title: Design, synthesis, biological evaluation, and structure-activity relationship (SAR) discussion of dipeptidyl boronate proteasome inhibitors, part I: comprehensive understanding of the SAR of alpha-amino acid boronates.
abstract: New series of dipeptidyl boronate inhibitors of 20S proteasome were designed and synthesized. The comprehensive understanding of the SAR was obtained by utilizing the variation of four substituents. From the screened compounds in enzyme, novel inhibitors 49 and 50 were identified to be highly potent druglike candidates with IC(50) values of 1.2 and 1.6 nM, respectively, which showed better activities than the drug bortezomib on the market. Two hematologic human tumor cell lines, HL-60 and U266, were significantly sensitive to both candidates and showed nearly the same potency as the standard bortezomib with IC(50) values less than 10 nM. But as for most of the eight human solid tumor cell lines, both candidates were more potent than the standard with the IC(50) value range of 9.8-70 nM. The activity evaluation of the stereoisomers showed that changing R-isomers to S-isomers greatly reduced the potency and even induced inactivity.
authors.affiliation: Jiangsu Simcere Pharmaceutical Research Institute and Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, Xuan Wu District, Nanjing 210042, PRC. zhyqscu@hotmail.com
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Xinrong
authors.initials: X
authors.lastname: Zhu
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Yuejie
authors.initials: Y
authors.lastname: Li
authors.forename: Yuheng
authors.initials: Y
authors.lastname: Ma
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Yuan
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Yang
authors.initials: Y
authors.lastname: Hu
authors.forename: Li
authors.initials: L
authors.lastname: Ai
authors.forename: Qingzhi
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001897:Boronic Acids / Q000737:chemistry*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D061988:Proteasome Inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D001897:Boronic Acids; D004151:Dipeptides; D004791:Enzyme Inhibitors; D061988:Proteasome Inhibitors