학술논문
Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562.
Document Type
Article
Author
Source
Subject
*PI3K/AKT pathway
*LEUKEMIA
*ANTINEOPLASTIC agents
*CELL cycle
*CELL lines
*APOPTOSIS
*CANCER cells
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Language
ISSN
1475-6366
Abstract
A novel series of 4-(4-Methoxyphenyl)-2-(methylthio)pyrimidine-5-carbonitrile was developed linked to an aromatic moiety via N-containing bridge and then evaluated for their cytotoxic activity against MCF-7 and K562 cell lines. Seven compounds exhibited the highest activity against both cell lines where compounds 4d and 7f were the most active against K562 cell line. Exploring their molecular mechanisms by enzyme inhibition assay on PI3Kd/y and AKT-1 showed that compound 7f was promising more than 4d with IC50 = 6.99 ±0.36, 4.01 ±0.55, and 3.36 ±0.17 µM, respectively. Also, flowcytometric analysis revealed that 7f caused cell cycle arrest at S-phase followed by caspase 3 dependent apoptosis induction. Mechanistically, compound 7f proved to modulate the expression of PI3K, p-PI3K, AKT, p-AKT, Cyclin D1, and NFKβ. Furthermore, in-vivo toxicity study indicated good safety profile for 7f. These findings suggest that the trimethoxy derivative 7f has strong potential as a multi-acting inhibitor on PI3K/AKT axis targeting breast cancer and leukaemia. [ABSTRACT FROM AUTHOR]