YK-4-279

Iupac Name：4,7-dichloro-3-hydroxy-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-indol-2-one

Molecular Weight：366.194

Modify Date.: 2022-11-22 20:12

Introduction:

An oncogenic fusion protein found in Ewing's sarcoma, a family of undifferentiated tumors which occur throughout the body. The binding of ES-FLI1 to RNA helicase A (RHA) promotes its oncogenic function. Inhibits protein-protein interactions between ES-FLI1 and RHA. At 10 μM, YK-4-279 blocks RHA binding to ES-FLI1 and induces apoptosis of a panel of Ewing's sarcoma tumor cell lines with IC50 values ranging from 0.5 to 2 μM.1 At 1.5 mg per dose, YK-4-279 reduces the growth of Ewing's sarcoma orthotopic xenografts in mice after treatment with the inhibitor for two weeks.

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1. Names and Identifiers

1.1 Name: YK-4-279
1.2 Synonyms: 2H-Indol-2-one, 4,7-dichloro-1,3-dihydro-3-hydroxy-3-[2-(4-methoxyphenyl)-2-oxoethyl]- 4,7-Dichloro-1,3-dihydro-3-hydroxy-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2H-indol-2-one 4,7-Dichloro-1,3-dihydro-3-hydroxy-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2H-indol-2-one YK-4-279 4,7-dichloro-3-hydroxy-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-indol-2-one CS-1785 YK-4-279 USP/EP/BP

1.3 CAS No.: 1037184-44-3

1.4 CID: 44632017

1.5 Molecular Formula: C17H13Cl2NO4 (isomer)

1.6 Inchi: InChI=1S/C17H13Cl2NO4/c1-24-10-4-2-9(3-5-10)13(21)8-17(23)14-11(18)6-7-12(19)15(14)20-16(17)22/h2-7,23H,8H2,1H3,(H,20,22)

1.7 InChkey: HLXSCTYHLQHQDJ-UHFFFAOYSA-N

1.8 Canonical Smiles: COC1=CC=C(C=C1)C(=O)CC2(C3=C(C=CC(=C3NC2=O)Cl)Cl)O

1.9 Isomers Smiles: COC1=CC=C(C=C1)C(=O)CC2(C3=C(C=CC(=C3NC2=O)Cl)Cl)O

2. Properties

2.1 Density: 1.456

2.1 Melting point: 149-151℃

2.1 Boiling point: 608.9±55.0 °C(Predicted)

2.1 Refractive index: 1.631

2.1 Flash Point: 322.1±31.5 °C

2.1 Precise Quality: 365.02200

2.1 PSA: 75.63000

2.1 logP: 3.55270

2.1 Storage: Store at -20° C.

2.2 Chemical Properties: A crystalline solid

2.3 pKa: 10.43±0.20(Predicted)

2.4 StorageTemp: Store at -20° C.

3. Use and Manufacturing

3.1 Methods of Manufacturing: In these schemes, ketone (4.0 equiv.) and a catalytic amount of diethylamine (10 drops) are added to a solution of substituted isatin (1.0 equiv.) in methanol (5 mL). The mixture is stirred at room temperature until starting material (substituted isatin) disappears completely. The resulting solution is concentrated and applied to flash chromatography eluting with hexane / ethyl acetate to afford pure product in quantitative yield. Further purification is done by recrystallization with hexane / ethyl acetate. An example compound synthesized by the above scheme includes: 4, 7-Dichloro-3- hydroxy-3-[2-(4-methoxyphenyl-2-oxoethyl)]-l, 3-dihydroindol-2-one: white solid; mp 149- 151 °C; 1H NMR (DMSO, 400 MH 1 z) delta 10.93 (s, 1H), 7.86 (d, 2H, J = 9.2 Hz), 7.26 (d, 1H, J = 8.8 Hz), 6.98 (d, 2H, J= 8.8 Hz), 6.86 (d, 1H, J = 8.4 Hz), 6.39 (s, 1H), 4.31 (d, 1H, J= 18.0 Hz), 3.80 (s, 3H), 3.61 (d, 1H, J= 18.0 Hz).Example 2' Synthesis of dehydrated 4, 7 dichloroisatm analogs [0144] A solution of 4, 7-dichloroisatin in 96percent H2S04 was stirred at room temperature to yield the reduced analogs. Example compounds: R2 = 4'-OCH3 (PT-1-33); 2', 4'- OCH3 (PT-1-39); 2', 3', 4', -OCH3 (PT-1-41); 4'-OC2H5 (PT-1-43); and 4'-N(CH3)2 (PT-1-38).General procedure: A solution of 4, 7-dichloroisatin in 96percent H2S04 was stirred at room temperature to yield the reduced analogs. Example compounds: R2 = 4 -OCH3 (PT-1-33); 2', 4'-OCH3 (PT-1-39); 2', 3', 4', -OCH3 (PT-1-41); 4'-OC2H5 (PT-1-43); and 4'-N(CH3)2 (PT-1-38).

4. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

no data available

2.2 GHS label elements, including precautionary statements

Pictogram(s)	no data available
Signal word	no data available
Hazard statement(s)	no data available
Precautionary statement(s)
Prevention	no data available
Response	no data available
Storage	no data available
Disposal	no data available

2.3 Other hazards which do not result in classification

no data available

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5. NMR Spectrum

13C NMR : Predict

1H NMR : Predict

6. Other Information

6.0 体外研究: YK-4-279 eliminates cyclin D levels by blocking the interaction of EWS-FLI1 with RHA in EWS-FLI1-containing TC32 cells. YK-4-279 also specifically inhibits ESFT cell growth and induces apoptosis. YK-4-279 also inhibits ERG and ETV1 biological activity in fusion-positive prostate cancer cells, and further decreases cell motility and invasion.

6.1 体内研究: In vivo, YK-4-279 (1.5 mg/dose i.p.) inhibits the growth of ESFT xenograft tumors. In mouse model, YK-4-279 selectively prevents prostate cancer growth and metastasis in fusion-positive LNCaP-luc-M6 tumors.

6.2 Chemical Properties: A crystalline solid

6.3 Storage Conditions: In these schemes, ketone (4.0 equiv.) and a catalytic amount of diethylamine (10 drops) are added to a solution of substituted isatin (1.0 equiv.) in methanol (5 mL). The mixture is stirred at room temperature until starting material (substituted isatin) disappears completely. The resulting solution is concentrated and applied to flash chromatography eluting with hexane / ethyl acetate to afford pure product in quantitative yield. Further purification is done by recrystallization with hexane / ethyl acetate. An example compound synthesized by the above scheme includes: 4, 7-Dichloro-3- hydroxy-3-[2-(4-methoxyphenyl-2-oxoethyl)]-l, 3-dihydroindol-2-one: white solid; mp 149- 151 °C; 1H NMR (DMSO, 400 MH 1 z) delta 10.93 (s, 1H), 7.86 (d, 2H, J = 9.2 Hz), 7.26 (d, 1H, J = 8.8 Hz), 6.98 (d, 2H, J= 8.8 Hz), 6.86 (d, 1H, J = 8.4 Hz), 6.39 (s, 1H), 4.31 (d, 1H, J= 18.0 Hz), 3.80 (s, 3H), 3.61 (d, 1H, J= 18.0 Hz).Example 2' Synthesis of dehydrated 4, 7 dichloroisatm analogs [0144] A solution of 4, 7-dichloroisatin in 96percent H2S04 was stirred at room temperature to yield the reduced analogs. Example compounds: R2 = 4'-OCH3 (PT-1-33); 2', 4'- OCH3 (PT-1-39); 2', 3', 4', -OCH3 (PT-1-41); 4'-OC2H5 (PT-1-43); and 4'-N(CH3)2 (PT-1-38).General procedure: A solution of 4, 7-dichloroisatin in 96percent H2S04 was stirred at room temperature to yield the reduced analogs. Example compounds: R2 = 4 -OCH3 (PT-1-33); 2', 4'-OCH3 (PT-1-39); 2', 3', 4', -OCH3 (PT-1-41); 4'-OC2H5 (PT-1-43); and 4'-N(CH3)2 (PT-1-38).

7. Computational chemical data

Molecular Weight: 366.194g/mol
Molecular Formula: C₁₇H₁₃Cl₂NO₄
Compound Is Canonicalized: True
XLogP3-AA: 3.1
Exact Mass: 365.0221633
Monoisotopic Mass: 365.0221633
Complexity: 509
Rotatable Bond Count: 4
Hydrogen Bond Donor Count: 2
Hydrogen Bond Acceptor Count: 4
Topological Polar Surface Area: 75.6
Heavy Atom Count: 24
Defined Atom Stereocenter Count: 0
Undefined Atom Stereocenter Count: 1
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 1
CACTVS Substructure Key Fingerprint: AAADccB6OAAGAAAAAAAAAAAAAAAAAWAAAAAwYAAAAAAAAFgBQAAAHgIQCAAADE6BmCIyxoLABgCIAqVSUAKCCAAlJQAIiAFGTsgOJjbFt5vEcShm5BHY+YedzeDeoAAQIAIDABBAACBABAYAIAAAAAAAAA==

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Purity:99%Packing: 200kg/bag FOB
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Time: 2019/02/25

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YK-4-279