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DC_AC50
3-amino-N-(2-bromo-4,6-difluorophenyl)-6,7-dihydro-5H- cyclopenta [b] thieno [3,2-e] pyridine-2-carboxamide
licensed DC_AC50 to Suring Therapeutics, in Suzhou, China
INNOVATORS Jing Chen of Emory University School of Medicine, Hualiang Jiang of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, Chuan He of the University of Chicago, and coworkers
http://www.google.com/patents/WO2014116859A1?cl=en
COMPD IS LC-1 COMPD 50
Scheme 1 (Compounds LCI -LCI 9):
Experimental procedure for Scheme 1 :
Step a: To 1 equivalent of sodium metal in anhydrous diethyl ether is added 1-2 equivalents of ethyl formate and 1-2 equivalents of cyclopentanone. The resulting mixture is stirred overnight. The mother liquor is filtered by suction filtration to obtain crude intermediate 2.
Step b: To a solution of intermediate 2 in an organic solvent, is added 0.1 to 1 equivalent of glacial acetic acid. The reaction is stirred at 50-100 °C, then 2′ and 0.1 to 1 equivalent of glacial acetic acid are added. The resulting reaction mixture is refluxed for 1-5 hours, filtered and recrystallized to produce product 3; the said organic solvent may optionally be tetrahydrofuran, ether, dimethylformamide, ethyleneglycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. Step c: To a solution of compound 3 in an organic solvent, is added 1 equivalent of methyl bromoacetate and an appropriate amount of base. The reaction mixture is stirted at room temperature to produce intermediate 4. The said organic solvent may optionally be tetrahydrofuran, aether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. The said base may optionally be potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and their aqueous solution in various concentrations.
Step d: The base described in Step c is added to a solution of compound 4 in an organic solvent. The reaction mixture is stirred and heated to produce intermediate 5. Step e: An appropriate amount of di-tert-butyl dicarbonate and alkali are added to a solution of compound 5 in an organic solvent. The reaction is stirred to produce intermediate 6.
Step f: An appropriate amount of base is added to a solution of compound 6 in an organic solvent, which is then hydro lyzed to produce intermediate 7.
Step g: 3′ and a stoichiometric amount of condensing agent are added to a solution of compound 7 in an organic solvent. The reaction mixture is stirred until 3′ reacts completely to produce the final product. The said organic so ί vers t may optional iy be tetrahydrofuran, aether, dimethyl formamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. The said condensing agent may optionally be DCC, EDO, HOBt, and GDI. Step h: To a solution of compound 7 in an organic solvent is added aqueous hydrochloric acid or trifluoroacetic acid. The reaction mixture is stirred vigorously to yield the BOC- deprotected final product.
Scheme 2 (Compounds LCI -LCI 9)
LCI ~LC39
Experimental procedure for Scheme 2(Compounds LC1-LC19):
Step a: Dissolve 1 equivalent of sodium in anhydrous ether, which shall be added slowly under an ice bath and rapid stirring condition. Add 1 equivalent of ethyl formate and 1 equivalent of cyclopentanone in a constant pressure dropping funnel, add 0.5 ml ethanol as an initiator, after 1 hour of stirring in ice bath, and stir overnight at room temperature until the reaction of sodium is finished. Perform suction filtration, wash with absolute ether to produce crude product for the following steps of reaction.
Step b: Dissolve the product in above steps directly in ethanol and control its amount, add an appropriate amount of glacial acetic acid, and stir and reflux under 70°C. Add cyano- sulfamide into the reaction solution, and add an appropriate amount of glacial acetic acid, react and reflux for about 3 hours. Recrystallize with ethanol to produce crude product.
Step c: Add 1 equivalent of the appropriate aniline or phenol and 2 equivalents of potassium carbonate solid in a round-bottomed flask that is placed in ice bath, add anhydrous THF to fully dissolve the solid, add 1.5 equivalents of bromoacetyl bromide into a constant pressure dropping funnel and dilute with THF, which is slowly dropped into the former said round- bottomed flask that is moved to room temperature in 10 min late and react for 1 hour; extract and dry with anhydrous sodium sulfate, filtrate by suction, and perform rotary evaporation to remove the solvent, and the crude product is obtained, which is to be used directly in the next step of reaction.
Step d: Dissolve the product from Step 2 into DMF under normal temperature by mixing, add 3 equivalents of 10% KOH solution, which is then transferred to an oil bath of 70°C and react, and add I equivalent of the product from step 3. Stir for about 3 hours and then extract directly with ethyl acetate, and recrystallize the crude product with ethanol to produce pure end product.
