title: Design, synthesis and biological evaluation of tripeptide boronic acid proteasome inhibitors.
abstract: A series of tripeptide boronate proteasome inhibitors were designed and synthesized on the basis of our previously built tripeptide aldehyde 3D-QSAR models. All the synthesized compounds were evaluated for their proteasome-inhibitory activities in an isolated 20S rabbit proteasome, and selected compounds were evaluated for their antitumor activities in vitro against four human cancer cell lines. Biological results showed bulky and negative substituents at P(2) position improved the proteasome-inhibitory potency obviously, which completely conformed to the theoretical models, while those at P(3) position thoroughly deviated from the 3D-QSAR model. Most of the screened compounds showed less than 1 nM inhibitory potency and high selectivity against 20S proteasome, of which 7f is the most potent (IC(50)=0.079 nM) and twofold more active than bortezomib (IC(50)=0.161 nM). Cell viability indicated hydrophilic 4-hydroxyphenyl substituent at P(2) or P(3) position was not favorable to the cellular activities. Especially for the two hematologic cancer cell lines, HL-60 and U266, 7f inhibited them at the level of less than 10 nM and was more potent than the control bortezomib. It is being considered a promising new lead to be developed for the treatment of various cancers.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhu
authors.forename: Shuyang
authors.initials: S
authors.lastname: Yao
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
authors.forename: Zemei
authors.initials: Z
authors.lastname: Ge
authors.forename: Jingrong
authors.initials: J
authors.lastname: Cui
authors.forename: Tieming
authors.initials: T
authors.lastname: Cheng
authors.forename: Runtao
authors.initials: R
authors.lastname: Li
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D061988:Proteasome Inhibitors; D021281:Quantitative Structure-Activity Relationship; D011817:Rabbits
chemical_list: D001897:Boronic Acids; D009842:Oligopeptides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors