 703-80-0 purity| 703-80-0 application| 703-80-0 NMR| 703-80-0 COA| 703-80-0 structure
A118328 [15128-52-6]
2,3-Dihydro-1H-carbazol-4(9H)-one
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A654623 [4771-48-6]
4-Methyl-1H-indole-3-carbaldehyde
Similarity: 0.94
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P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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