Steps a and b: Intermediate 3 is prepared in accordance with the method outlined in Scheme 1. Step c: 3′ and bromoacetyl bromide are condensed in the presence of a suitable base to produce intermediate 9. The said base may optionally be potassium hydroxide, sodium hydroxide, sodiumcarbonate, potassium carbonate, cesium carbonate, and their aqueous solution in various concentrations.
Step d: An appropriate amount of base is added to a solution of compound 3 in an organic solvent, and the reaction mixture is heated to 40-100 °C. Intermediate 9 is added, and the heated solution is stirred for 1-10 hours to yield the final product. The said organic solvent may optionally be tetrahydrofuran, aether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. The said base may optionally be potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and their aqueous solution in various concentrations.
NMR and mass spectral data: LC-1 (Compound 50)- 3-amino-N-(2-bromo-4,6-difluorophenyl)-6,7-dihydro-5H- cyclopenta [b] thieno [3,2-e] pyridine-2-carboxamide
1H NMR (CDCI3, 400 MHz) δ 9.15 (s, 1H),
7.61 (s, 1H), 7.13(m, 1H), 6.60 (m, 1H), 6.27 (s, 2H), 3.20 (t, 2H),
2.98 (t, 2H), 2.39 (m, 2H); ESI-MS (EI) m/z 422 (M+)
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DC_AC50
3-amino-N-(2-bromo-4,6-difluorophenyl)-6,7-dihydro-5H- cyclopenta [b] thieno [3,2-e] pyridine-2-carboxamide
licensed DC_AC50 to Suring Therapeutics, in Suzhou, China
INNOVATORS Jing Chen of Emory University School of Medicine, Hualiang Jiang of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, Chuan He of the University of Chicago, and coworkers
COPPER TRANSPORT
Chaperone proteins (green) transfer copper ions to
copper-dependent proteins (lilac) via ligand exchange between two
cysteines (-SH groups) on each protein. DC_AC50 binds the chaperone and
inhibits this interaction.
Credit: Nat. Chem.
Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation
- Nature Chemistry, (2015)
- doi:10.1038/nchem.2381
Jing Chen of Emory University School of Medicine, Hualiang Jiang of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, Chuan He of the University of Chicago, and coworkers have now developed a selective way of blocking copper transport in cancer cells (Nat. Chem.
2015, DOI: 10.1038/nchem.2381). By screening a database of 200,000
druglike small molecules, the researchers discovered a promising
compound, DC_AC50, for cancer treatment. They zeroed in on the compound
by testing how well database hits inhibited a protein-protein
interaction leading to copper transport and reduced proliferation of
cancer cells.
Scientists had already found a molecule, tetrathiomolybdate, that
interferes with copper trafficking and have tested it in clinical trials
against cancer. But tetrathiomolybdate is a copper chelator: It
inhibits copper transport in cells by nonselectively sequestering copper
ions. Sometimes, the chelator snags too much copper, inhibiting
essential copper-based processes in normal cells and causing side
effects.
In contrast, DC_AC50 works by inhibiting interactions between
proteins in the copper-trafficking pathway: It prevents chaperone
proteins, called Atox1 and CCS, from passing copper ions to enzymes that
use them to run vital cellular processes. Cancer cells are heavy users
of Atox1 and CCS, so DC_AC50 affects cancer cells selectively.
The team has licensed DC_AC50 to Suring Therapeutics, in Suzhou,
China, for developing anticancer therapies. The group also plans to
further tweak DC_AC50 to develop more-potent versions.
Thomas O’Halloran
of Northwestern University, who has studied tetrathiomolybdate,
comments that “the challenge in drug design is hitting one of these
copper-dependent processes without messing with housekeeping functions
that normal cells depend upon. DC_AC50 appears to block the function of
copper metallochaperone proteins without interacting directly with their
cargo, copper ions. As the first member of a new class of inhibitors,
it provides a new way to interrogate the physiology of copper
trafficking disorders and possibly intervene.”
PATENThttp://www.google.com/patents/WO2014116859A1?cl=en
COMPD IS LC-1 COMPD 50
Scheme 1 (Compounds LCI -LCI 9):
Step a: To 1 equivalent of sodium metal in anhydrous diethyl ether is added 1-2 equivalents of ethyl formate and 1-2 equivalents of cyclopentanone. The resulting mixture is stirred overnight. The mother liquor is filtered by suction filtration to obtain crude intermediate 2.
