title: Discovery of pyrrole-indoline-2-ones as Aurora kinase inhibitors with a different inhibition profile.
abstract: A series of pyrrole-indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3' position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50=2.19 microM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots.
authors.affiliation: Development Center for Biotechnology, No. 101, Lane 169, Kangning Street, Xizhi City, Taipei County, Taiwan 221, ROC.
authors.forename: Chao-Cheng
authors.initials: CC
authors.lastname: Chiang
authors.forename: Yu-Hsiang
authors.initials: YH
authors.lastname: Lin
authors.forename: Shu Fu
authors.initials: SF
authors.lastname: Lin
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Lai
authors.forename: Chiawei
authors.initials: C
authors.lastname: Liu
authors.forename: Win-Yin
authors.initials: WY
authors.lastname: Wei
authors.forename: Sheng-chuan
authors.initials: SC
authors.lastname: Yang
authors.forename: Ru-Wen
authors.initials: RW
authors.lastname: Wang
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Teng
authors.forename: Shih-Hsien
authors.initials: SH
authors.lastname: Chuang
authors.forename: Jia-Ming
authors.initials: JM
authors.lastname: Chang
authors.forename: Ta-Tung
authors.initials: TT
authors.lastname: Yuan
authors.forename: Ying-Shuen
authors.initials: YS
authors.lastname: Lee
authors.forename: Paonien
authors.initials: P
authors.lastname: Chen
authors.forename: Wei-Kuang
authors.initials: WK
authors.lastname: Chi
authors.forename: Ju-Ying
authors.initials: JY
authors.lastname: Yang
authors.forename: Hung-Jyun
authors.initials: HJ
authors.lastname: Huang
authors.forename: Chu-Bin
authors.initials: CB
authors.lastname: Liao
authors.forename: Jiann-Jyh
authors.initials: JJ
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064107:Aurora Kinase B; D064127:Aurora Kinases; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D007211:Indoles; D011758:Pyrroles; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases