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Xuemei Jin,권우선,김태수,허정녕,정현철,최지원,노경태 대한화학회 2018 Bulletin of the Korean Chemical Society Vol.39 No.3
Phosphatidylinositol 3-kinase beta (PI3Kβ) is the dominant isoform of PI3K and has been implicated in thrombosis as well as phosphatase and tensin homologue-loss-induced tumorigenesis. PI3Kβ has been considered to be an attractive target for anticancer drug discovery, and several PI3Kβ inhibitors have progressed into clinical trials. Here, we disclose the discovery of two natural products (PBY-0002 and PBY-0006) that have inhibitory effects on PI3Kβ. These two natural products were identified through pharmacophore-based virtual screening, molecular docking, and a molecular dynamics simulation. Furthermore, an in vitro assay against human gastric cancer cell lines revealed that these two compounds showed anticancer activity. To identify the binding modes of PBY-0002 and PBY-0006 further, we performed a systematical investigation with comparison to the binding mode of GSK2636711, which is a known PI3Kβ inhibitor. The results demonstrated that PBY-0002 and PBY-0006 were tightly embedded into the ATP-binding site via hydrogen bonds and π-cation interactions. These two natural products can provide a promising starting point for the rational design of potent analogs with inhibitory activity against PI3Kβ.
Synthesis and biological evaluation of benzoxepinoindol-1-one analogs as Brd4 bromodomain inhibitors
정고니,이주연,박치훈,윤은영,허정녕 대한화학회 2023 Bulletin of the Korean Chemical Society Vol.44 No.3
A novel series of benzo[6,7]oxepino[4,3,2-cd]indol-1(2H)-one derivatives were synthesized via a one-pot aldol condensation and SNAr reaction by coupling indolin-2-ones with 2-fluorobenzaldehydes. In addition, molecular docking studies of the designed compound 2 revealed strong hydrogen bonds in the hot binding pocket of Brd4. All compounds were evaluated for their enzymatic activity in Brd4 bromodomain inhibition.