Abstract：
:Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential anti-tumor agents. Novel series of cyanopyridyl-aminothiadiazoles (synthesized from reaction of 1-(3-cyano-4,6-diphenylpyridin-2-yl)-3-phenylthiourea (14) with hydrazonoyl halides) and cyanopyridyl-aminothiazolyl-thiadiazoles (synthesized from treatment of 14 with ethyl chloroacetate followed by reaction of the obtained cyanopyridyl-aminothiazole with hydrazonoyl halides) were synthesized and evaluated for their CHK1 inhibitory potential using a cell-based assay cascade. The tested compounds exhibited a potent and selective CHK1 inhibitory activity at nanomolar levels that reflected their ability to abrogate cell cycle arrest and potentiate the cytotoxic effect of the genotoxic drug gemcitabine in colon cancer cells. Molecular modeling simulation revealed that, the most active compound 28a docked well into the enzyme active site and their complex is stabilized by a key H-bonding with the backbone amide of Cys-87 as well as multiple favorable hydrophobic interactions with different hydrophobic binding regions of the enzyme.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Gomha SM,Abdulla MM,Abou-Seri SMdoi
10.1016/j.ejmech.2015.01.019subject
Has Abstractpub_date
2015-03-06 00:00:00pages
459-70eissn
0223-5234issn
1768-3254pii
S0223-5234(15)00039-2journal_volume
92pub_type
杂志文章,收录出版abstract：:Phosphodiesterase (PDE) 7 is a high affinity cAMP-specific PDE whose functional role in T-cells has been the subject of some controversy. Recent findings on tissue distribution, however, support the hypothesis that PDE7 could be a good target for the treatment of airway diseases, T-cell related diseases or central ner...
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