title: Synthesis and structure-activity relationship study of antimicrotubule agents phenylahistin derivatives with a didehydropiperazine-2,5-dione structure.
abstract: Plinabulin (11, NPI-2358) is a potent microtubule-targeting agent derived from the natural diketopiperazine "phenylahistin" (1) with a colchicine-like tubulin depolymerization activity. Compound 11 was recently developed as VDA and is now under phase II clinical trials as an anticancer drug. To develop more potent antimicrotubule and cytotoxic derivatives based on the didehydro-DKP skeleton, we performed further modification on the tert-butyl or phenyl groups of 11, and evaluated their cytotoxic and tubulin-binding activities. In the SAR study, we developed more potent derivatives 33 with 2,5-difluorophenyl and 50 with a benzophenone in place of the phenyl group. The anti-HuVEC activity of 33 and 50 exhibited a lowest effective concentration of 2  and 1 nM for microtubule depolymerization, respectively. The values of 33 and 50 were 5 and 10 times more potent than that of CA-4, respectively. These derivatives could be a valuable second-generation derivative with both vascular disrupting and cytotoxic activities.
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Koji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Benjamin
authors.initials: B
authors.lastname: Nicholson
authors.forename: Gordafaried
authors.initials: G
authors.lastname: Deyanat-Yazdi
authors.forename: Barbara
authors.initials: B
authors.lastname: Potts
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Akiko
authors.initials: A
authors.lastname: Oda
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kitagawa
authors.forename: Sumie
authors.initials: S
authors.lastname: Orikasa
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasui
authors.forename: Miki
authors.initials: M
authors.lastname: Akamatsu
authors.forename: Takumi
authors.initials: T
authors.lastname: Chinen
authors.forename: Takeo
authors.initials: T
authors.lastname: Usui
authors.forename: Yuki
authors.initials: Y
authors.lastname: Shinozaki
authors.forename: Fumika
authors.initials: F
authors.lastname: Yakushiji
authors.forename: Brian R
authors.initials: BR
authors.lastname: Miller
authors.forename: Saskia
authors.initials: S
authors.lastname: Neuteboom
authors.forename: Michael
authors.initials: M
authors.lastname: Palladino
authors.forename: Kaneo
authors.initials: K
authors.lastname: Kanoh
authors.forename: George Kenneth
authors.initials: GK
authors.lastname: Lloyd
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D018360:Crystallography, X-Ray; D054659:Diketopiperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C571526:3-((5-tert-butyl-1H-imidazol-4-yl)methylene)-6-(2,5-difluorobenzylidene)piperazine-2,5-dione; C571527:3-(3-benzoylbenzylidene)-6-((5-tert-butyl-1H-imidazol-4-yl)methylene)piperazine-2,5-dione; D000970:Antineoplastic Agents; D054659:Diketopiperazines; D007093:Imidazoles; D050257:Tubulin Modulators; C119340:phenylahistin