55653-17-3Relevant academic research and scientific papers
4-Arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects
Kry?tof, Vladimír,Canka?, Petr,Fry?ová, Iveta,Slouka, Jan,Kontopidis, George,D?ubák, Petr,Hajdúch, Marián,Srovnal, Josef,De Azevedo Jr., Walter F.,Orság, Martin,Paprská?ová, Martina,Rol?ík, Jakub,Látr, Ale?,Fischer, Peter M.,Strnad, Miroslav
, p. 6500 - 6509 (2007/10/03)
In a routine screening of our small-molecule compound collection we recently identified 4-arylazo-3,5-diamino-1H-pyrazoles as a novel group of ATP antagonists with moderate potency against CDK2-cyclin E. A preliminary SAR study based on 35 analogues suggests ways in which the pharmacophore could be further optimized, for example, via substitutions in the 4-aryl ring. Enzyme kinetics studies with the lead compound and X-ray crystallography of an inhibitor-CDK2 complex demonstrated that its mode of inhibition is competitive. Functional kinase assays confirmed the selectivity toward CDKs, with a preference for CDK9-cyclin T1. The most potent inhibitor, 4-[(3,5-diamino-1H-pyrazol-4-yl) diazenyl]phenol 31b (CAN508), reduced the frequency of S-phase cells of the cancer cell line HT-29 in antiproliferation assays. Further observed cellular effects included decreased phosphorylation of the retinoblastoma protein and the C-terminal domain of RNA polymerase II, inhibition of mRNA synthesis, and induction of the tumor suppressor protein p53, all of which are consistent with inhibition of CDK9.
On the chemistry of cinnoline I. synthesis and reactions of (4-Amino-cinnolin-3-yl)-p-tolyl-methanones
Amer, Atef M.,El-Bermaui, Mohamed A.,Ahmed, Ahmed F. S.,Soliman, Somya M.
, p. 1409 - 1418 (2007/10/03)
The synthesis of a series of (4-Amino-cinnolin-3-yl)-p-tolyl-methanones from aryl-hydrazonomalononitrile in a one step procedure is reported. The (4-amino-cinnolin-3-yl)-p-tolyl-methanones could be annelated to the corresponding 1,2-dihydro-4-(p-tolyl)-2-oxopyrido[3,2-c]cinnoline derivatives via (4-acetamido-cinnolin-3-yl)-p-tolyl-methanones. Treatment of 1,2-dihydro-9-methyl-4-(p-tolyl)-pyrido[3,2-c]cinnoline-2-one with POCl1 and P2S5 gave 2-chloro-9-methyl-4-(p-tolyl)-pyrido[3,2-c]cinnoline and 1,2-dihydro-9-methyl-4-(p-tolyl)-pyrido[3,2-c]cinnoline-2-thione. Treatment of the ketone with malononitrile afforded 2-amino-3-cyano-9-methyl-4-(p-tolyl)-pyrido[3,2-c]cinnoline. Using these ketones, a facile and convenient route towards substituted pyrimidino[5,4-c]-cinnolines was developed. Chemical and spectroscopic evidences for the structures of the new compounds are presented.
