山国破文在线 http://www.paper.edu.cn Design, synthesis and in vitro test of 2, 3-dihydrobenzo bll 4thiazepine-4(5H)-ones as novel non-ATP competitive glycogen synthase kinase-3B(GSK-3B)inhibitors Huang Zhaohui Hu Hairong2, Lei jiayi, Chu Yong *, Ye deyong* 1: School of Pharmacy, Fudan University, Shanghai, China, 200032 2: School of Life Sciences, Fudan University, Shanghai, China, 200433 Abstract Glycogen synthase kinase-3B(GSK-3B) is a serine/threonine kinase that has recently emerged as a key target for neurodegenerative diseases and diabetes. Most of Known ATP-binding pocket of GSK-3, which might lead widespread effects. Non-ATP-competitive GSK-3 inhibitors actually represent a more efficient pathway for providing real promising drugs for therapeutic intervention. As an initial step of our work to discover such non-ATP-competitive GSK-3 inhibitors, a virtual screening was conducted by Autodock program, which docked the small drug-like molecules of Maybridge library at the non-ATP-binding site of GSK-3B. 2, 3-Dihydrobenzo[bl[ thiazepine-4(5HH-ones(1)with variable substitutes ranked in the top of hits, likely potentially havin inhibition and highly selectivity to GSK-3B. Eight derivatives of (1)had been designed based on the virtual screening result and successfully synthesized through Knoevenagel reaction, cyclization and N-alkylation. Among them, 5-benzyl-2-(furan-2-yl)-2, 3-dihydrobenzo bl[l, 4] thiazepin-4(5H)-one(4c) showed moderate inhibition to GSK-3B in vitro(IC5o:47.69+ 2.38uM) tested by the National Center rug Screening of China. Further Docking study showed 4c can bind to the specific non-ATP-binding pocket of GsK-3B like TDZd 8. The discovered new active compound (4c)is structurally different to other inhibitors of GSK-3B and worthy of further study as a novel lead compound Key words: Glycogen synthase kinase-3B, inhibitor, virtual screening, synthesi10 Design, synthesis and in vitro test of 2, 3-dihydrobenzo[b][1, 4]thiazepine-4(5H)-ones as novel non-ATP competitive glycogen synthase kinase-3β(GSK-3β) inhibitors Huang Zhaohui1#, Hu Hairong2#, Lei Jiayi1 , Chu Yong1 *, Ye Deyong1 * 1: School of Pharmacy, Fudan University, Shanghai, China, 200032 2: School of Life Sciences, Fudan University, Shanghai, China, 200433 Abstract Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase that has recently emerged as a key target for neurodegenerative diseases and diabetes. Most of known inhibitors are bound in the ATP-binding pocket of GSK-3, which might lead widespread effects. Non-ATP-competitive GSK-3 inhibitors actually represent a more efficient pathway for providing real promising drugs for therapeutic intervention. As an initial step of our work to discover such non-ATP-competitive GSK-3 inhibitors, a virtual screening was conducted by Autodock program, which docked the small drug-like molecules of Maybridge library at the non-ATP-binding site of GSK-3β. 2, 3-Dihydrobenzo[b][1, 4] thiazepine-4(5H)-ones (1) with variable substitutes ranked in the top of hits, likely potentially having inhibition and highly selectivity to GSK-3β. Eight derivatives of (1) had been designed based on the virtual screening result and successfully synthesized through Knoevenagel reaction, cyclization and N-alkylation. Among them, 5-benzyl-2-(furan-2-yl)-2, 3-dihydrobenzo[b][1, 4] thiazepin-4(5H)-one (4c) showed moderate inhibition to GSK-3β in vitro (IC50: 47.69 ± 2.38µM) tested by the National Center for Drug Screening of China. Further Docking study showed 4c can bind to the specific non-ATP-binding pocket of GSK-3β like TDZD 8. The discovered new active compound (4c) is structurally different to other inhibitors of GSK-3β and worthy of further study as a novel lead compound. Key words: Glycogen synthase kinase-3β, inhibitor, virtual screening, synthesis 中国科技论文在线 http://www.paper.edu.cn