N-imidazopyridine derivatives of noscapine as potent tubulin-binding anticancer agents: chemical synthesis and cellular evaluation.

In this study we present a novel class of N-imidazopyridine (impy) derivatives (12-15) of noscapine by tethering the imidazo[1,2-a]pyridine core to the N-atom of the isoquinoline ring of the lead molecule noscapine. These derivatives were found to have better docking scores (- 6.213 to - 7.897 kcal/mol) than noscapine (- 4.960 kcal/mol). Further, the calculated binding energy ranged between - 25.85 to - 35.57 kcal/mol, as determined by MD simulations and MM-PBSA calculations. Tubulin binding assay also revealed higher binding affinity for compounds 12, 13, 14, and 15 with the equilibrium dissociation constant (K_D) value of 78 ± 3.8 µM, 66 ± 1.7 µM, 56 ± 1.8 µM, and 35 ± 2.4 µM, respectively. These derivatives also exhibited potent cytotoxicity against breast cancer cell lines (MCF-7 & MDA-MB-231), with IC₅₀ values ranging from 3.7 to 32.4 µM, without any toxicity to normal human embryonic kidney (HEK) cells (IC₅₀ value > 1500 µM). FACS analysis revealed early apoptotic (45%) and late apoptotic cells (35%) when treated with the N-imidazopyridine derivatives (15) and arrested the cell cycle at the G2/M phase. Moreover, the impy derivative 15 was found to reduce the volume of implanted tumor in nude mice using xenografts of MCF-7 cells without any severe toxicity. Thus, we can infer that N-imidazopyridine-noscapinoids have increased potential as anticancer agents.