Locking PDK1 in DFG-out conformation through 2-oxo-indole containing molecules: Another tools to fight glioblastoma was written by Sestito, Simona;Daniele, Simona;Nesi, Giulia;Zappelli, Elisa;Di Maio, Danilo;Marinelli, Luciana;Digiacomo, Maria;Lapucci, Annalina;Martini, Claudia;Novellino, Ettore;Rapposelli, Simona. And the article was included in European Journal of Medicinal Chemistry in 2016.Safety of 1-(3,4-Difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid This article mentions the following:
The phosphoinositide-dependent kinase-1 (PDK1) is one of the main components of the PI3K/Akt pathway. Also named the “master kinase” of the AGC family, PDK1 plays a critical role in tumorigenesis, by enhancing cell proliferation and inhibiting apoptosis, as well as in cell invasion and metastasis formation. Although there have been done huge efforts in discovering specific compounds targeting PDK1, nowadays no PDK1 inhibitor has yet entered the clinic. With the aim to pick out novel and potent PDK1 inhibitors, herein the authors report the design and synthesis of a new class of mols. obtained by merging the 2-oxo-indole nucleus with the 2-oxo-pyridonyl fragment, two moieties with high affinity for the PDK1 hinge region and its DFG-out binding site, resp. To this purpose, a small series of compounds were synthesized and a tandem application of docking and Mol. Dynamic (MD) was employed to get insight into their mode of binding. The OXID-pyridonyl hybrid, possessing the lower IC50 (IC50 = 112 nM), was also tested against recombinant kinases involved in the PI3K/PDK1/Akt pathway and was subjected to vitro studies to evaluate the cytotoxicity and the inhibition of tumor cell migration. All together the results let us to consider the OXID-pyridonyl hybrid, as a lead compound of a new generation of PDK1 inhibitors and encourage us to further studies in this direction. In the experiment, the researchers used many compounds, for example, 1-(3,4-Difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (cas: 1001413-01-9Safety of 1-(3,4-Difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid).
1-(3,4-Difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (cas: 1001413-01-9) belongs to pyridine derivatives. The ring atoms in the pyridine molecule are sp2-hybridized. The nitrogen is involved in the π-bonding aromatic system using its unhybridized p orbital. The lone pair is in an sp2 orbital, projecting outward from the ring in the same plane as the σ bonds. Pyridine, its benzo and pyridine-based compounds play diverse roles in organic chemistry. Pyridine-based materials are valued for their optical and physical properties as well as their medical potential. Safety of 1-(3,4-Difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid