Synthesis of new steroidal imidazo [1,2-a] pyridines: DNA binding studies, cleavage activity andin vitrocytotoxicity

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Abstract

A one-pot strategy for the catalytic synthesis of series of new 5α-cholestan-6-spiro-5′-phenylamino-2H-imidazo [1′,2′-a] pyridines (4–14) has been investigated. The synthesized products were obtained in good yields (85–90%) and the protocol uses Multi-component Reaction (MCR) involving steroidal ketones, 2-aminopyridines, isocyanides and propylphosphonic anhydride (®T3P) as a catalyst. After characterization by spectral and analytical data, the interaction studies of compounds (4–6) with DNA were studied by UV–vis, fluorescence spectroscopy, gel electrophoresis and molecular docking. The compounds bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb; 2.35 × 104, 3.71 × 104 and 3.24 × 104 M−1, respectively, indicating the higher binding affinity of compound 5 towards DNA. Gel electrophoresis showed the concentration dependent cleavage activity of compounds 4–6 with DNA. Molecular docking studies suggested that compounds bind through minor groove to DNA. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay depicted promising anti-proliferative activity of compound 4–9 against different given cancer cells. In Western blotting, the expressions of relevant apoptotic markers depicted an apoptosis by steroidal imidazopyridines in A549 cells. Annexin V-FITC/PI staining data indicated that compounds could effectively induce apoptosis in A549 cells in a dose-dependent manner. FACS analysis shows that the compound 6 bring about cell cycle arrest at 2.62 μM concentration.

Graphical abstract

A one-pot reaction of steroidal ketones, amino pyridines and isocyanides in presence of ®T3P is described which afford novel steroidal imidazo [1,2-a] pyridines in excellent yields.

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