Structure of 1591-38-4
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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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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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Purchased from AmBeed: 77326-36-4 ; 104-87-0 ; 2148-56-3 ; 63329-53-3 ; 1591-37-3 ; 387-45-1 ; 936-08-3 ; 1123-56-4 ; 2819989-75-6 ; 703-80-0 ; 1885-29-6 ; 115643-59-9 ; 15764-16-6 ; 487-68-3 ; 145737-61-7 ; 5779-95-3 ; 88-68-6 ; 6575-11-7 ; 77326-62-6 ; 88-65-3 ; 4635-59-0 ; 5779-94-2 ; 56043-01-7 ; 5779-93-1 ; 1591-38-4 ; 446-52-6 ; 62803-47-8 ; 1885-31-0 ; 620-23-5 ; 54166-95-9 ; 22179-72-2 ; 529-20-4 ; 100-52-7 ; 123-11-5 ; 1711-06-4 ; 454-89-7 ; 170875-01-1 ; 883032-29-9 ; 2819989-61-0 ; 1915012-21-3 ; 2819989-58-5 ; 2819989-60-9 ; 2819989-57-4 ; 2819989-68-7 ; 2819989-67-6 ; 111478-13-8 ; 73096-42-1 ; 2835-78-1 ; 118-92-3 ; 22458-07-7 ; 80258-99-7 ; 24782-64-7 ; 1108790-90-4 ; 175204-03-2 ; 97-96-1 ; 780802-33-7 ; 89-98-5
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CAS No. : | 1591-38-4 |
Formula : | C8H10N2O2 |
M.W : | 166.18 |
SMILES Code : | O=C(N)C1=C(OC)C=CC=C1N |
MDL No. : | MFCD18389707 |
InChI Key : | AQAHTARDEJNYPN-UHFFFAOYSA-N |
Pubchem ID : | 12264814 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319 |
Precautionary Statements: | P264-P280-P302+P352-P305+P351+P338-P332+P313-P337+P313-P362 |
* 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 |
---|---|---|
79% | With water; potassium carbonate; In water; at 150℃; for 0.5h;Microwave irradiation; | General procedure: Adapted from a literature procedure,1 the appropriate organonitrile (1.0 eq.) and K2CO3(0.2eq.)wereaddedtoamicrowavetubewithastir-barwithdeionizedwater(8.5mLpermmolsubstrate).Afterirradiationundermicrowaveat150Cfor30minutes,thereactionmixturewascooled,extractedwithEtOAc(320mL),thecombinedphasesdriedoverMgSO4andexcesssolventremovedinvacuo.TheresiduewaspurifiedbyFCC,ifrequired,togivethetitlecompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 40 2'-Carbamoyl-3'-methoxyoxanilic acid methyl ester. 96 6-Amino-o-anisamide (4.98 g, 0.03 mole) is condensed with 3.04 ml. (0.033 mole) of methyl oxalyl chloride in a manner similar to example 3, giving 4.24 g of the title compound, m.p. 195-198 C., after crystallization from methanol. Elemental Analysis for C11 H12 N2 O5: Calc'd: C, 52.38; H, 4.80; N, 11.11. Found: C, 52.30; H, 4.94; H, 11.40. | ||
EXAMPLE 23 2'-Carbamoyl-3'-methoxyoxanilic acid methyl ester. 96 6-Amino-o-anisamide (4.98 g., 0.03 mole) is condensed with 3.04 ml. (0.033 mole) of methyl oxalyl chloride in a manner similar to example 12, giving 4.24 g. of the title compound, m.p. 195-198 C., after crystallization from methanol. Elemental Analysis for C11 H12 N2 O5: Calc'd: C, 52.28; H, 4.80; N, 11.11. Found: C, 52.30; H, 4.94; H, 11.40. | ||
EXAMPLE 23 2'-Carbamoyl-3'-methoxyoxanilic acid methyl ester. 96 6-Amino-o-anisamide (4.98 g., 0.03 mole) is condensed with 3.04 ml. (0.033 mole) of methyl oxalyl chloride in a manner similar to example 12, giving 4.24 g. of the title compound, m.p. 195-198 C., after crystallization from methanol. Elemental Analysis for C11 H12 N2 O5: Calc'd: C, 52.28; H, 4.80; N, 11.11: Found: C, 52.30; H, 4.94; H, 11.40. |
EXAMPLE 23 2'-Carbamyl-3'-methoxyoxanilic acid methyl ester. 96. 6-Amino-o-anisamide (4.98 g., 0.03 mole) is condensed with 3.04 ml. (0.033 mole) of methyl oxalyl chloride in a manner similar to example 12, giving 4.24 g. of the title compound, m.p. 195-198 C., after crystallization from methanol. Elemental Analysis for C11 H12 N2 O5: Calc'd: C, 52.28; H, 4.80; N, 11.11. Found: C, 52.30; H, 4.94; H, 11.40. | ||
EXAMPLE 40 2'-Carbamoyl-3'-methoxyoxanilic acid methyl ester. 96 6-Amino-o-anisamide (4.98 g, 0.03 mole) is condensed with 3.04 ml. (0.033 mole) of methyl oxalyl chloride in a manner similar to example 3, giving 4.24 g of the title compound, m.p. 195-198 C., after crystallization from methanol. Elemental Analysis for C11 H12 N2 O5: Calc'd: C, 52.38; H, 4.80; N, 11.11. Found: C, 52.30; H, 4.94; H, 11.40. | ||
