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

• Published in: European journal of medicinal chemistry 2014-09, Vol.84, p.312-334
• Main Authors: Wang, Hsiao-Chun, Jagtap, Ajit Dhananjay, Chang, Pei-Teh, Liu, Jia-Rong, Liu, Chih-Peng, Tseng, Hsiang-Wen, Chen, Grace Shiahuy, Chern, Ji-Wang
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Aurora B; Aurora Kinase B - antagonists & inhibitors; Aurora Kinase B - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Dihydropyridines - chemical synthesis; Dihydropyridines - chemistry; Dihydropyridines - pharmacology; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hep G2 Cells; Humans; Indoles - chemistry; Indolin-2-one; Kinase inhibitor; Malonates - chemistry; Molecular Structure; Pyridones - chemistry; Structure-Activity Relationship; Urea - analogs & derivatives; Urea - chemistry; Xenograft Model Antitumor Assays
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.07.033

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. [Display omitted] •Novel pyridoneamidoindolin-2-one derivatives (21–25 and 31–36) were synthesized.•These compounds were identified as potent and selective Aurora B inhibitors.•These potent Aurora B inhibitors were cytotoxic to A549 and HepG2 cells.•Compound 31h induced apoptosis in A549 cells through extrinsic pathway.