Explorations of novel pyridine-pyrimidine hybrid phosphonate derivatives as aurora kinase inhibitors.

[Display omitted] • A series of novel pyridine-pyrimidine hybrid phosphonate derivatives were synthesized and characterized by spectral methods. • In vitro Enzyme assay and molecular docking study helped to predict the target enzyme. • Compounds 4f, 4j and 4o had shown good potential to inhibit Aurora kinase. • Compounds 4f, 4j and 4o exhibited relatively no cytotoxicity to normal LO2cells. For developing novel therapeutic agents with good anticancer activities, a series of novel pyridine-pyrimidine hybrid phosphonate derivatives 4(a–q) were synthesized by the Kabachnik-Fields method using CAN as catalyst. The compound 4o exhibited the most potent anticancer activity with an IC 50 value of 13.62 μM, 17.49 μM, 5.81 μM, 1.59 μM and 2.11 μM against selected cancer cell lines A549, Hep-G2, HeLa, MCF-7, and HL-60, respectively. Compound 4o displayed seven times more selectivity towards Hep-G2 cancer cell lines compared to the human normal hepatocyte cell line LO2 (IC 50 value 95.33 μM). Structure-Activity Relationship (SAR) studies were conducted on the variation in the aromatic ring (five-membered heterocyclic ring, six-membered heterocyclic ring) and the variation of substituents on the phenyl ring (electron donating groups, electron withdrawing groups). Furthermore, the mechanism of anticancer activity was clarified by further explorations in bioactivity by using in vitro aurora kinase inhibitory activity and molecular docking studies. The results showed that the compound 4o at IC 50 concentration demonstrated distinctive morphological changes such as cell detachment, cell wall deformation, cell shrinkage and reduced number of viable cells in cancer cell lines. Compound 4o induced early apoptosis and late apoptosis of 27.7% and 6.1% respectively. [ABSTRACT FROM AUTHOR]