Step b: To a solution of intermediate 2 in an organic solvent, is added 0.1 to 1 equivalent of glacial acetic acid. The reaction is stirred at 50-100 °C, then 2′ and 0.1 to 1 equivalent of glacial acetic acid are added. The resulting reaction mixture is refluxed for 1-5 hours, filtered and recrystallized to produce product 3; the said organic solvent may optionally be tetrahydrofuran, ether, dimethylformamide, ethyleneglycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. Step c: To a solution of compound 3 in an organic solvent, is added 1 equivalent of methyl bromoacetate and an appropriate amount of base. The reaction mixture is stirted at room temperature to produce intermediate 4. The said organic solvent may optionally be tetrahydrofuran, aether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. The said base may optionally be potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and their aqueous solution in various concentrations.
Step d: The base described in Step c is added to a solution of compound 4 in an organic solvent. The reaction mixture is stirred and heated to produce intermediate 5. Step e: An appropriate amount of di-tert-butyl dicarbonate and alkali are added to a solution of compound 5 in an organic solvent. The reaction is stirred to produce intermediate 6.
Step f: An appropriate amount of base is added to a solution of compound 6 in an organic solvent, which is then hydro lyzed to produce intermediate 7.
Step g: 3′ and a stoichiometric amount of condensing agent are added to a solution of compound 7 in an organic solvent. The reaction mixture is stirred until 3′ reacts completely to produce the final product. The said organic so ί vers t may optional iy be tetrahydrofuran, aether, dimethyl formamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. The said condensing agent may optionally be DCC, EDO, HOBt, and GDI. Step h: To a solution of compound 7 in an organic solvent is added aqueous hydrochloric acid or trifluoroacetic acid. The reaction mixture is stirred vigorously to yield the BOC- deprotected final product.
Scheme 2 (Compounds LCI -LCI 9)
Experimental procedure for Scheme 2(Compounds LC1-LC19):
Step a: Dissolve 1 equivalent of sodium in anhydrous ether, which shall be added slowly under an ice bath and rapid stirring condition. Add 1 equivalent of ethyl formate and 1 equivalent of cyclopentanone in a constant pressure dropping funnel, add 0.5 ml ethanol as an initiator, after 1 hour of stirring in ice bath, and stir overnight at room temperature until the reaction of sodium is finished. Perform suction filtration, wash with absolute ether to produce crude product for the following steps of reaction.
Step b: Dissolve the product in above steps directly in ethanol and control its amount, add an appropriate amount of glacial acetic acid, and stir and reflux under 70°C. Add cyano- sulfamide into the reaction solution, and add an appropriate amount of glacial acetic acid, react and reflux for about 3 hours. Recrystallize with ethanol to produce crude product.
Step c: Add 1 equivalent of the appropriate aniline or phenol and 2 equivalents of potassium carbonate solid in a round-bottomed flask that is placed in ice bath, add anhydrous THF to fully dissolve the solid, add 1.5 equivalents of bromoacetyl bromide into a constant pressure dropping funnel and dilute with THF, which is slowly dropped into the former said round- bottomed flask that is moved to room temperature in 10 min late and react for 1 hour; extract and dry with anhydrous sodium sulfate, filtrate by suction, and perform rotary evaporation to remove the solvent, and the crude product is obtained, which is to be used directly in the next step of reaction.
Step d: Dissolve the product from Step 2 into DMF under normal temperature by mixing, add 3 equivalents of 10% KOH solution, which is then transferred to an oil bath of 70°C and react, and add I equivalent of the product from step 3. Stir for about 3 hours and then extract directly with ethyl acetate, and recrystallize the crude product with ethanol to produce pure end product.
Steps a and b: Intermediate 3 is prepared in accordance with the method outlined in Scheme 1. Step c: 3′ and bromoacetyl bromide are condensed in the presence of a suitable base to produce intermediate 9. The said base may optionally be potassium hydroxide, sodium hydroxide, sodiumcarbonate, potassium carbonate, cesium carbonate, and their aqueous solution in various concentrations.
Step d: An appropriate amount of base is added to a solution of compound 3 in an organic solvent, and the reaction mixture is heated to 40-100 °C. Intermediate 9 is added, and the heated solution is stirred for 1-10 hours to yield the final product. The said organic solvent may optionally be tetrahydrofuran, aether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. The said base may optionally be potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and their aqueous solution in various concentrations.
NMR and mass spectral data: LC-1 (Compound 50)- 3-amino-N-(2-bromo-4,6-difluorophenyl)-6,7-dihydro-5H- cyclopenta [b] thieno [3,2-e] pyridine-2-carboxamide
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