- Synthesis and biological evaluation of 3-aminoisoquinolin-1(2H)-one based inhibitors of the dual-specificity phosphatase Cdc25B
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The cell division cycle 25B dual specificity phosphatase (Cdc25B) regulates the normal progression of the mammalian cell cycle by dephosphorylating and activating cyclin-dependent kinase (Cdk) complexes, particularly in response to DNA damage. Elevated Cdc25B levels enable a bypass of normal cell cycle checkpoints, and the overexpression of Cdc25B has been linked to a variety of human cancers. Thus, Cdc25B is an attractive target for the development of anticancer therapeutics. Herein we describe the synthesis and biological evaluation of a series of non-quinoid inhibitors of Cdc25B containing the 3-aminoisoquinolin-1(2H)-one pharmacophore. In addition to several strategies that address specific substitution patterns on isoquinolines, we have applied a regioselective Pd-catalyzed cross-coupling methodology to synthesize a new lead structure, 6-(3-aminophenyl)-3-(phenylamino)isoquinolin-1(2H)-one (13), which proved to be a reversible, competitive Cdc25B inhibitor with a Ki of 1.9 μM. Compound 13 prevented human cancer cell growth and blocked Cdc25B-mediated mitotic checkpoint bypass. Molecular docking studies support binding near the catalytic site.
- George Rosenker, Kara M.,Paquette, William D.,Johnston, Paul A.,Sharlow, Elizabeth R.,Vogt, Andreas,Bakan, Ahmet,Lazo, John S.,Wipf, Peter
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p. 2810 - 2818
(2015/03/04)
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- ISOQUINOLINE AMINOPYRAZOLE DERIVATIVES, THEIR MANUFACTURE AND USE AS PHARMACEUTICAL AGENTS FOR THE TREATMENT OF CANCER
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Objects of the present invention are the compounds of formula (I) their pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture, as well as the use of the above-mentioned compounds in the control or prevention of illnesses such as cancer.
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Page/Page column 63-64
(2008/06/13)
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- Hydroformylation
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The present invention relates to a process for hydroformylating in the presence of a catalyst comprising at least one complex of a metal of transition group VIII with mono-phosphorus compounds which are capable of dimerizing via noncovalent bonds as ligands, to such catalysts and to their use.
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- A Convenient Synthesis of 2-Acylphenylacetonitriles
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The reaction of 2-cyanomethylbenzoyl chloride with Grignard reagents in the presence of cuprous iodide at -5°C easily affords 2-acylphenylacetonitriles with good yield.
- Canepa, Alicia S.,Bravo, Rodolfo D.
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p. 579 - 588
(2007/10/03)
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