2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2014 Sep 12:84:312-34. doi: 10.1016/j.ejmech.2014.07.033.
Hsiao-Chun Wang 1,  Ajit Dhananjay Jagtap 1,  Pei-Teh Chang 1,  Jia-Rong Liu 1,  Chih-Peng Liu 2,  Hsiang-Wen Tseng 2,  Grace Shiahuy Chen 3,  Ji-Wang Chern 4
Affiliations

Affiliations

  • 1 School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, LinSen South Road, Taipei 10051, Taiwan.
  • 2 Biomedical Engineering Research Laboratories, Industrial Technology Research Institute, No. 321, Section 2, Guangfu Road, Hsinchu 30011, Taiwan.
  • 3 Department of Applied Chemistry, Providence University, No. 200, Section 7, Taiwan Boulevard, Taichung 43301, Taiwan. Electronic address: grace@pu.edu.tw.
  • 4 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.
PMID: 25036791 DOI: 10.1016/j.ejmech.2014.07.033
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.

Keywords

Anticancer; Aurora B; Indolin-2-one; Kinase inhibitor; Structure–activity relationship.

Figures