title: Design, synthesis and docking studies of novel dipeptidyl boronic acid proteasome inhibitors constructed from αα- and αβ-amino acids.
abstract: A series of novel dipeptidyl boronic acid proteasome inhibitors constructed from αα- and αβ-amino acids were designed and synthesized. Their structures were elucidated by (1)H NMR, (13)C NMR, LC-MS and HRMS. These compounds were evaluated for their β5 subunit inhibitory activities of human proteasome. The results showed that dipeptidyl boronic acid inhibitors composed of αα-amino acids were as active as bortezomib. Interestingly, the activities of those derived from αβ-amino acids lost completely. Of all the inhibitors, compound 22 (IC50=4.82 nM) was the most potent for the inhibition of proteasome activity. Compound 22 was also the most active against three MM cell lines with IC50 values less than 5 nM in inhibiting cell growth assays. Molecular docking studies displayed that 22 fitted very well in the β5 subunit active pocket of proteasome.
authors.affiliation: Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jingmiao
authors.initials: J
authors.lastname: Shi
authors.affiliation: College of Science, Nanjing Forestry University, Nanjing 210037, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Lei
authors.affiliation: College of Life Science, Nanjing Normal University, Nanjing 210023, China.
authors.forename: Wenkui
authors.initials: W
authors.lastname: Wu
authors.affiliation: College of Science, Nanjing Forestry University, Nanjing 210037, China.
authors.forename: Huayun
authors.initials: H
authors.lastname: Feng
authors.affiliation: Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, Nanjing 210037, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.affiliation: Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, Nanjing 210037, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Chen
authors.affiliation: College of Life Science, Nanjing Normal University, Nanjing 210023, China. Electronic address: zhyqscu@hotmail.com.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, Nanjing 210037, China.
authors.forename: Shihe
authors.initials: S
authors.lastname: Hu
authors.affiliation: Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, Nanjing 210037, China.
authors.forename: Zhaogang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: jc@cpu.edu.cn.
authors.forename: Cheng
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology*; D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D001897:Boronic Acids; D004151:Dipeptides; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: Cytotoxicity; Dipeptidyl boronic acid; Docking study; Proteasome inhibitor; Structure–activity relationship