Development of 9-(-arylmethylamino) congeners of noscapine: the microtubule targeting drugs for the management of breast cancer.

Unlabelled: Noscapine is a natural lead molecule with anticancer activity at a higher concentrations. So, there is an urge for the development of more potent derivatives of noscapine. In this study, we have approached for development of 9--arylmethylamino derivatives of noscapine that kills cancer cells without affecting the normal cells. They were designed by substituting -aryl methyl pharmacophore at the C-9 position and screened out top-ranked three derivatives using molecular docking. Further, their theoretical free energy of binding with tubulin was calculated followed by chemical synthesis and experimental validation. In vitro antiproliferative activity of noscapine and its 9--arylmethylamino derivatives () was carried out using MCF-7 (a triple receptors positive) and MDA-MB-231 (a triple receptor negative) breast cancer cell lines. Further, cytotoxicity to normal cells was examined using human embryonic kidney cells (HEK cells). Inhibition to cell cycle progression and induction of apoptosis was monitored using FACS. The binding of noscapine and with tubulin was examined using fluorescence quenching assay. The 9--arylmethylamino derivatives of noscapine () were found to inhibit the proliferation of cancer cells at a much lower concentration (IC values range between 9.1 to 47.3 µM) compared to noscapine (IC value is 45.8-59.3 µM). Surprisingly, the proliferation of HEK cells was not inhibited even at a concentration of 100 µM (cytotoxicity is < 5%). These derivatives induced apoptosis by arresting cells at G2/M-phase and also bind to tubulin. The 9-(-arylmethylamino) noscapinoids have the potential to be a novel therapeutic agent for the treatment of breast cancer.

Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03445-3.