We present N-
imidazopyridine-noscapinoids, a new class of
noscapine derivatives that bind to
tubulin and exhibit antiproliferative activity against triple positive (MCF-7) and triple negative (MDA-MB-231)
breast cancer cells. The N-atom of the
isoquinoline ring of
noscapine scaffold was altered in silico by coupling the imidazo [(Ye et al., 1998; Ke et al., 2000) 1,21,2-a]
pyridine pharmacophore to rationally develop a series of N-
imidazopyridine-noscapinoids (7-11) with high
tubulin binding affinity. The predicted ΔGbinding of the N-
imidazopyridine-noscapinoids 7-11 varied from -27.45 to -36.15 kcal/mol, a much lower value than
noscapine with ΔGbinding -22.49 kcal/mol. The cytotoxicity of N-
imidazopyridine-noscapinoids was evaluated using
hormone dependent MCF-7, triple negative MDA-MB-231
breast cancer cell lines and primary
breast cancer cells. The cytotoxicity of these compounds (represented as IC50 concentration) ranges between 4.04 and 33.93 μM against
breast cancer cells without affecting normal cells (IC50 value > 952 μM). All the compounds (7-11) perturbed the cell cycle progression at G2/M phase and triggered apoptosis. Among all the N-
imidazopyridine-noscapinoids, N-5-Bromoimidazopyridine-noscapine (9) showed promising antiproliferative activity and was selected for detailed investigation. The onset of apoptosis treated with 9 using MDA-MB-231 revealed morphological changes like cellular shrinkage,
chromatin condensation, membrane blebbing, and apoptotic bodies formation. Along with elevated
reactive oxygen species (ROS), there was a loss of mitochondrial membrane potential, suggesting induction of apoptosis to
cancer cells. Compound 9 was also found to significantly regress the implanted tumour in nude mice as xenografts of MCF-7 cells without any apparent side effects after
drug administration. We conclude that N-
imidazopyridine-noscapinoids possess excellent potential as a promising
drug for treating breast
cancers.