title: Development of novel proteasome inhibitors based on phthalazinone scaffold.
abstract: In this study we designed a series of proteasome inhibitors using pyridazinone as initial scaffold, and extended the structure with rational design by computer aided drug design (CADD). Two different synthetic routes were explored and the biological evaluation of the phthalazinone derivatives was investigated. Most importantly, electron positive triphenylphosphine group was first introduced in the structure of proteasome inhibitors and potent inhibition was achieved. As 6c was the most potent inhibitor of proteasome, we examined the structure-activity relationship (SAR) of 6c analogs.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Lingfei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Fengrong
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Niu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: leiliang@bjmu.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D010793:Phthalazines; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: Drug design; Phthalazinone; Proteasome inhibitors; Structure–activity relationship; Triphenylphosphine