期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 6, 页码 2779-2798出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm5019687
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资金
- Italian Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), Progetti di Ricerca di Interesse Nazionale (PRIN) [2009PX2T2E, 2012ZHN9YH]
- Italian Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), Futuro in Ricerca [RBFR10ZJQT]
- European Union [FP7 COST/TD0905]
- Universita di Salerno (Italy)
- Universita di Salerno
Selective inhibitors of the two paralogue KAT3 acetyltransferases (CBP and p300) may serve not only as precious chemical tools to investigate the role of these enzymes in physiopathological mechanisms but also as lead structures for the development of further antitumor agents. After the application of a molecular pruning approach to the hardly optimizable and not very cell-permeable garcinol core structure, we prepared many analogues that were screened for their inhibitory effects using biochemical and biophysical (SPR) assays. Further optimization led to the discovery of the benzylidenebarbituric acid derivative 7h (EML425) as a potent and selective reversible inhibitor of CBP/p300, noncompetitive versus both acetyl-CoA and a histone H3 peptide, and endowed with good cell permeability. Furthermore, in human leukemia U937 cells, it induced a marked and time-dependent reduction in the acetylation of lysine H4K5 and H3K9, a marked arrest in the G0/G1 phase and a significant increase in the hypodiploid nuclei percentage.
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