title: Synthesis and in-vitro biological activity of macrocyclic urea Chk1 inhibitors.
abstract: A variety of macrocyclic urea compounds were prepared as potent Chk1 inhibitors by modifying the C5 position of the benzene ring of the macrocyclic urea with ether moieties, aliphatic carbon chains, amide and halides. Enzymatic activity less than 20nM was observed in 29 of 40 compounds. Compounds 14, 46d, and 48j provided the best overall results in the cellular assays as they abrogated doxorubicin-induced cell cycle arrest (IC(50)=3.31, 3.08, and 3.13microM) and enhanced doxorubicin cytotoxicity (IC(50)=0.54, 1.27, and 0.96microM) while displaying no single agent activity, respectively.
authors.affiliation: Cancer Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA. gaoquanli@wisc.edu
authors.forename: Gaoquan
authors.initials: G
authors.lastname: Li
authors.forename: Zhi-Fu
authors.initials: ZF
authors.lastname: Tao
authors.forename: Yunsong
authors.initials: Y
authors.lastname: Tong
authors.forename: Magdalena K
authors.initials: MK
authors.lastname: Przytulinska
authors.forename: Peter
authors.initials: P
authors.lastname: Kovar
authors.forename: Philip
authors.initials: P
authors.lastname: Merta
authors.forename: Zehan
authors.initials: Z
authors.lastname: Chen
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
authors.forename: Thomas
authors.initials: T
authors.lastname: Sowin
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Nan-Horng
authors.initials: NH
authors.lastname: Lin
mesh_terms: D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D006367:HeLa Cells; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014508:Urea / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D047028:Macrocyclic Compounds; D047428:Protein Kinase Inhibitors; D014508:Urea; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1