EXAMPLE 40 2'-Carbamoyl-3'-methoxyoxanilic acid methyl ester. 96 6-Amino-o-anisamide (4.98 g, 0.03 mole) is condensed with 3.04 ml. (0.033 mole) of methyl oxalyl chloride in a manner similar to example 3, giving 4.24 g of the title compound, m.p. 195-198C., after crystallization from methanol. Elemental Analysis for C11 H12 N2 O5: Calc'd: C, 52.38; H, 4.80; N, 11.11. Found: C, 52.30; H, 4.94; H, 11.40. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In tetrahydrofuran; at 35℃; for 2h;Cooling with ice; | Step 3 (1550) To a solution of <strong>[1591-38-4]2-amino-6-methoxybenzamide</strong> (960 mg, 5.78 mmol) and triethylamine (701 mg, 6.93 mol) in THF (20 mL) was added dropwise ethyl chloroglyoxylate (868 mg, 6.36 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was diluted with ethyl acetate, the mixture was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained concentrated residue was washed with ethanol, ethyl ((2-(aminocarbonyl)-3-methoxyphenyl)amino)(oxo)acetate to give a yellow powder (1.56 g, 100%). |
EXAMPLE 34 2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester. 100/94 6-Amino-o-anisamide (8.75 g, 0.0527 mole) is condensed with 6.2 ml (0.0554 mole) of ethyl oxalyl chloride in a manner similar to example 3, giving 8.35 g of the title compound, m.p. 170-173 C., after crystallization from ethanol. Elemental Analysis for C12 H14 N2 O5: Calc'd: C, 54.13; H, 5.30; N, 10.52. Found: C, 54.36; H, 5.20; N, 10.66. | ||
EXAMPLE 18 2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester. 100/94. 6-Amino-o-anisamide (8.75 g., 0.0527 mole) is condensed with 6.2 ml. (0.0554 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 8.35 g. of the title compound, m.p. 170-173 C., after crystallization from ethanol. Elemental Analysis for C12 H14 N2 O5: Calc'd: C, 54.13; H, 5.30; N, 10.52. Found: C, 54.36; H, 5.20; N, 10.66. |
EXAMPLE 18 2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester. 100/94 6-Amino-o-anisamide (8.75 g., 0.0527 mole) is condensed with 6.2 ml. (0.0554 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 8.35 g. of the title compound, m.p. 170-173 C., after crystallization from ethanol. Elemental Analysis for C12 H14 N2 O5: Calc'd: C, 54.13; H, 5.30; N, 10.52: Found: C, 54.36; H, 5.20; N, 10.66. | ||
EXAMPLE 18 2'-Carbamyl-3'-methoxyoxanilic acid ethyl ester. 100/94. 6-Amino-o-anisamide (8.75 g., 0.0527 mole) is condensed with 6.2 ml. (0.0554 mole) of ethyl oxalyl chloride in a manner similar to example 12, giving 8.35 g. of the title compound, m.p. 170-173 C., after crystallization from ethanol. Elemental Analysis for C12 H14 N2 O5: Calc'd: C, 54.13; H, 5.30; N, 10.52. Found: C, 54.36; H, 5.20; N, 10.66. | ||
EXAMPLE 34 2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester. 100/94 6-Amino-o-anisamide (8.75 g, 0.0527 mole) is condensed with 6.2 ml (0.0554 mole) of ethyl oxalyl chloride in a manner similar to example 3, giving 8.35 g of the title compound, m.p. 170-173C., after crystallization from ethanol. Elemental Analysis for C12 H14 N2 O5: Calc'd: C, 54.13; H, 5.30; N, 10.52. Found: C, 54.36; H, 5.20; N, 10.66. | ||
In pyridine; dichloromethane; | EXAMPLE 1 [2-(aminocarbonyl)-3-methoxyphenylamino]oxoacetic acid ethyl ester 6-Amino-o-anisamide(8.75 g.) is condensed with 6.2 ml. of ethyl oxalyl chloride in 100 ml. methylene chloride in the presence of 9.6 ml. of pyridine at 10 C. Aqueous work-up and evaporation of the methylene chloride followed by recrystallization from ethanol gives the title compound, m.p. 170-173 C. Anal. Calcd. for C12 H14 N2 O5: C, 54.13; H, 5.30; N, 10.52. Found: C, 54.36; H, 5.20; N, 10.66. Potency: 12.5 mg/kg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 115℃; for 20.0h; | To a solution of 2-amino-6-methoxy-benzamide (1.00 g, 6.01 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (1.28 g, 6.59 mmol) in N,N-dimethylacetamide (15 mL) were added NaHSO3 (58.5 wt %, 0.68 g, 6.50 mmol) and p-TSA (0.23 g, 1.20 mmol) and the reaction mixture was heated at 115 C. for 20 hours, and cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered. The solid was suspended in dichloromethane (30 mL), stirred for 1 h, filtered, and dried under vacuum to give 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5-methoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.1 g (55%) |
55% | With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl acetamide; at 115℃; for 20.0h; | To a solution of 2-amino-6-methoxy-benzamide (1.00 g, 6.01 mmol) and <strong>[1039948-89-4]4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde</strong> (1.28 g, 6.59 mmol) in N,N-dimethylacetamide (15 mL) were added NaHSO3 (58.5 wt %, 0.68 g, 6.50 mmol) and p-TSA (0.23 g, 1.20 mmol) and the reaction mixture was heated at 115 C. for 20 hours, and cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered. The solid was suspended in dichloromethane (30 mL), stirred for 1 h, filtered, and dried under vacuum to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.1 g (55%). |
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