کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1395612 | 1501132 | 2014 | 23 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: 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](/preview/png/1395612.png)
• 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.
Figure optionsDownload as PowerPoint slide
Journal: European Journal of Medicinal Chemistry - Volume 84, 12 September 2014, Pages 312–334