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

• 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.

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.

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