103003-01-6Relevant articles and documents
Development of the First Generation of Disulfide-Based Subtype-Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors
Liu, Yifu,Xie, Zuoquan,Zhao, Dan,Zhu, Jin,Mao, Fei,Tang, Shuai,Xu, Hui,Luo, Cheng,Geng, Meiyu,Huang, Min,Li, Jian
, p. 2227 - 2244 (2017/04/03)
Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metabolism. We previously described bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, on the basis of the scaffold of 16, we identify two novel types of disulfide-based PDK1 inhibitors. The most potent analogue, 3a, effectively inhibits PDK1 both at the molecular (kinact/Ki = 4.17 × 103 M-1 s-1) and the cellular level (down to 0.1 μM). In contrast to 16, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2-4. 3a also significantly alters glucose metabolic pathways in A549 cells by decreasing ECAR and increasing ROS. Moreover, in the xenograft models, 3a shows significant antitumor activity with no negative effect to the mice weight. Collectively, these data demonstrate that 3a may be an excellent lead compound for the treatment of cancer as a first-generation subtype-selective and covalent PDK1 inhibitor.
Disubstituted pyrimidines as Lck inhibitors
Hunt, Julianne A.,Beresis, Richard T.,Goulet, Joung L.,Holmes, Mark A.,Hong, Xinfang J.,Kovacs, Ernest,Mills, Sander G.,Ruzek, Rowena D.,Wong, Frederick,Hermes, Jeffrey D.,Park, Young-Whan,Salowe, Scott P.,Sonatore, Lisa M.,Wu, Lin,Woods, Andrea,Zaller, Dennis M.,Sinclair, Peter J.
supporting information; experimental part, p. 5440 - 5443 (2010/04/26)
We have developed a family of 4-benzimidazolyl-N-piperazinethyl-pyrimidin-2-amines that are subnanomolar inhibitors of Lck. A subset of these Lck inhibitors, with heterocyclic substituents at the benzimidazole C5, are also low-nanomolar inhibitors of cell
Synthesis and antibacterial activity of thiazolopyrazine-incorporated tetracyclic quinolone antibacterial agents. 2
Jinbo,Kondo,Taguchi,Inoue,Sakamoto,Tsukamoto
, p. 2791 - 2796 (2007/10/02)
A novel series of 8-(2-substituted morpholino)-9,1-[(N- methylimino)methano]-7-fluoro-5-oxo-5H-thiazolo[3,2-α]quinoline-4- carboxylic acids, designated 8a-j, with a unique tetracyclic structure were synthesized, and the in vitro and in vivo antibacterial activities against Gram-positive strains, including methicillin-resistant Staphylococcus aureus isolates (MRSA), and Gram-negative strains were evaluated. These morpholino derivatives, 8a-j, showed excellent in vitro antibacterial activities against Gram-positive bacteria. The substitutions at the C-2 position of the 8- morpholino moiety of compound 8 play an important role in the enhancement of in vivo antibacterial activity. The unsubstituted morpholino derivative 8a, the 2,6-dimethyl derivative 8c, and the 2-ethylmorpholino derivative 8d showed poor in vivo antibacterial activity, while 8b, 8f-h, and 8j exhibited good activities. The 2-(methoxymethyl)morpholino derivative, 8h, showed the most potent activity in vivo. The therapeutic effects of 8h on systemic infection against S. aureus IID 803 were over 10-fold more potent than that of ofloxacin. Compound 8h, which showed superior oral bioavailability, has a chiral center. The enantiomers of 8h were synthesized, and the in vitro and in vivo antibacterial activities were evaluated. Both enantiomers, (S)-8h and (R)-8h, and the racemic compound 8 exhibited similar activities in vitro and in vivo. Compounds 8b and 8f-h also showed good levels of antibacterial activity against MRSA strains. The morpholino derivatives with unique tetracyclic structures are characterized by strong antibacterial activities against MRSA strains.
