The first synthesis of 3-methoxalylchromone was described. The reaction of the latter with electron-rich aminoheterocycles afforded a set of heteroannelated pyridines bearing a CO(2)Me substituent located at the α-position of the pyridine core.
CDC25
phosphatases are key cell cycle regulators and represent
very attractive but challenging targets for anticancer drug discovery.
Here, we explored whether fragment-based screening represents a valid
approach to identify inhibitors of CDC25B. This resulted in identification
of 2-fluoro-4-hydroxybenzonitrile, which directly binds to the catalytic
domain of CDC25B. Interestingly, NMR data and the crystal structure
demonstrate that this compound binds to the pocket distant from the
active site and adjacent to the protein–protein interaction
interface with CDK2/Cyclin A substrate. Furthermore, we developed
a more potent analogue that disrupts CDC25B interaction with CDK2/Cyclin
A and inhibits dephosphorylation of CDK2. Based on these studies,
we provide a proof of concept that targeting CDC25 phosphatases by
inhibiting their protein–protein interactions with CDK2/Cyclin
A substrate represents a novel, viable opportunity to target this
important class of enzymes.
The reaction of electron-rich aminoheterocycles with 1,3-CCC-dielectrophiles, such as 3-formylchromones, acylpyruvates, and chalcone, provided diversely fused pyridines. Starting from 5-amino-1-(2,3-O-isopropylidene-b-D-ribofuranosyl)-1H-pyrazole, nucleosides containing a pyrazolo[3,4-b]pyridine fragment were obtained, which can be considered as adenosine deaminase (ADA) inhibitors.
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