title: Bioisosteric replacement of an acylureido moiety attached to an indolin-2-one scaffold with a malonamido or a 2/4-pyridinoylamido moiety produces a selectively potent Aurora-B inhibitor.
abstract: Bioisosteric replacement of acylureido moiety in 6-acylureido-3-pyrrolylmethylidene-2-oxoindoline derivatives resulted in a series of malonamido derivatives with indolin-2-one scaffold (11-14). Further conformational restrictions of the malonamido moiety led to 2-oxo-1,2-dihydropyridine (21-25) or a 4-oxo-1,4-dihydropyridine derivatives (31-36). 4-Oxo-1,4-dihydropyridine derivatives were more potent Aurora B inhibitors than their 2-oxo-1,2-dihydropyridine counterparts and demonstrated cytotoxicities against A549 and HepG2 cells in the submicromolar range. In A549 cells, 31h decreased phosphorylation of histone H3, triggered polyploidy, induced expression of pro-apoptotic Fas and FasL with subsequent activation of caspase 8, resulting into apoptosis. In a Huh7-xenograft mouse model, 31h demonstrated potent in vivo efficacy with a daily dose of 5 mg/kg.
authors.affiliation: School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, LinSen South Road, Taipei 10051, Taiwan.
authors.forename: Hsiao-Chun
authors.initials: HC
authors.lastname: Wang
authors.affiliation: School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, LinSen South Road, Taipei 10051, Taiwan.
authors.forename: Ajit Dhananjay
authors.initials: AD
authors.lastname: Jagtap
authors.affiliation: School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, LinSen South Road, Taipei 10051, Taiwan.
authors.forename: Pei-Teh
authors.initials: PT
authors.lastname: Chang
authors.affiliation: School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, LinSen South Road, Taipei 10051, Taiwan.
authors.forename: Jia-Rong
authors.initials: JR
authors.lastname: Liu
authors.affiliation: Biomedical Engineering Research Laboratories, Industrial Technology Research Institute, No. 321, Section 2, Guangfu Road, Hsinchu 30011, Taiwan.
authors.forename: Chih-Peng
authors.initials: CP
authors.lastname: Liu
authors.affiliation: Biomedical Engineering Research Laboratories, Industrial Technology Research Institute, No. 321, Section 2, Guangfu Road, Hsinchu 30011, Taiwan.
authors.forename: Hsiang-Wen
authors.initials: HW
authors.lastname: Tseng
authors.affiliation: Department of Applied Chemistry, Providence University, No. 200, Section 7, Taiwan Boulevard, Taichung 43301, Taiwan. Electronic address: grace@pu.edu.tw.
authors.forename: Grace Shiahuy
authors.initials: GS
authors.lastname: Chen
authors.affiliation: School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, LinSen South Road, Taipei 10051, Taiwan; Department of Life Science, College of Life Science, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan. Electronic address: jwchern@ntu.edu.tw.
authors.forename: Ji-Wang
authors.initials: JW
authors.lastname: Chern
mesh_terms: D000577:Amides / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008314:Malonates / Q000737:chemistry; D015394:Molecular Structure; D011728:Pyridones / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D007211:Indoles; D008314:Malonates; D011728:Pyridones; C456900:indolin-2-one; D014508:Urea; D064107:Aurora Kinase B; C008314:malonamide
keywords: Anticancer; Aurora B; Indolin-2-one; Kinase inhibitor; Structure–activity relationship